case study neonatal hyperbilirubinemia

4 Hyperbilirubinemia (Jaundice) Nursing Care Plans

Hyperbilirubinemia is the elevation of serum bilirubin levels that is related to the hemolysis of RBCs and subsequent reabsorption of unconjugated bilirubin from the small intestines. The condition may be benign or place the neonate at risk for multiple complications/untoward effects.

The newborn ‘s liver is immature, which contributes to icterus, or jaundice. The liver cannot clear the blood of bile pigments that result from the normal postnatal destruction of red blood cells. The higher the blood bilirubin level is, the deeper jaundice and the greater risk for neurological damage. Physiological jaundice is normal, while pathological jaundice is more serious, which occurs within 24 hours of birth, and is secondary to an abnormal condition, such ABO- Rh incompatibility . The normal rise in bilirubin levels in preterm infants is slower than in full-term infants. It lasts longer, which predisposes the infant to hyperbilirubinemia or excessive bilirubin levels in the blood.

Physiological jaundice is the most common type of newborn hyperbilirubinemia. This unconjugated hyperbilirubinemia presents in newborns after 24 hours of life and can last up to the first week. Pathological jaundice is defined as the appearance of jaundice in the first 24 hours of life due to an increase in serum bilirubin levels greater than 5 mg/dl/day, conjugated bilirubin levels ≥ 20% of total serum bilirubin, peak levels higher than the normal range, and the presence of clinical jaundice greater than two weeks. Breast milk jaundice occurs in breastfed newborns between the first and third day of life but peaks by day 5 to 15, with a decline occurring by the third week of life (Morrison, 2021).

In the past, hemolytic disease of the newborn was most often caused by an Rh blood type incompatibility. Because the prevention of Rh antibody formation has been available for almost 50 years, the disorder is now most often caused by an ABO incompatibility. In both instances, because the fetus has a different blood type than the mother, the mother builds antibodies against the fetal red blood cells, leading to hemolysis of the cells, severe anemia , and hyperbilirubinemia.

Table of Contents

Nursing problem priorities, nursing assessment, nursing diagnosis, nursing goals, 1. initiating patient education and health teachings, 2. promoting safety and preventing injuries and complications, 3. administer medications and provide pharmacologic support, 4. monitoring results of diagnostic and laboratory procedures, recommended resources, references and resources, nursing care plans and management.

The nursing care plan for clients with hyperbilirubinemia involves preventing injury /progression of the condition, providing support/appropriate information to family, maintaining physiological homeostasis with bilirubin levels declining, and preventing complications.

The following are the nursing priorities for patients with hyperbilirubinemia (jaundice):

• Bilirubin level monitoring. Regularly monitoring the bilirubin levels in the patient’s blood to assess the severity of hyperbilirubinemia.
• Identification of underlying cause. Investigating and identifying the underlying cause of hyperbilirubinemia to guide treatment decisions.
• Phototherapy. Initiating and managing phototherapy to help break down bilirubin and reduce its levels in the blood.
• Blood transfusion . Considering blood transfusion in severe cases of hyperbilirubinemia to remove excess bilirubin and provide additional red blood cells.
• Neonatal assessment . Conducting a thorough neonatal assessment to evaluate the overall health and identify any additional concerns associated with hyperbilirubinemia.
• Parent education. Educating parents about the causes, management, and signs of worsening hyperbilirubinemia, as well as the importance of follow-up care.
• Liver function evaluation . Assessing liver function to determine if there are any underlying liver disorders contributing to hyperbilirubinemia.
• Coordinating with pediatric specialists. Collaborating with pediatricians and specialists to ensure comprehensive care and appropriate management of hyperbilirubinemia.
• Support for breastfeeding . Providing guidance and support to breastfeeding mothers to optimize feeding practices, which can help with bilirubin elimination.
• Long-term follow-up. Planning for long-term follow-up to monitor the resolution of hyperbilirubinemia and identify any potential long-term effects or complications.

Assess for the following subjective and objective data :

• See nursing assessment cues under Nursing Interventions and Actions.

Following a thorough assessment, a nursing diagnosis is formulated to specifically address the challenges associated with hyperbilirubinemia (jaundice) based on the nurse ’s clinical judgment and understanding of the patient’s unique health condition. While nursing diagnoses serve as a framework for organizing care, their usefulness may vary in different clinical situations. In real-life clinical settings, it is important to note that the use of specific nursing diagnostic labels may not be as prominent or commonly utilized as other components of the care plan. It is ultimately the nurse’s clinical expertise and judgment that shape the care plan to meet the unique needs of each patient, prioritizing their health concerns and priorities.

Goals and expected outcomes may include:

• The mother will verbalize understanding of the cause, treatment, and possible outcomes of hyperbilirubinemia.
• The mother will identify signs/symptoms requiring prompt notification of the healthcare provider.
• The mother will demonstrate appropriate care for the infant.
• The neonate will display indirect bilirubin levels below 12 mg/dl in term infants at three days of age.
• The neonate will show resolution of jaundice by the end of the 1st wk of life.
• The neonate will be free of CNS involvement.
• The neonate will complete the exchange transfusion without complications.
• The neonate will display decreasing serum bilirubin levels.
• The neonate will maintain body temperature and fluid balance within the normal limits.
• The neonate will be free of skin/tissue injury.
• The neonate will demonstrate expected interaction patterns.

Nursing Interventions and Actions

Therapeutic interventions and nursing actions for patients with hyperbilirubinemia (jaundice) may include:

Neonatal jaundice is the main reason for admission from home to a neonatal unit. Many neonates are readmitted with extreme hyperbilirubinemia or bilirubin encephalopathy at or around day five and had been discharged as healthy from birth hospitalization. As the newborn is usually at home at the time of the bilirubin peaking, much of the onus for detecting the development of severe hyperbilirubinemia and evaluating the success of breastfeeding falls on the parents and community medical services (Kaplan et al., 2019).

Assess the family situation and support systems. Parents need guidance throughout the infant’s hospitalization to help to prepare them for this new experience. The mother is usually concerned with her ability to care for such a small and helpless creature. When she feels ready, she may assist the nurse in diapering, bathing , feeding , and other activities. Often the mother is discharged without her infant. This is difficult for the entire family and complicates attachment and bonding.

Assess the client’s and family members ’ knowledge and level of understanding. This helps in determining specific needs and clarifying previous information. The client and her family are assessed for their understanding of the diagnosis and their ability to cope during the unexpected extended period of recovery.

Provide parents with an appropriate written explanation of home phototherapy, listing technique and potential problems, and safety precautions. Non-specific written instructions are most likely a key factor contributing to the low attendance rate for early community follow-up for jaundice, as studied by Kaplan et al.. Some mothers provided reasons contributing to poor attendance. Poor understanding and insufficient explanation of the potential dangers of hyperbilirubinemia were leading factors. It is possible that the medical/nursing team, at the time of discharge, did not fully expound to parents the full reasons necessitating early follow-up (Kaplan et al., 2019).

Discuss appropriate monitoring of home therapy, e.g., periodic recording of infant’s weight, feedings, intake/output, stools, temperature, and proper reporting of infant status. Home phototherapy is recommended only for full-term infants after the first 48 hr of life, whose serum bilirubin levels are between 14 and 18 mg/dl with no increase in direct reacting bilirubin concentration. Nowadays, home phototherapy is very popular due to the importance of preventing mother-infant separation and continuity of care at home (Morrison, 2021).

Provide information about the types of jaundice, pathophysiological factors, and future implications of hyperbilirubinemia. Encourage to ask questions; reinforce or clarify information as needed. This promotes understanding the disease condition, correction of misconceptions, and reducing feelings of guilt and fear . Neonatal jaundice may be pathological, physiological, or breast milk–induced in etiology. Parents need an explanation of the rationale for phototherapy and why their infant needs it. Although phototherapy has not been used long enough that long-term effects can be studied, there appears to be minimal risk to an infant from the procedure, provided the infant’s eyes remain covered, and dehydration from increased insensitive water loss does not occur.

Discuss home management of mild or moderate physiological jaundice, including increased feedings, diffused exposure to sunlight (checking infant frequently), and a follow-up serum testing program. Parents’ understanding helps foster their cooperation once the infant is discharged. The information helps parents carry out home management safely and appropriately and recognize the importance of all aspects of the management program. Note: Exposure to direct sunlight is contraindicated as an infant’s tender skin is highly susceptible to thermal injury. Even though there is no evidence so far that infants who received phototherapy are at greater risk for developing skin cancer , all infants who receive phototherapy should (as should all infants) have sunscreen applied when they are in the sun and follow-up assessments in the coming years to detect skin cancer that possibly could occur from the therapy.

Provide information about maintaining milk supply through a breast pump and reinstating breastfeeding when jaundice necessitates interruption of breastfeeding. This helps mothers maintain adequate milk supply to meet the infant’s needs when breastfeeding is resumed. Infants weighing more than 1500 g (3.3 lb) may be able to bottle feed if a small, soft nipple with a large hole is used to minimize the energy and effort required for sucking. Breast milk may be manually expressed by the mother and placed in a bottle for her preterm infant.

Demonstrate means of assessing the infant for increasing bilirubin levels (e.g., blanching the skin with digital pressure to reveal the color of the skin, weight monitoring, or behavioral changes), especially if the infant is to be discharged early. To aid the parents in recognizing signs and symptoms of increasing bilirubin levels. Observing the infant’s skin, sclera , and mucous membranes for jaundice is included in the nursing care. Blanching of the skin over bony prominences enhances the evaluation for jaundice. Observing and reporting the progression of jaundice from the face to the abdomen and feet is important because the progression may indicate increasing bilirubin levels.

Provide parents with a 24-hr emergency telephone number and the name of the contact person, stressing the importance of reporting increased jaundice This decreases anxiety and prepares an immediate seek timely medical evaluation /intervention. Increased awareness of the importance of jaundice and early referring to hospitals among families can help reduce the complications of jaundice (Sardari et al., 2019).

Review rationale for specific hospital procedures/therapeutic interventions (e.g., phototherapy, exchange transfusions) and changes in bilirubin levels, especially if the neonate must remain in the hospital for treatment while the mother is discharged. This assists parents in understanding the importance of therapy, keep parents informed about the infant’s status and promotes informed decision-making . Note: Some hospitals have overnight rooms that allow the mother/father to remain with the infant. The use of intensive phototherapy in conjunction with hydration and close monitoring of serum bilirubin levels has greatly reduced the need for exchange transfusions. Exchange transfusion reduces the serum concentration of indirect bilirubin and can prevent heart failure in infants with severe anemia or polycythemia.

Discuss possible long-term effects of hyperbilirubinemia and the need for continued assessment and early intervention. Kernicterus is caused by a high bilirubin level in a baby’s blood. If left untreated, the bilirubin can then spread into the brain , where it causes long-term damage, which includes cerebral palsy , mental retardation, sensory difficulties, delayed speech, poor muscle coordination , learning difficulties, and enamel hypoplasia or yellowish-green staining of teeth, and even death .

Discuss the need for Rh immune globulin (RhIg) within 72 hours following delivery for an Rh-negative mother with an Rh-positive infant who has not been previously sensitized. Rh-Ig may minimize the incidence of maternal isoimmunization in non-sensitized mothers and may help to prevent erythroblastosis fetalis in subsequent pregnancies. Rh incompatibility is not commonly seen today because if Rh-negative women receive Rho immune globulin (RHIG or RhoGAM) within 72 hours after the birth of an Rh-positive newborn, the process of antibody formation will be halted, and sensitization will not occur.

Make appropriate arrangements for follow-up serum bilirubin testing at the same laboratory facility. Treatment is discontinued once serum bilirubin concentrations fall below 14 mg/dl, but serum levels must be rechecked in 12–24 hr to detect possible rebound hyperbilirubinemia. Although phototherapy may prevent an increase in bilirubin levels, it does not affect the underlying cause of jaundice. If phototherapy fails to keep the total serum bilirubin at acceptable levels to prevent kernicterus, an exchange transfusion may be indicated.

Provide appropriate referral for a home phototherapy program, if necessary. The lack of available support systems and education may necessitate visiting nurses to monitor the home phototherapy program. /Home phototherapy programs are being used for newborns with mild to moderate physiological jaundice. The infant’s pediatrician makes a referral for home care based on the newborn’s health, bilirubin levels (generally between 10 to 14 mg/dL), evidence of jaundice, and the family’s suitability for complying with the home program.

Educate the parents regarding home phototherapy. The parents can use a phototherapy blanket in a bassinet or a fiberoptic pad for home phototherapy. These allow the infant to be held, reducing the risk of eye damage. Written instructions are given to parents. Parents keep a daily record of their infant’s temperature, weight, intake and output , stools, and feedings. The parents must ensure that the infant’s eyes are covered under the lights to prevent injury to the infant’s retina and place a small diaper over the infant’s gonad area to protect their ovaries or testes.

Promoting safety and preventing injuries and complications in patients with hyperbilirubinemia (jaundice) involves implementing measures to mitigate the risks associated with elevated bilirubin levels. This includes strict adherence to phototherapy protocols, ensuring proper eye protection during phototherapy sessions, monitoring vital signs and hydration status, closely observing for signs of neurotoxicity or kernicterus, promptly addressing any concerning symptoms, providing education to parents on safe handling and care practices, and maintaining a collaborative approach among healthcare professionals to promptly identify and manage any complications that may arise.

Assess infant/maternal blood group and blood type. ABO incompatibility affects 20% of all pregnancies and most commonly occurs in mothers with type O blood, whose anti-A and anti-B antibodies pass into fetal circulation, causing RBC agglutination and hemolysis. ABO and Rh incompatibilities increase the risk for jaundice. Maternal antibodies cross the placenta in Rh-negative women who had previously been sensitized due to Rh-positive infants. Antibodies attach to fetal RBCs and increase the risk of hemolysis.

Assess the infant in daylight. This prevents distortion of actual skin color through the use of artificial lighting. Most infants do not appear jaundiced at birth because the maternal circulation has evacuated the rising indirect bilirubin level. With birth, progressive jaundice, usually occurring within the first 24 hours of life, will begin, indicating that a hemolytic process is occurring in both Rh and ABO incompatibility.

Review infant’s condition at birth, noting the need for resuscitation or evidence of excessive ecchymosis or petechiae, cold stress, asphyxia, or acidosis. Asphyxia and acidosis reduce the affinity of bilirubin to albumin. A study found that perinatal asphyxia was negatively associated with neonatal hyperbilirubinemia. This might be explained by acidosis in asphyxia is generally corrected soon after birth before significant hyperbilirubinemia develops in preterm infants. Although one study from Pakistan showed birth asphyxia was a risk factor for severe jaundice (Aynalem et al., 2020).

Review intrapartal records for specific risk factors, such as low birth weight (LBW) or intrauterine growth restriction (IUGR), prematurity, abnormal metabolic processes, vascular injuries, abnormal circulation, sepsis , or polycythemia. Certain clinical conditions may cause a reversal of the blood-brain barrier, allowing bound bilirubin to separate either at the cell membrane level or within the cell itself, increasing the risk of CNS involvement. The higher the blood bilirubin level is, the deeper jaundice and the greater the risk for neurological damage.

Observe the infant on the sclera and oral mucosa, yellowing of skin immediately after blanching, and specific body parts. Assess oral mucosa, posterior portion of the hard palate , and conjunctival sacs in dark-skinned newborns. The yellow discoloration of the skin and sclera in neonates diagnosed with jaundice results from the accumulation of unconjugated bilirubin. Neonatal jaundice first becomes visible on the face and forehead (Hansen & Aslam, 2017). Clinical appearance of jaundice is evident at bilirubin levels >7–8 mg/dl in full-term infants. Note: Yellow underlying pigment may be normal in dark-skinned infants.

Evaluate maternal and prenatal nutritional levels; note possible neonatal hypoproteinemia, especially in preterm infants. Hypoproteinemia in the newborn may result in jaundice. One gram of albumin carries 16 mg of unconjugated bilirubin. Lack of sufficient albumin increases the amount of unbound circulating (indirect) bilirubin, which may cross the blood-brain barrier. The binding of compounds to albumin may reduce their toxicity, such as in the case of unconjugated bilirubin in the neonate. Albumin is also involved in maintaining acid-base balance as it acts as a plasma buffer (Gounden et al., 2021).

Note infant’s age at onset of jaundice; differentiate the type of jaundice (i.e., physiological, breast milk–induced, or pathological). Physiological jaundice usually appears between the 2nd and 3rd days of life, as excess RBCs needed to maintain adequate oxygenation for the fetus are no longer required in the newborn and are hemolyzed, thereby releasing bilirubin, the final breakdown product of heme. Breast milk jaundice usually appears between the 4th and 6th days of life, affecting only 1%–2% of breastfed infants. Some women’s breast milk is thought to contain an enzyme (pregnanediol) that inhibits glucuronyl transferase (the liver enzyme that conjugates bilirubin) or contain several times the normal breast milk concentration of certain free freezer fatty acids, which are also thought to inhibit the conjugation of bilirubin. Pathological jaundice appears within the first 24 hr of life and is more likely to lead to the development of kernicterus/bilirubin encephalopathy.

Assess infant for progression of signs and behavioral changes. Excessive unconjugated bilirubin (associated with pathologic jaundice) has an affinity for extravascular tissue, including the basal ganglia of brain tissue. Behavior changes associated with kernicterus usually occur between the 3rd and 10th days of life and rarely occur before 36 hours of life. The characteristic clinical manifestations of kernicterus that are routinely described and are consistent with neuropathological findings include athetoid cerebral palsy , paralysis of upward gaze, and hearing disorders. However, these may represent only “the tip of the iceberg” (Amin et al., 2018).

Evaluate infant for pallor, edema , or hepatosplenomegaly These signs may be associated with hydrops fetalis, Rh incompatibility, and in utero hemolysis of fetal RBCs. With Rh incompatibility, an infant may not appear pale at birth despite the red cell destruction that occurred in utero because the accelerated production of red cells during the last few months in utero compensates to some degree for the destruction. The liver and spleen may be enlarged from attempts to destroy damaged blood cells. Suppose the number of red cells has significantly decreased. In that case, the blood in the vascular circulation may be hypotonic to interstitial fluid, causing fluid to shift from the lower to higher isotonic pressure by osmosis , resulting in extreme edema . Hydrops fetalis is a Greek term that refers to a pathologic accumulation of at least two or more cavities with a fluid collection in the fetus.

Assess the neonate’s bilirubin blood levels regularly. Phototherapy success is determined by frequently measuring serum bilirubin levels. Neonatal hyperbilirubinemia is extremely common because almost every newborn develops an unconjugated serum bilirubin level of more than 1.8 mg/dL during the first week of life. Significant jaundice was defined according to gestational and postnatal age and leveled off at 14 mg/dL at four days in preterm infants and 17 mg/dL in the term infants (Hansen & Aslam, 2017).

Assess infant for signs of hypoglycemia . Hypoglycemia necessitates fat stores for energy-releasing fatty acids, which compete with bilirubin for binding sites on albumin. A study reported that 70.8% of late preterm neonates and 29.1% of term neonates has at least one neonatal morbidity like neonatal jaundice, hypoglycemia , respiratory morbidities, and sepsis . They observed jaundice in 55.1% of late preterm neonates who required phototherapy, and hypoglycemia was found in 8.8% of late preterm neonates (Salman et al., 2021).

Initiate early oral feedings within 4–6 hours following birth, especially if the infant is breastfed. This establishes proper intestinal flora necessary for reducing bilirubin to urobilinogen; decreases the enterohepatic circulation of bilirubin (bypassing the liver with the persistence of ductus venosus), and decreases reabsorption of bilirubin from the bowel by promoting passage of meconium . A delay in enteral feeding may limit intestinal motility and bacterial colonization, resulting in decreased bilirubin clearance (Aynalem et al., 2020).

Keep infant warm and dry; frequently monitor skin and core temperature. Cold stress potentiates the release of fatty acids, which compete for binding sites on albumin, thereby increasing freely circulating (unbound) bilirubin. A neutral thermal environment permits the infant to maintain a normal core temperature with minimum oxygen consumption and caloric expenditure. Preterm infants have little or no muscular activity; they remain in an extended posture because of a lack of muscle tone; they cannot shiver.

Apply transcutaneous jaundice meter. Since visual assessment of jaundice is not accurate, both the American Academy of Pediatrics and the Spanish Association of Pediatrics recommend that all newborns as of 35 weeks of gestation undergo screening for hyperbilirubinemia by measuring either total serum bilirubin (SB) or transcutaneous bilirubin (TcB). Transcutaneous bilirubinometry measures the bilirubin subcutaneously, and therefore, TcB is not the same value as SB. although current jaundice meters have been designed to agree as closely as possible with SB (Maya-Enero et al., 2021).

Discontinue breastfeeding for 24–48 hr, as indicated. Assist mother as needed with the pumping of breasts and reestablishment of breastfeeding. Opinions vary as to whether interrupting breastfeeding is necessary when jaundice occurs. However, formula ingestion increases GI motility and excretion of stool and bile pigment, and serum bilirubin levels begin to fall within 48 hours after discontinuation of breastfeeding. Certain factors present in the breast milk of some mothers may also contribute to the increased enterohepatic circulation of bilirubin (breast milk jaundice). Beta-glucuronidase may play a role by uncoupling bilirubin from its binding to glucuronic acid, thus making it available for reabsorption (Hansen & Aslam, 2017).

Monitor laboratory studies, as indicated . See Diagnostic and Laboratory Procedures

Calculate plasma bilirubin-albumin binding capacity. This aids in determining the risk of kernicterus and treatment needs. When the total bilirubin value divided by total serum protein level is <3.7, the danger of kernicterus is very low. However, the risk of injury is dependent on the degree of prematurity, presence of hypoxia or acidosis, and drug regimen (e.g., sulfonamides , chloramphenicol ) (Hansen & Aslam, 2017).

Initiate phototherapy per protocol, using fluorescent bulbs above the infant or bile blanket (except for newborns with Rh disease). Phototherapy causes photooxidation of bilirubin in subcutaneous tissue, thereby increasing the water solubility of bilirubin, which allows rapid excretion of bilirubin in stool and urine . The rate of bilirubin reduction is related to phototherapy, so an exchange transfusion is the only appropriate treatment. Phototherapy is discontinued when the bilirubin level steadily declines to 14 mg/dL.

Administer enzyme induction agent  ( phenobarbital , ethanol) as appropriate. Medications are not usually administered in infants diagnosed with physiologic neonatal jaundice. However, in certain instances, phenobarbital, an inducer of hepatic bilirubin metabolism, has been used to enhance bilirubin metabolism. Several studies have shown that phenobarbital effectively reduces mean serum bilirubin values during the first week of life (Hansen & Aslam, 2017).

Assist with preparation and administration of exchange transfusion. Exchange transfusion can be used as therapy for blood incompatibility, wherein it removes approximately 85% of sensitized red cells. It reduces the serum concentration of indirect bilirubin and can prevent heart failure in infants with severe anemia or polycythemia. The type of blood used for transfusion is O Rh-negative blood, even if an infant’s blood type is positive; if Rh-positive or type A or B blood was given, the maternal antibodies that entered the infant’s circulation would destroy this blood also, and the transfusion would be ineffective.

Note the condition of the infant’s cord before transfusion if the umbilical vein is to be used. If the cord is dry, administer saline soaks for 30–60 min before the procedure. Soaks may be necessary to soften the cord and umbilical vein before transfusion for IV access and ease the umbilical catheter’s passage. In general, access via the umbilical vein is the recommended exchange transfusion method for treating severe hyperbilirubinemia in neonates. However, some reports have shown that exchange transfusion via the umbilical vessels is a relatively high-risk procedure (Chen et al., 2008).

Verify infant’s and mother’s blood type and Rh factor. Note blood type and Rh factor of blood to be exchanged. Exchange transfusions are most often associated with Rh incompatibility problems. Using Rho(D)-positive blood would only increase hemolysis and bilirubin levels because antibodies in an infant’s circulation would destroy new RBCs. The type of blood used for transfusion is O Rh-negative blood, even if an infant’s blood type is positive.

Assess the infant’s weight prior to transfusion and for consequent weight changes. Adverse events are more frequent in infants of lower gestation and birth weights and those who were sicker. These results are similar to other studies because sicker and smaller infants have multiple comorbidities and are at risk of more complications (Chacham et al., 2019). Additionally, weight change reveals weight gain related to fluid overload . Fluid overload can cause respiratory and cardiac complications.

Assess the infant for neurologic changes. Irritability, twitching, convulsions, or seizures are signs of neurotoxicity resulting from jaundice. An increasing bilirubin level becomes dangerous if the level rises above 20 mg/dL in a term infant and perhaps as low as 12 mg/dL in a preterm infant because brain damage from bilirubin-induced neurologic dysfunction (BIND), a wide spectrum of disorders caused by increasingly severe hyperbilirubinemia ranging from mild dysfunction to acute bilirubin encephalopathy (ABE) (invasion of bilirubin into brain cells), can occur.

Assess infant for excessive bleeding from IV site following the transfusion. Infusion of heparinized blood (or citrated blood without calcium replacement) alters coagulation for 4–6 hr following the exchange transfusion and may result in bleeding . Thrombocytopenia was seen in 57.4% of neonates undergoing exchange transfusion. It was observed that there was a decrease in the platelet count following the transfusion with a nadir at 24 hours and full recovery at or after 72 hours (Chacham et al., 2019).

Monitor venous pressure, pulse, color, and respiratory rate/ease before, during, and after transfusion. Suction as needed. This establishes baseline values, identifies potentially unstable conditions (e.g., apnea or cardiac dysrhythmia /arrest), and maintains the airway. Exchange transfusion is not free of risk, with the estimated morbidity rate at 5% and the mortality rate as high as 0.5%. The most common adverse events are apnea , bradycardia, cyanosis , vasospasm, and hypothermia with metabolic abnormalities (Wagle & Aslam, 2017). Bradycardia may occur if calcium is injected too rapidly. 

Monitor for signs of electrolyte imbalance (e.g., lethargy , seizure activity, and apnea ;  hyperreflexia, bradycardia, or diarrhea ). Hypocalcemia and hyperkalemia may develop during and following exchange transfusion. Hypocalcemia is one of the most frequent adverse events, with the incidence ranging from 22.5% to 98%. Hypocalcemia following exchange transfusion is due to certain chelating properties of citrate, which is present in a very high concentration in the donor blood as a component of the anticoagulant (Chacham et al., 2019).

Assess the infant for any congenital diseases such as other hemolytic diseases and cardiac failure. An infant born with cardiac failure and edema resulting from hemolytic disease is a candidate for immediate exchange transfusion with fresh whole blood. When red cells have significantly decreased due to a hemolytic disease, the blood in the vascular circulation may be hypotonic to interstitial fluid, causing fluid to shift from lower to higher isotonic pressure by osmosis in extreme edema.

Maintain the infant’s temperature prior to, during, and after the procedure. Place infant under radiant warmer with servomechanism. A transfusion should be done under a radiant heat warmer to keep the infant warm during what can be a lengthy procedure to prevent energy expenditure from having to maintain body temperature. This also helps prevent vasospasm, reduces the risk of ventricular fibrillation , and decreases blood viscosity.

Warm the blood prior to infusion by placing it in blood warmer. Donor blood must be maintained at room temperature, or hypothermia from the cold insult could result. Use only commercial blood warmers to warm the blood, not hot towels or a radiant heat warmer, to avoid destroying red cells.

Ensure freshness of blood (not more than two days old), with heparinized blood preferred. Older blood is more likely to hemolyze, thereby increasing bilirubin levels. Moreover, old stored blood has high levels of leucocyte-secreted cytokines that significantly raise the risk of non-hemolytic febrile transfusion reactions. Heparinized blood is always fresh but must be discarded if not used within 24 hr. Blood transfusion using heparinized blood can be employed to avoid citrate toxicity in neonates undergoing exchange transfusion. Moreover, repetitive small top-up transfusions can also be carried out with fresh heparinized blood collected as and when needed from a dedicated safe walking donor (Ahmed & Ibrahim, 2018).

Avoid overheating of blood prior to transfusion. Too much heat in the blood promotes hemolysis and the release of potassium , causing hyperkalemia. The risk of hemolysis with heated blood requires the choice of heating temperature to be considered. In their study, Van der Walt and Russel (Van der Walt & Russel, 1978) argue that the blood should ideally be heated to a human body temperature of 37°C (98.6℉), but that any temperature between 32°C (89.6℉) and 37°C (98.6℉) is acceptable (Poder et al., 2015).

Ensure availability of resuscitative equipment. Access to resuscitative equipment provides immediate support if necessary. Exchange transfusions can lead to complications such as life-threatening bleeding, sepsis, cardiac arrhythmias, and even death, apart from transient hypocalcemia , hyperkalemia, bradycardia, and thrombocytopenia (Chacham et al., 2019).

Maintain NPO status for 4 hr prior to the procedure, or aspirate gastric contents. The infant should be nil orally as soon as the decision is made to perform an exchange transfusion. Pass an oro- nasogastric tube and aspirate stomach contents. Leave the tube in situ and on free drainage for the duration of the procedure (The Royal Children’s Hospital, 2004). This reduces the risk of possible regurgitation and aspiration during the procedure.

Carefully document events during transfusion, recording the amount of blood withdrawn and injected (usually 7–20 ml at a time). Documentation helps prevent errors in fluid replacement. The amount of blood exchanged is approximately 170 ml/kg of body weight. A double-volume exchange transfusion ensures that between 75% and 90% of circulating RBCs are replaced. The process is time-consuming and labor -intensive but remains the ultimate treatment to prevent kernicterus (Wagle & Aslam, 2017).

Administer albumin prior to transfusion if indicated. Although somewhat controversial, administration of albumin may increase the albumin available for bilirubin binding, thereby reducing levels of freely circulating serum bilirubin. Synthetic albumin is not thought to increase available binding sites. Due to the elicited increase in plasma bilirubin, albumin administration to reduce bilirubin-induced neurological damage invalidates the use of plasma total bilirubin as an indicator of the overall risk of bilirubin neurotoxicity (Vodret et al., 2015).

Administer medications, as indicated . See Pharmacologic Management

Administer antibiotics as indicated. Antibiotics prevent and/or treat infections. After a transfusion, the infant is closely observed to be certain that there is no umbilical vessel inflammation of the cord if this was the transfusion site, which would suggest infection .

Assist with administration of intravenous immunoglobulin (IVIG) as indicated. IVIG has been shown to reduce the need for exchange transfusion in hemolytic disease of the newborn due to Rh or ABO incompatibility. The number needed to treat to prevent one exchange transfusion was noted to be 2.7 and was estimated to be ten if all the infants with strongly positive direct Coombs test were to receive the medication . Although IVIG has been proven safe, a retrospective review reported an almost 30-times increased risk of necrotizing enterocolitis in late preterm and term infants (Wagle & Aslam, 2017).

Note the presence or development of biliary or intestinal obstruction. Phototherapy is contraindicated in these conditions because the photoisomers of bilirubin produced in the skin and subcutaneous tissues by exposure to light therapy cannot be readily excreted. The risk of secondary intestinal obstruction may increase after phototherapy. The velocity of blood flow in the upper mesenteric artery at the end of the diastolic period is accelerated post-phototherapy, indicating that the mesenteric vascular smooth muscle may undergo diastolic changes during phototherapy, leading to mesenteric ischemia , which may be one of the causes of intestinal obstruction in premature infants (Wang et al., 2021).

Monitor the neonate’s skin and core temperature every two hours or more frequently until stable. Regulate incubator/ Isolette temperature as appropriate. Fluctuations in body temperature can occur in response to light exposure, radiation , and convection. When the jaundiced newborn is treated with blue phototherapy, apart from the areas protected by the black blindfold and the diaper, all other areas are exposed to illumination. As a result, neonates diagnosed with jaundice treated with blue light often experience alterations in body temperature (Wang et al., 2021).

Note color and frequency of stools and urine. Frequent, greenish, loose stools and greenish urine indicate the effectiveness of phototherapy with the breakdown and excretion of bilirubin. The nurse must determine loose, greenish stools caused by photodegradation products from true diarrhea .

Monitor fluid intake and output; weigh infant twice a day. Note signs of dehydration (e.g., reduced urine output, depressed fontanels , dry or warm skin with poor turgor, and sunken eyes). Dehydration may occur during phototherapy, particularly in premature infants. By measuring the skin moisture content of premature infants before and after phototherapy, Maayan-Metzger et al. found that the mean skin moisture loss increased by 26.4% during phototherapy, with the most significant loss observed in the elbow socket, groin, and back (Wang et al., 2021). Note: Infant may sleep for longer periods in conjunction with phototherapy, increasing the risk of dehydration if a frequent feeding schedule is not maintained.

Evaluate the appearance of skin and urine, noting brownish-black color. An uncommon side effect of phototherapy involves exaggerated pigment changes (bronze baby syndrome), which may occur if conjugated bilirubin levels rise. The changes in skin color may last for 2–4 months but are not associated with harmful sequelae. The bronze baby syndrome is an irregular pigmentation resulting from phototherapy in newborn infants diagnosed with neonatal jaundice that is mainly noticeable in the skin, mucous membranes, and urine and generally occurs in neonates with elevated serum conjugated bilirubin levels (Wang et al., 2021).

Note behavioral changes or signs of deteriorating condition (e.g., lethargy , hypotonia, hypertonicity, or extrapyramidal signs). Such changes may indicate the deposition of bile pigment in the basal ganglia and developing kernicterus. Following neonatal phototherapy, the serum level of total free calcium is often diminished, leading to hypocalcemia, which is higher among premature infants than that among full-term infants (Wang et al., 2021).

Assess for the presence of rash and petechiae. Certain newborns develop petechiae and skin rashes from phototherapy, which gradually fade when phototherapy is discontinued. Petechiae may be associated with light-induced thrombocytopenia; thus, the platelet count should be closely monitored during phototherapy. A small number of infants diagnosed with cholestatic jaundice develop a purpuric rash and bullous eruptions after phototherapy, which may increase the total circulating porphyrin levels (Wang et al., 2021).

Note fussiness or increased crying episodes and irritability. It has been reported that newborns receiving phototherapy have more frequent crying episodes than those receiving no therapy for clinical jaundice, which may be associated with changes in the circadian rhythm during neonatal phototherapy.

Document the type of fluorescent lamp, the total number of hours since bulb replacement, and the measured distance between lamp surface and infant. Light emission may decay over time. The infant should be approximately 18–20 in (45 cm) from the light source for maximal benefit. Note: A fiberoptic blanket connected to an illuminator (light source) allows the infant to be “wrapped” in therapeutic light without risk to corneas. In addition, infants can be held and fed without interrupting therapy.

Measure the quantity of photon energy of fluorescent bulbs (white or blue light) using a photometer. The intensity of light striking the skin surface from the blue spectrum (blue lights) determines how close to the light source the infant should be placed. The photometer should register between 8 and 10 mW/cm 2 /nm of light when placed flush with the infant’s abdomen. Blue and special blue lights are considered more effective than white light in promoting bilirubin breakdown, but they create difficulty in evaluating the newborn for cyanosis. The American Academy of Pediatrics defines standard phototherapy as 8-10 mW/cm 2 per nm and intensive phototherapy as more than 30 mW/cm 2 per nm in the 430-490 nm band (Sawyer & Nimavat, 2018).

Cover the testes and penis of a male infant. The infant is undressed except for a diaper to protect the ovaries or testes, and so as much skin surface as possible is exposed to light. Some phototherapy lights may affect reproduction. Potential and embryonic development because of the combined effects of light penetration in the tissues. The light had probably stimulated some neuroendocrine structures in the skin. Koc et al. reported the seminiferous tubule diameters were thinner than the control group after phototherapy in rats. Similar histological changes were obtained in cryptorchid testis in humans (Cetinkursun et al., 2006).

Apply patches to closed eyes; inspect eyes every two hours when patches are removed for feedings. Monitor placement frequently. Retinal damage represents another challenge associated with phototherapy for neonatal jaundice. The light-sensitive retinas absorb photons more readily when exposed to blue light, most effective at degrading bilirubin. Following continuous or stronger blue light irradiation, the retinal function degenerates due to a significantly increased retinal cell death rate (Wang et al., 2021). In addition to eye shields, many centers also prescribe lubricating eye drops for an infant receiving phototherapy (Sawyer & Nimavat, 2018).

Cleanse the infant’s eyes using sterile or normal saline water. As the incidence of conjunctivitis is increased among children receiving phototherapy who wear eye masks over prolonged periods, thorough eye care, such as cleaning eye secretions and surrounding skin with normal saline cotton balls, must be applied (Wang et al., 2021). 

Reposition the infant every two hours. This allows equal exposure of skin surfaces to fluorescent light, prevents excessive exposure of individual body parts, and limits pressure areas.

Carefully wash the perianal area after each passage of stool; inspect the skin for possible irritation or breakdown. Early intervention helps prevent irritation and excoriation from frequent or loose stools. An infant’s stools under bilirubin lights are often bright green because of the excessive bilirubin being excreted as a result of the therapy. They are also frequently loose and may be irritating to the skin.

Encourage an increased oral fluid intake. To prevent the loss of water and electrolytes caused by phototherapy, water and electrolytes must be replenished when necessary. The warming effect of conventional phototherapy increases water loss from the body surface, while light-emitting diode (LED) phototherapy, which is currently widely used, causes less water loss (Wang et al., 2021).

Bring infant to parents for feedings. Encourage stroking, cuddling, eye contact, and talking to the infant during feedings. Encourage parents to interact with the infant in the nursery between feedings. This fosters the attachment process, which may be delayed if phototherapy requires separation. Visual, tactile, and auditory stimulation helps the infant overcome sensory deprivation. Intermittent phototherapy does not negatively affect the photooxidation process. Note: Dependent on infant condition and policies/capabilities of the hospital, phototherapy may be provided in conjunction with rooming-in.

Ensure that the infant’s chest is properly shielded during phototherapy. 50% of premature infants receiving phototherapy were diagnosed with patent ductus arteriosus, the re-opening of the ductus arteriosus may be evoked by blue light penetrating the chest wall of the premature infant and causing relaxation of the smooth muscle of the cardiovascular system by activating the Ca2+ dependent K+ channel. It has been reported that appropriate shielding of the chest during phototherapy may reduce the incidence of patent ductus arteriosus (Wang et al., 2021).

Administering medications and providing pharmacologic support in patients with hyperbilirubinemia (jaundice) involves careful consideration of the specific medications used, their dosages, and their potential effects on bilirubin metabolism and liver function.

• 10% calcium gluconate . From 2–4 ml of calcium, gluconate may be administered after every 100 ml of blood infusion to correct hypocalcemia and minimize possible cardiac irritability (Wani et al., 2018). The general approach is to give IV calcium during exchange transfusion, but this issue is still controversial. There is not enough literature data about calcium requirements during exchange transfusion. Complications such as tetany convulsions and death have been reported when blood products containing adenine-citrate dextrose (ACD) were used for exchange transfusion despite IV calcium infusion (Aydin et al., 2021).
• Sodium bicarbonate . Sodium bicarbonate corrects acidosis. Relatively higher serum pH may be attributed to higher serum bicarbonate concentration in freshly CPDA-treated blood. The serum bicarbonate concentration in CPDA-treated blood usually starts decreasing after three days of storage.
• Protamine sulfate . Protamin sulfate counteracts anticoagulant effects of heparinized blood. Some clinicians remain skeptical about the safety of heparinized blood transfusion due to the possible risk of heparin -induced bleeding. This skepticism may be valid for hemostatically unstable neonates due to comorbid hemorrhagic conditions such as hemophilia , thrombocytopenia, DIC, or vitamin K deficiency. If overheparinization is clinically suspected during or after the transfusion, protamine sulfate can be used to neutralize it (Ahmed & Ibrahim, 2018).
• Administer enteral or parenteral fluid as indicated. Fluids compensate for insensible and intestinal fluid losses and supply nutrients if feedings are withheld during phototherapy for infants with severe hyperbilirubinemia. Due to this increase in insensible water loss, recommendations have been made to increase maintenance fluid by 10 ml/kg/day in premature infants exposed to conventional phototherapy (Sawyer & Nimavat, 2018).

Monitoring the results of diagnostic and laboratory procedures is crucial in the management of hyperbilirubinemia (jaundice) to assess the severity of the condition, identify the underlying cause, and guide appropriate treatment decisions. Various diagnostic tests and laboratory procedures are employed to evaluate liver function, bilirubin levels, and other relevant parameters.

• Direct and indirect bilirubin . Bilirubin appears in two forms: direct bilirubin, which is conjugated by the liver enzyme glucuronyl transferase, and indirect bilirubin, which is unconjugated and appears in a free form in the blood or bound to albumin. Elevated levels of indirect bilirubin best predict the infant’s potential for kernicterus. Elevated indirect bilirubin levels of 18–20 mg/dl in the full-term infant or13–15 mg/dl in preterm or sick infants are significant (Hansen & Aslam, 2017).
• Total serum bilirubin level . Usually, a total serum bilirubin level test is the only one required in an infant with moderate jaundice who presents on the typical second or third day of life without a history or physical findings suggestive of a pathologic process (Hansen & Aslam, 2017).
• Direct/indirect Coombs’ test on cord blood . Positive results of the indirect Coombs test indicate the presence of antibodies (Rh-positive or anti-A, anti-B) in the mother’s and newborn’s blood; positive results of the direct Coombs test indicate the presence of sensitized (Rh-positive, anti-A, or anti-B) RBCs in the neonate.
• CO2-combining power; Reticulocyte count and peripheral smear . A decrease is consistent with hemolysis. Excessive hemolysis causes reticulocyte count to increase. Smear identifies abnormal or immature RBCs. The reticulocyte count provides an indirect insight into the bone marrow condition by distinguishing if the anemia is related to inadequate RBC production or accelerated loss/destruction (Szigeti & Staros, 2014).
• Hemoglobin /hematocrit (Hb/Hct) . Elevated Hb/Hct levels (Hb 22 g/dl; Hct 65%) indicate polycythemia, possibly caused by delayed cord clamping, maternal-fetal transfusion, twin-to-twin transfusion, maternal diabetes , or chronic intrauterine stress and hypoxia, as seen in low birth weight (LBW) infant or infant with compromised placental circulation. Hemolysis of excess RBCs causes elevated bilirubin levels with 1 g of Hb yielding 35 mg of bilirubin. Low Hb levels (14 mg/dl) may be associated with hydrops fetalis or Rh incompatibility occurring in utero and causing hemolysis, edema, and pallor.
• Total serum protein or serum albumin levels . Low serum protein levels (3.0 g/dl) indicate a reduced binding capacity for bilirubin. Serum albumin levels appear to be a useful adjunct in evaluating the risk of toxicity levels because albumin binds bilirubin in a ratio of 1:1 at the primary high-affinity binding site (Hansen & Aslam, 2017).
• Serum calcium and potassium . Measure urea and electrolytes regularly until the infant is stable, as indicated. Donor blood containing citrate as an anticoagulant binds calcium, decreasing serum calcium levels. In addition, if blood is more than two days old, RBC destruction releases potassium, creating a risk of hyperkalemia and cardiac arrest (The Royal Children’s Hospital, 2004).
• Glucose . Perform blood glucose levels immediately post-procedure and then hourly until the infant is stable (The Royal Children’s Hospital, 2004). There is a significant rise in post-exchange serum glucose , attributed to high dextrose content in the donor blood and anticoagulants for preservation. Although normal mean blood sugar was observed at 12 hours post-exchange, one needs to be cautious as rebound hypoglycemia may occur during the initial hours (Wani et al., 2018).
• Serum pH levels. The serum pH of donor blood is typically 6.8 or less. Acidosis may result when fresh blood is not used, and the infant’s liver cannot metabolize citrate used as an anticoagulant, or when donor blood continues anaerobic glycolysis with the production of acid metabolites. Low serum potassium after exchange transfusion coincided with higher serum pH, which is known to cause a shift of serum potassium into the intracellular compartment (Wani et al., 2018).
• Platelets and WBCs . Thrombocytopenia during phototherapy has been reported in some infants. A decrease in WBCs suggests a possible effect on peripheral lymphocytes . There is a significant association between the decrease in platelet count with the duration of phototherapy and lower gestational age in the neonate (Sarkar et al., 2021).
• Riboflavin levels . Since the wavelength of absorption of blue light by riboflavin is similar to that of bilirubin, both riboflavin and bilirubin will decompose at the same time when a newborn with jaundice receives blue light therapy, leading to the loss of riboflavin in the body. The riboflavin deficiency will reduce the synthesis of active riboflavin adenine dinucleotide, impair hydrogen delivery of erythrocytes , reduce glutathione reductase, and weaken the activity of erythrocyte glutathione reductase, thus aggravating hemolysis (Wang et al., 2021).

Recommended nursing diagnosis and nursing care plan books and resources.

Disclosure: Included below are affiliate links from Amazon at no additional cost from you. We may earn a small commission from your purchase. For more information, check out our privacy policy .

Ackley and Ladwig’s Nursing Diagnosis Handbook: An Evidence-Based Guide to Planning Care We love this book because of its evidence-based approach to nursing interventions. This care plan handbook uses an easy, three-step system to guide you through client assessment, nursing diagnosis, and care planning. Includes step-by-step instructions showing how to implement care and evaluate outcomes, and help you build skills in diagnostic reasoning and critical thinking.

Nursing Care Plans – Nursing Diagnosis & Intervention (10th Edition) Includes over two hundred care plans that reflect the most recent evidence-based guidelines. New to this edition are ICNP diagnoses, care plans on LGBTQ health issues, and on electrolytes and acid-base balance.

Nurse’s Pocket Guide: Diagnoses, Prioritized Interventions, and Rationales Quick-reference tool includes all you need to identify the correct diagnoses for efficient patient care planning. The sixteenth edition includes the most recent nursing diagnoses and interventions and an alphabetized listing of nursing diagnoses covering more than 400 disorders.

Nursing Diagnosis Manual: Planning, Individualizing, and Documenting Client Care  Identify interventions to plan, individualize, and document care for more than 800 diseases and disorders. Only in the Nursing Diagnosis Manual will you find for each diagnosis subjectively and objectively – sample clinical applications, prioritized action/interventions with rationales – a documentation section, and much more!

All-in-One Nursing Care Planning Resource – E-Book: Medical-Surgical, Pediatric, Maternity, and Psychiatric-Mental Health   Includes over 100 care plans for medical-surgical, maternity/OB, pediatrics, and psychiatric and mental health. Interprofessional “patient problems” focus familiarizes you with how to speak to patients.

Other recommended site resources for this nursing care plan:

• Nursing Care Plans (NCP): Ultimate Guide and Database MUST READ! Over 150+ nursing care plans for different diseases and conditions. Includes our easy-to-follow guide on how to create nursing care plans from scratch.
• Nursing Diagnosis Guide and List: All You Need to Know to Master Diagnosing Our comprehensive guide on how to create and write diagnostic labels. Includes detailed nursing care plan guides for common nursing diagnostic labels.

Other care plans related to the care of the pregnant mother and her baby:

• Abortion (Termination of Pregnancy) | 8 Care Plans
• Cervical Insufficiency (Premature Dilation of the Cervix) | 4 Care Plans
• Cesarean Birth | 11 Care Plans
• Cleft Palate and Cleft Lip | 7 Care Plans
• Gestational Diabetes Mellitus | 8 Care Plans
• Hyperbilirubinemia (Jaundice) | 4 Care Plans
• Labor Stages, Induced, Augmented, Dysfunctional, Precipitous Labor | 45 Care Plans
• Neonatal Sepsis | 8 Care Plans
• Perinatal Loss (Miscarriage, Stillbirth) | 6 Care Plans
• Placental Abruption | 4 Care Plans
• Placenta Previa | 4 Care Plans
• Postpartum Hemorrhage | 8 Care Plans
• Postpartum Thrombophlebitis | 5 Care Plans
• Prenatal Hemorrhage (Bleeding in Pregnancy) | 9 Care Plans
• Preeclampsia and Gestational Hypertension  | 6 Care Plans
• Prenatal Infection | 5 Care Plans
• Preterm Labor | 7 Care Plans
• Puerperal & Postpartum Infections  | 5 Care Plans
• Substance Abuse in Pregnancy | 9 Care Plans

Resources and journals you can use to further your reading about Hyperbilirubinemia (Jaundice).

• Ahmed, S.G., & Ibrahim, U.A. (2018, April). Donor Blood Selection Criteria For Neonatal Red Cell Transfusion: General And Tropical Perspectives. The Tropical Journal of Health Sciences , 25 (2).
• Amin, S. B., Smith, T., & Timler, G. (2018, October 23). Developmental influence of unconjugated hyperbilirubinemia and neurobehavioral disorders . Pediatric Research , 85 , 191-197.
• Aydin, B., Yilmaz, H. C., Botan, E., Aktepe, A. O., & Dilli, D. (2021, December). Is it necessary to give calcium infusion during the exchange transfusion in newborns? Transfusion and Apheresis Science , 30 (6), 103236.
• Aynalem, S., Abayneh, M., Metaferia, G., Demissie, A. G., Gidi, N. W., Demtse, A. G., Berta, H., Worku, B., Nigussie, A. K., Mekasha, A., Bonger, Z. T., McClure, E. M., Goldenberg, R. L., & Muhe, L. M. (2020). Hyperbilirubinemia in Preterm Infants Admitted to Neonatal Intensive Care Units in Ethiopia . Global Pediatric Health , 7 , 1-8.
• Cetinkursun, S., Demirbag, S., Cincik, M., Baykal, B., & Gunal, A. (2006, January-February). Effects of Phototherapy on Newborn Rat Testicles . Archives of Andrology , 52 (1), 61-70.
• Chacham, S., Kumar, J., Dutta, S., & Kumar, P. (2019, April-June). Adverse Events Following Blood Exchange Transfusion for Neonatal Hyperbilirubinemia: A Prospective Study. Journal of Clinical Neonatology , 8 (2), 79-84.
• Chen, H.-N., Lee, M.-L., & Tsao, L.-Y. (2008, October). Exchange Transfusion Using Peripheral Vessels Is Safe and Effective in Newborn Infants. Pediatrics , 122 (4).
• Gounden, V., Vashisht, R., & Jialal, I. (2021, September 28). Hypoalbuminemia – StatPearls . NCBI. Retrieved May 15, 2022.
• Hansen, T. W., & Aslam, M. (2017, December 27). Neonatal Jaundice: Background, Pathophysiology, Etiology . Medscape Reference. Retrieved May 15, 2022.
• Kaplan, M., Zimmerman, D., Shoob, H., & Stein-Zamir, C. (2019, November 19). Post-discharge neonatal hyperbilirubinemia surveillance . Acta Pediatrica , 109 (5), 923-929.
• Kim, M.-S., Chung, Y., Kim, H., Ko, D.-H., Jung, E., Lee, B. S., Hwang, S.-H., Oh, H.-B., Kim, E. A.-R., & Kim, K.-S. (2020). Neonatal exchange transfusion: Experience in Korea . Transfusion and Apheresis Science , 59 .
• Koc, H., Altunhan, H., Dilsiz, A., Kaymakci, A., Duman, S., Oran, B., & Erkul, I. (1999, July). Testicular Changes in Newborn Rats Exposed to Phototherapy . Pediatric and Developmental Pathology , 2 (4), 333-336.
• Leifer, G. (2018). Introduction to Maternity and Pediatric Nursing . Elsevier.
• Maayan-Metzger, A., Yosipovitch, G., Hadad, E., & Sirota, L. (2001). Transepidermal Water Loss and Skin Hydration in Preterm Infants During Phototherapy . American Journal of Perinatology , 18 (7), 393-396.
• Maya-Enero, S., Candel-Pau, J., Garcia-Garcia, J., Duran-Jorda, X., & Lopez-Vilchez, M. A. (2021, January 6). Reliability of transcutaneous bilirubin determination based on skin color determined by a neonatal skin color scale of our own . European Journal of Pediatrics , 180 , 607-616.
• Morrison, K. L. (2021). Improving the Identification of Newborns at Risk for Hyperbilirubinemia. ProQuest .
• Poder, T. G., Nonkani, W. G., & Leponkouo, T. (2015, July). Blood Warming and Hemolysis: A Systematic Review With Meta-Analysis . Transfusion Medicine Reviews , 29 (3), 172-180.
• The Royal Children’s Hospital. (2004). Exchange Transfusion: Neonatal . The Royal Children’s Hospital. Retrieved May 19, 2022.
• Salman, M., Rathore, H., Arif, S., Ali, R., Khan, A. A., & Nasir, M. (2021, January 5). Frequency of Immediate Neonatal Complications (Hypoglycemia and Neonatal Jaundice) in Late Preterm and Term Neonates . Cureus. Retrieved May 15, 2022.
• Sardari, S., Mohammadizadeh, M., & Namnabati, M. (2019, January 19). Efficacy of Home Phototherapy in Neonatal Jaundice . Journal of Comprehensive Pediatrics , 10 (1).
• Sarkar, S. K., Biswas, B., Laha, S., Sarkar, N., Mondal, M., Angel, J., Dr, V., Abhisek, K., Kumar, V., Acharya, A., Biswas, P., Mal, S., Ghosh, D., & Mukherjee, T. (2021). A study on the effect of phototherapy on platelet count in neonates with unconjugated hyperbilirubinemia: a hospital-based prospective observational study . Asian Journal of Medical Sciences , 12 (5).
• Sawyer, T. L., & Nimavat, D. J. (2018, May 1). Phototherapy for Jaundice: Background, Indications, Contraindications . Medscape Reference. Retrieved May 20, 2022.
• Silbert-Flagg, J., & Pillitteri, A. (2018). Maternal & Child Health Nursing: Care of the Childbearing & Childrearing Family . Wolters Kluwer.
• Szigeti, R. G., & Staros, E. B. (2014, September 5). Reticulocyte Count and Reticulocyte Hemoglobin Content: Reference Range, Interpretation, Collection, and Panels . Medscape Reference. Retrieved May 15, 2022.
• Van der Walt, J.H., & Russel, W.J. (1978, August). Effect of Heating on the Osmotic Fragility of Stored Blood . British Journal of Anaesthesia , 50 (8), 815-820.
• Vodret, S., Bortolussi, G., Schreuder, A. B., Jasprova, J., Vitek, L., Verkade, H. J., & Muro, A. F. (2015). Albumin administration prevents neurological damage and death in a mouse model of severe neonatal hyperbilirubinemia . “ – Wiktionary. Retrieved May 19, 2022.
• Wagle, S., & Aslam, M. (2017, December 28). Hemolytic Disease of the Newborn Treatment & Management: Approach Considerations, Medical Care, Complications . Medscape Reference. Retrieved May 19, 2022.
• Wang, J., Guo, G., Cai, W.-Q., & Wang, X. (2021, March). Challenges of phototherapy for neonatal hyperbilirubinemia . Experimental and Therapeutic Medicine , 21 (3).
• Wani, M. I., Nazir, M., Lone, R., Rafiq, M., Ali, S. W., & Charoo, B. A. (2018, October 5). Impact of Double Volume Exchange Transfusion on Biochemical Parameters in Neonatal Hyperbilirubinemia . International Journal of Pediatric Research , 4 (2).

Reviewed and updated by M. Belleza, R.N.

Leave a Comment Cancel reply

Log in using your username and password

• Search More Search for this keyword Advanced search
• Latest content
• For authors
• Browse by collection
• BMJ Journals

You are here

• Volume 14, Issue 6
• Preventive effect of prenatal maternal oral probiotic supplementation on neonatal jaundice (POPS Study): A protocol for the randomised double-blind placebo-controlled clinical trial
• Article Text
• Article info
• Citation Tools
• Rapid Responses
• Article metrics

• http://orcid.org/0000-0002-9719-6331 Bekalu Kassie Alemu 1 , 2 ,
• May Wing Lee 1 ,
• Maran Bo Wah Leung 1 ,
• Wing Fong Lee 1 ,
• http://orcid.org/0000-0003-0010-2819 Yao Wang 1 , 3 ,
• Chi Chiu wang 1 , 4 ,
• So Ling Lau 1
• 1 Department of Obstetrics and Gynaecology , Faculty of Medicine, The Chinese University of Hong Kong , Hong Kong , Hong Kong SAR
• 2 Department of Midwifery , College of Medicine and Health Science, Debre Markos University , Debre Markos , Ethiopia
• 3 Institute of Health Sciences , The Chinese University , Hong Kong , Hong Kong SAR
• 4 School of Biomedical Sciences, Joint Laboratory for Reproductive Medicine , The Chinese University , Hong Kong , Hong Kong SAR
• Correspondence to Dr So Ling Lau; solinglau{at}cuhk.edu.hk

Introduction Neonatal jaundice is a common and life-threatening health problem in neonates due to overaccumulation of circulating unconjugated bilirubin. Gut flora has a potential influence on bilirubin metabolism. The infant gut microbiome is commonly copied from the maternal gut. During pregnancy, due to changes in dietary habits, hormones and body weight, maternal gut dysbiosis is common, which can be stabilised by probiotics supplementation. However, whether probiotic supplements can reach the baby through the mother and reduce the incidence of neonatal jaundice has not been studied yet. Therefore, we aim to evaluate the effect of prenatal maternal probiotic supplementation on the incidence of neonatal jaundice.

Methods and analysis This is a randomised double-blind placebo-controlled clinical trial among 94 pregnant women (47 in each group) in a tertiary hospital in Hong Kong. Voluntary eligible participants will be recruited between 28 and 35 weeks of gestation. Computer-generated randomisation and allocation to either the intervention or control group will be carried out. Participants will take either one sachet of Vivomixx (450 billion colony-forming units per sachet) or a placebo per day until 1 week post partum. Neither the study participants nor researchers will know the randomisation and allocation. The intervention will be initiated at 36 weeks of gestation. Neonatal bilirubin level will be measured to determine the primary outcome (hyperbilirubinaemia) while the metagenomic microbiome profile of breast milk and maternal and infant stool samples as well as pregnancy outcomes will be secondary outcomes. Binary logistic and linear regressions will be carried out to assess the association of the microbiome data with different clinical outcomes.

Ethics and dissemination Ethics approval is obtained from the Joint CUHK-NTEC Clinical Research Ethics Committee, Hong Kong (CREC Ref: 2023.100-T). Findings will be published in peer-reviewed journals and presented at international conferences.

Trial registration number NCT06087874 .

• Clinical Trial
• NEONATOLOGY
• Fetal medicine
• Maternal medicine
• Prenatal diagnosis

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See:  http://creativecommons.org/licenses/by-nc/4.0/ .

https://doi.org/10.1136/bmjopen-2023-083641

Statistics from Altmetric.com

Request permissions.

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

STRENGTHS AND LIMITATIONS OF THIS STUDY

This randomised, double-blind, placebo-controlled superiority trial for reaching the baby through the mother to tackle neonatal jaundice is the first of its kind.

Using multistrain probiotics (Vivomixx with eight strains of beneficial bacteria) known for its safety during pregnancy is one of the strengths of this trial.

Biological samples from the mother and baby (stool and breast milk) will be collected to triangulate the effect of the intervention on clinical outcomes with microbiome data.

The participant with her baby will be appointed for the seventh-day follow-up to collect samples and measure the baby’s transcutaneous bilirubin, and this may increase the dropout.

Introduction

Neonatal jaundice is a yellowish discolouration of the skin and sclera of neonates in the first month of life due to elevated levels of bilirubin in the blood (hyperbilirubinaemia). 1–3 Hyperbilirubinaemia is a total serum bilirubin (TSB) level measurement of more than 5 mg/dL or >85.5 µmol/L in 24 hours and 12 mg/dL or 205 µmol/L after a day. 4 Neonatal jaundice can be physiologic or pathologic in its type. The former usually appears after 24 hours of birth and goes off within 2 weeks of life while the latter arises within a day with a TSB level of more than 15 mg/dL and lasts beyond 14 days. 2 5 Physiological jaundice is associated with different factors such as ethnicity, geographical location, birth season, maternal smoking and pharmacotherapy. 6 It is also associated with low birth weight, 7–9 prematurity and sepsis. 8 Pathological jaundice is mostly caused by glucose-6-phosphate dehydrogenase deficiency, 8 10 ABO incompatibility and rhesus haemolysis. 11 Neonatal jaundice needs comprehensive management to avoid severe complications, such as brain damage. However, due to different barriers, evidence-based management of neonatal jaundice is still challenging. 12 Even though there are certain managements such as phototherapy, they have various impacts on the vision, hearing and alertness of the newborn. It also affects the circadian rhythm of babies and causes dehydration, hypocalcaemia and renal damage. 13

Neonatal jaundice is occurring in varied incidence (about 60%–90%) worldwide. 6 The incidence in North America is about 34%. 14 It is more prevalent among infants of Southeast and Far East Asian mothers and may be up to threefold higher than among whites. 6 15 Among the three main regions in China, the Central South Region has extreme hyperbilirubinaemia. A study in Hong Kong showed about 50%–70% of normal-term infants have the problem. 16 Though the bulk of neonatal jaundice causes is unknown, some of the associated factors include breast milk jaundice, breastfeeding jaundice and glucose-6-phosphate dehydrogenase deficiency as well as surgical disease. 17 It is also hypothesised due to elevated enterohepatic recirculation of unconjugated bilirubin, which is mediated by β-glucuronidase enzyme and bad bacteria in the gut. 18 19 Neonates’ gut flora, which is mainly copied from the mother in the uterus, during childbirth, and through breast feeding has a critical role in bilirubin metabolism by antagonising the activity of the β-glucuronidase enzyme and converting conjugated bilirubin into stercobilinogen (to be excreted via faeces) and urobilinogen (via urine). 20 21 In addition to converting conjugated bilirubin into excretable form, good bacteria in the gut keep the neonate’s gut healthy and increase defecation frequency. Even though the gut microbiome cannot have an impact on the pathological causes of hyperbilirubinaemia such as haemolysis, it may facilitate the excretion of conjugated bacteria. 22 23 Thus, it reduces enterohepatic recirculation. On the contrary, the recirculation of unconjugated bilirubin is facilitated during gut microbiome imbalance (dysbiosis). 24

Preventing gut dysbiosis is very crucial and could be one of the management modalities of neonatal jaundice. 25 The mechanism to modulate the infant’s gut is important. Modulating maternal gut microbiome could end up with beneficial bacteria enriched in breast milk. Our systematic review and meta-analysis proved this innovative approach. 26 The way for this modulation of breast milk is the enteromammary pathway/gut-breast axis, where intestinal dendritic cells and CD18 + cells play an important role in helping beneficial bacteria translocate from the maternal gut to the mammary system. 27–29 The infant gut microbiota is the collection of germs colonising the newborn’s intestine. It is thought to be established by breastfeeding and exposure during birth through the birth canal. 30 31 Bioactive components of human breast milk, oligosaccharides, which are non-digestible carbohydrates forming the third largest solid component in human milk particularly are significantly important to shaping infant gut microbiota by nurturing the beneficial bacteria. 32 Antimicrobial agents in breast milk also inactivate pathogens individually, additively and synergistically. 33 34 In the case of gut dysbiosis, pathogenic micro-organisms will be more abundant and play a role in enhancing the beta-glucuronidase enzyme, which indirectly promotes deconjugation and bilirubin reuptake into the enterohepatic circulation. 21

Supplementing pregnant women with products containing beneficial bacteria (probiotics) can maintain gut health. 21 35 36 Probiotics are supplements composed of live beneficial microorganisms to improve microbial balance, lower intestinal pH, decrease colonisation and invasion by pathogenic organisms, and modify the host immune response, mainly in the gastrointestinal tract. They consist of Saccharomyces boulardii, Streptococcus thermophilus, Lactobacillus and Bifidobacterium species. 37 Administration of probiotics directly to infants is evidenced to prevent and treat neonatal problems including jaundice through maintaining gut health, increasing stool frequency, decreasing beta-glucuronidase enzyme activity, compete with pathogens for food and receptors in the gut. 36 38 39 From lines of literature, we found that probiotic species can modulate the physiology of bilirubin metabolism. 21 Such bacteria include but are not limited to Bifidobacterium , Lactobacillus, Streptococcus and Saccharomyces species.

Bifidobacterium

As compared with non-jaundiced babies, those affected by jaundice had significantly lower levels of Bifidobacterium 39 ( B. adolescentis, B. bifidum and B. longum), 40 41 which imply Bifidobacterium has a bilirubin reduction effect. 40 42 An animal study suggested that faecal beta-glucuronidase enzyme was significantly reduced in animals fed diets containing Bifidobacterium ( B. longum ) supplements. 43 Another study conducted among 53 healthy volunteers confirmed that Bifidobacterium ( B. breve, B. lactis and B. bifidum ) has a suppressive effect on beta-glucuronidase activity. 44 45 B. infantis also has an impact on maintaining mucosal and immune systems, reducing sepsis and increasing defecation frequency. 46 47

Lactobacillus

Probiotic Lactobacillus rhamnosus GG has a significant effect on inhibition of serum bilirubin level and increasing defecation frequency to enhance bilirubin excretion. 48 L. rhamnosus and L. acidophilus are species that could reduce hospitalisation of neonates with hyperbilirubinaemia. 45 Lactobacillus bulgaricus as one of the bifid triple viable has a therapeutic effect on neonatal jaundice. 39 Lactobacillus plantarum has also a significant effect on the reduction of bilirubin and liver enzymes. 41

Saccharomyces boulardii

S. boulardii , in an animal model study, affects preventing bacterial translocation and improvement of intestinal barrier function in obstructive jaundice. 49

Streptococcus

S. thermophilus is also one of the bifid triple viable probiotic components and it is effective in treating neonatal jaundice. 39

Since their action on mucosal adhesion, immune system development and inhibition of pathogens is much better in combination than as a single species, multistrain probiotic products are chosen for better effect. 50 51 Therefore, for this project, Vivomixx, a food supplement that is produced according to food Good Manufacturing Practices and a widely studied product on pregnant women with various outcomes of interest could be used. We have selected Vivomixx from available products in the market like ‘PGut pregnancy probiotics’ 52 and ‘Prenatal-Probiotics’ 53 because of two main reasons. First, Vivomixx is a well-applied probiotic on pregnant women with a null adverse event. 54–61 Second, it contains a majority of probiotic species identified to affect neonatal jaundice/ bilirubin metabolism. 56

This is the first study that aims to investigate the preventive effect of maternal probiotic supplementation on the incidence of neonatal jaundice and bilirubin level, pregnancy outcomes, breast milk, as well as maternal and infant stool microbiome profile.

Methods and analysis

Study design, setting and period.

This is a randomised double-blind placebo-controlled parallel group superiority clinical trial in the Prince of Wales Hospital (PWH), Hong Kong from January 2024 to June 2025. This trial will be with pregnant women randomly assigned to either the probiotic group (Vivomixx with maltose) or the placebo group (maltose only). The trial protocol is reported as per the Standard Protocol Items: Recommendations for Interventional Trials guidelines. 62

Participants

Pregnant women who will attend their antenatal care and plan to deliver in PWH will be invited to participate in this study.

Inclusion criteria

Pregnant women from 18 to 45 years old.

Gestational age between 28 and 35 weeks.

Normal singleton pregnancy.

Not on standing dose of antibiotic treatment during enrolment and initiation of the intervention.

Plan to exclusively breastfeed.

Exclusion criteria

Pregnant women with any fetal abnormality.

Couple with glucose 6-phosphate dehydrogenase enzyme deficiency.

Couple with known rhesus or haemolytic disease history.

Any known risk of developing pathological jaundice.

Plan to give birth at other hospitals than PWH.

Women with any contraindications for breast feeding.

Non-exclusively breastfeeding babies.

Recruitment and randomisation

Pregnant women will be recruited between 28 and 35 weeks in the outpatient clinics in a tertiary-level hospital ( figure 1 ). After confirming the eligibility of pregnant women, the investigator will explain the study by using a printed information sheet that contains the title of the study, purpose, expected length of time for participation, description of all the procedures, confidentiality, voluntary participation, the right to refuse the intervention, withdraw from participation in the clinical trial at any time, contact information and all information will be kept securely. Sufficient time is allowed for their consideration, and all their questions will be answered. Pregnant women will voluntarily sign the written informed consent form ( online supplemental file 1 ). Computer-generated randomisation and allocation will be made by a third party other than the investigators and clinicians to allocate the pregnant women to either probiotic or placebo groups in (1:1) ratio. Neither the study participants nor researchers will know the randomisation and allocation. The intervention will be initiated at 36 weeks of gestation for both study groups. To date, the recruitment has not started yet.

Supplemental material

• Download figure
• Open in new tab
• Download powerpoint

Flow diagram of participant recruitment and follow-up in the POPS trial using Consolidated Standards of Reporting Trials. DOL, days of life; N, total screened for eligibility; n, number of participants in each stage of enrolment, intervention and follow-up, POPS, Perinatal Oral Probiotics Supplementation. 76

Intervention

The probiotic group pregnant women will take one sachet of probiotic (a maltose containing Vivomixx) product orally daily from 36 weeks of gestation up to the seventh day of postpartum while pregnant women in the control group will take one sachet placebo (only maltose) orally daily for the same duration. The best time to take the product is in the morning before breakfast. Each participant in both groups will be advised to dilute a sachet of product provided with a cap of cold water. Detailed information will be provided to each participant with an information sheet prepared in local language. Both active Vivomixx and placebo are similar in colour and taste with the same white sachet package. The probiotic product in this trial is a widely studied supplement among pregnant women for other research outcomes including vaginal microbiota and cytokine secretion, bacterial vaginosis, breast milk beneficial microbiota and cytokines, glycaemic control, neonatal gastrointestinal functional symptoms and gut microbiota as well as immune response. 54–59 Maximum gut microbiome colonisation is achieved in 2–3 weeks of supplementation. 63

Investigators have trial identified about 12 different microbiome species from the literature that have direct or indirect bilirubin reduction effects ( table 1 ). There are commercially available probiotic products that contain many of these species. Vivomixx is one of the accessible well-studied products for its safety during pregnancy. It is a non-GMO, gluten-free, high-potency microbiotic food supplement, containing eight strains of live bacteria (450 billion bacteria per sachet) including S. thermophilus DSM24731/NCIMB 30438, Bifidobacterium breve DSM24732/NCIMB 30441, Bifidobacterium longum DSM24736/NCIMB 30435, Bifidobacterium infantis DSM24737/NCIMB 30436, Lactobacillus acidophilus DSM24735/NCIMB 30442, Lactobacillus plantarum DSM24730/NCIMB 30437, Lactobacillus paracasei DSM24733/NCIMB 30439, Lactobacillus delbrueckii ssp. bulgaricus DSM24734/NCIMB 30440 . 64 From lines of affidavits, we have cross-evaluated and found that seven of the strains affect the bilirubin metabolism. It can be stored at room temperature for up to week without having a major effect on potency. Otherwise, it is safe at 4°C–8℃. 65 66 We prepared an icebag that can keep the product at a low temperature during transportation to home and each participant will store the product in a refrigerator at home. It will be stored, distributed and administered as per the product instruction by clinicians.

• View inline

Summary of probiotic species that have direct or indirect effect on neonatal jaundice from different literatures

Outcome measures

Primary outcome.

Hyperbilirubinaemia will be the primary outcome of this study. For all participants’ babies, sternal transcutaneous bilirubin (TcB) level will be measured within 2 days and on the seventh day of life by Dräger Meter JM-105, which is a non-invasive device. When TcB exceeds or is within 3 mg/dL of the phototherapy treatment threshold or if the TcB is 15 mg/dL, TSB will be measured as a confirmatory test. 67 Hyperbilirubinaemia will be declared when TSB is >5 mg/dL/24 hours or >12 mg/dL after 1 day. Since our intervention will be initiated during pregnancy, all outcomes of each type of jaundice including jaundice diagnosed within 24 hours will be compared between the two groups by considering the intrauterine exposure to probiotics. The TcB measurement device is studied in different settings including a study conducted in Hong Kong in 2016 at Baby-friendly Hospital 68 and Tuen Mun Hospital, 69 and in a tertiary hospital in Malaysia. 70 It is a very quick, effective and non-invasive method of measurement. It is also a reliable method with a better correlation coefficient with TSB measurement. 71–73 The bilirubin level will be plotted on the standard neonatal bilirubin level nomogram chart to decide if the infant has considerable jaundice. A measurement of TcB level above the 95th percentile on the nomogram will be regarded as a high risk for subsequent hyperbilirubinaemia 67 and will be investigated with TSB and followed. 74 There is also a phototherapy and exchange transfusion threshold determining nomogram based on gestational age and age in hours. 67 This threshold-determining nomogram will be used and the need for phototherapy and exchange transfusion will also be assessed as outcomes. By taking in utero exposure into consideration, all newborns irrespective of their health status and admission status to the special care baby unit will be included in the study.

Secondary outcomes

Secondary outcomes involve (1) Pregnancy outcomes will be collected by a questionnaire which contains different outcome measure variables including fetal well-being, preterm labour, pre-eclampsia, diabetes mellitus, infection/sepsis, induction of labour, mode of delivery, GA at birth, birth weight, Apgar score and …etc. (2) Milk and stool microbiome: Breast milk samples will be collected within the second and on the seventh day of giving birth. It will be kept at 4°C during transportation and stored at 80°C freezer. The maternal stool will be collected before initiation of the intervention (at 36 weeks of gestation) and after 3 weeks of intervention. Infant stool will be collected simultaneously with breast milk samples ( figure 2 ). Both maternal and infant stool samples will be collected using a tube containing DNA stabiliser and then aliquoted and frozen at 80°C. Both samples will be processed based on the commercially available kit protocol. Metagenomic sequencing will be used to characterise the microbiome in each sample. For analytical measurement, the number of participants from whom provided probiotics were detected (relative risk) and the mean concentration of provided probiotic species in the breast milk and infant stool will be measured. Maternal stool sample microbiome profiles before and after intervention in both probiotic and placebo groups will be compared. (3) Safety for the mother and fetus/ infant: An independent safety monitoring committee and all research team members will monitor each participant for any adverse events, in particular, gastrointestinal symptoms and possible allergies. Mothers and infants will be followed regularly for possible side effects such as allergic reactions, stomach upset, diarrhoea, flatulence (passing gas) and bloating. 37 Apart from discomfort causing symptoms such as bloating other severe side effects are uncommon. However, in any case, such a moderate to severe side effects, such as decreased/absent/fetal movement, fever, uncommon vaginal fluid leakage, severe headache, decreased abdominal girth or overdistended abdomen, the intervention will be stopped, the participant will be linked to the Accident and Emergency Department. If any adverse events occur in infants, infants will be linked to the paediatrics department.

Timeline of the POPS study from recruitment to end of follow-up. POPS, Perinatal Oral Probiotics Supplementation

Follow-up, compliance and dietary intake data

Pregnant women will be reminded to collect preintervention and postintervention stool samples, start the intervention at 36 weeks of gestation and be advised to report when labour starts or any discomfort. For better retention of participants, a reminder message will be sent to each participant using WhatsApp in the local language at four different time points. The pregnant women will be reminded to record daily on the diary form regarding the dose and time they take the supplement, supplemented with any use of prescribed antibiotics or adverse events such as any diarrhoea, hospitalisation, etc. In addition, they will also be reminded to keep their usual diet only and not to take any other probiotic products. The unused supplements report will be collected. Maternal dietary intake and diversity will be evaluated using standard individual dietary diversity measurement guidelines. 75 76

Data and sample collection

For this randomised controlled clinical trial, data will be collected at least at three time points.

Recruitment: At this stage, participants’ characteristics such as age, marital status, educational level and other sociodemographic characteristics, obstetrics and gynaecological characteristics, medical and surgical factors, reproductive history-related factors including family size, behavioural-related factors (smoking or alcohol use), allergies, use of supplements/vitamins/probiotics, prior lactation history, use of standing dose of antibiotics, plan for the place of birth, current pregnancy condition (gestational age, type of pregnancy (singleton), presentation, fetal heartbeat, placental location, fetal weight, any supplement/ vitamin/ probiotic in the previous 1 month. Preintervention maternal stool samples will be collected from women in both groups. The intervention will be initiated at 36 weeks of gestation and after 3 weeks of intervention, postintervention data will be collected.

Within 2 days of life and before discharge:

Having sufficient rest after delivery, mothers will be contacted until before discharge home for data collection at their most convenient time. The time for data collection will be marked. Data including gestational age at delivery, date and time of delivery, mode of delivery, any antibiotic use; infant birth weight, Apgar score, urination status of the infant and time of initiation of breast feeding will be documented. Breast milk and infant stool samples will be collected, and the volume of samples collected, and storage temperature for both samples. Moreover, the neonate’s TcB level will be measured and documented.

Follow-up on the seventh day of infant life: Breast milk and infant stool samples will be collected. Both the volume and storage temperature of samples will also be recorded. Infant body weight and bilirubin level will be measured. Breastfeeding status will be recorded. The diary record for supplements will be returned and the final sachet count report will be recorded.

In general, the data collection will be exclusively by the research staff appointed for this research using a pretested questionnaire. After recruitment, every mother will be counselled at each contact for better compliance with the intervention.

Data handling and quality assurance

All the data collected through this study will be handled by the principal investigator and researchers and kept confidential. Data quality will be checked regularly by all investigators separately and a trial managing committee.

Sample size

The sample size in this protocol is calculated using the G*power V.3.1.9.4 statistical software. 77 Due to the lack of previous studies on pregnant women targeting bilirubin level reduction in neonates, we used a previous study conducted to assess the effect of a probiotic on neonatal hyperbilirubinaemia by providing the lactobacillus RGG directly to neonates in Turkey to calculate our study sample size (PMID: 30968632). 78 The effect size was calculated using mean, SD and sample size, which are the most common parameters to measure effect size. In the paper conducted in Turkey, the mean and SD of bilirubin level and the sample size were mentioned, and we took the third-day bilirubin measurement records. The effect size was computed as 0.663. Finally, the sample size is calculated using the following assumptions: Two tailed, power 80, effect size 0.663, α=0.05, 1:1 allocation ratio. This yields about 74 (37 in each arm), and then we considered a 20% drop-out using the formula N=(n/1−DO). The final sample size, therefore, computed 94 (47 in each group). 48 We have also calculated the sample size using a reduction of the incidence of neonatal jaundice in controls (p=46.6%) and in the probiotics group (p=14.6%) and yield (n=62; 31 in each group), which is smaller than the first sample size. To calculate this sample size, we used additional parameters (α=0.05, power=0.8, enrolment ratio 1:1) and calculated using an online platform. 79

Statistical analysis

This study will use the Consolidated Standards of Reporting Trials guidelines. 80 An intention-to-treat approach will be used to assess the cause-and-effect relation to maintain the effect of randomisation. Baseline characteristics will be compared between allocated treatment groups using frequencies and descriptive statistics. Pearson’s χ 2 test and Fisher’s exact test will be run to assess the difference of different factors between the two intervention groups ( online supplemental table ). To assess the exclusive effect of the intervention on the occurrence of neonatal jaundice, a binary logistic regression model will be fitted. Additionally, to examine the effect of the intervention on the mean bilirubin level of neonates, mean beneficial bacteria level in breast milk, and in maternal and infant stool, linear regression will be employed. The microbial DNA will be extracted from different specimens, including breast milk, and maternal and infant stool samples using commercial kits. Quality control and metagenomics sequencing will be employed and analysed by bioinformatics experts to obtain microbiome information including taxonomy and function.

Study status

Participant recruitment has not started yet.

Patient and public involvement

The public representative was involved in the Joint CUHK-NTEC Clinical Research Ethics Committee, whose membership includes lay persons from the community, apart from clinical and nursing staffs. Results of the trial will be disseminated to the community including study participants through presentations in workshops and posters as well as flyers that will be posted in the outpatient clinics for ease of access. Plan for participant involvement in participant recruitment is not considered in this study. This trial has subsequent follow-up schedules. In each visit, participants will be asked for any adverse effects. A diary form is also prepared to mark down the dose taken and any side effects.

Ethics and dissemination

All the procedures in this clinical trial will be conducted as per the ethical principles of the Declaration of Helsinki of the World Medical Association and the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Guideline for Good Clinical Practice (GCP) for medical research involving human subjects. Ethical approval was obtained from the CUHK-NTEC (The Chinese University of Hong Kong and New Territories East Cluster) Clinical Research Ethics Committee (CREC) Hong Kong (with CREC Reference number 2023.100-T). Participants will be identified and screened with eligibility criteria by reviewing their medical records and questioning them for these criteria. For those who fulfilled the inclusion criteria, adequate information will be provided by using the printed information sheet. Written informed consent will be taken from each participant after their approval. Codes instead of names will be used and all data will be kept confidential. These codes will be used throughout each communication among the research team and for data analysis.

In focus on increasing visibility, using any recognised benefits of the interventions resulting from this study and further evaluation, enhancing academic collaborations, linking relevant research areas in this field and identifying further areas where research could be effectively managed, this study result will be disseminated through presentations in academic seminars, workshops, and national and international symposiums. It will be submitted to The Chinese University of Hong Kong for archival and possible dissemination. The aggregated findings of this trial will be published in peer-reviewed academic journals for better visibility. A lay summary of the results and links to publications will be made available on databases.

Emerging evidence increasingly indicates that the microbiome established in early life, even before birth, plays a pivotal role in shaping human health and disease outcomes in later years. 81 Neonatal jaundice, a prevalent problem in newborns, is attributed to dysfunction in bilirubin metabolism, production and excretion. 82 Despite treatments such as phototherapy and exchange transfusion are commonly employed, however, preventive approaches for neonatal jaundice are limited. Gut flora is instrumental in converting conjugated bilirubin into stercobilinogen and urobilinogen, facilitating its excretion as stercobilin in faeces and urobilin in urine. 20 Interestingly, the neonatal gut microbiome is primarily established by the maternal gut and milk microbiome during pregnancy and lactation periods. 83 84 Therefore, remodelling the maternal microbiome provides us with a potential opportunity to shape the gut microbiome in newborns.

Probiotics have been proven to be an effective intervention to shape the maternal-offspring microbiome. Of note, lines of evidence suggest maternal probiotic supplementation not only positively influences the breast milk and infant’s gut microbiome but also enhances maternal health during pregnancy. 26 Importantly, no adverse effects from these supplements during pregnancy have been reported to date. Previous studies showed that directly administering probiotics to neonates enables them to treat and prevent neonatal jaundice. 39 85 However, direct neonatal administration of probiotics is not always practical. Therefore, we questioned if breast milk can be modulated by probiotic supplementation during pregnancy thereby reshaping the infant’s gut microbiome and reducing neonatal complications such as jaundice.

To this end, we hypothesised perinatal probiotic supplementation in pregnancies may serve as a feasible approach to preventing neonatal jaundice and designed this randomised controlled trial to evaluate its effect. Our study will revolutionise current neonatal care practices, offering a non-invasive, safe, inexpensive and potentially highly effective preventive strategy for neonatal jaundice. It also underscores the critical role of the maternal microbiome in infant health, paving the way for new approaches in prenatal care.

Ethics statements

Patient consent for publication.

Consent obtained directly from patient(s).

Acknowledgments

The Hong Kong Obstetrical & Gynaecological Trust Fund granted funding for the team to handle this study. The Clinical Research Pharmacy in the Prince of Wales Hospital, Hong Kong has signed agreement with this study team to store the investigational food products (Vivomixx and placebo) and dispense by keeping the cold chain of the product. The authors would like to acknowledge Mendes, the innovative microbiotic company in Europe, for supplying the investigational food product (Vivomixx and placebo). The trial team would like to sincerely acknowledge the Department of Obstetrics and Gynaecology, at the Chinese University of Hong Kong for supporting the trial in logistics.

• Maisels MJ ,
• McDonagh AF
• Burman-Roy S ,
• Murphy MS , et al
• Olusanya BO ,
• Kandasamy D ,
• Roginski C , et al
• Osibanjo FB ,
• Tiwari PK ,
• Kumar A , et al
• Hsiao K-J ,
• Wuu K-D , et al
• Li Z-K , et al
• Trasancos C ,
• Li A , et al
• Coleman K , et al
• Villaveces A ,
• Dhillon P , et al
• Wong RM , et al
• Agarwal R ,
• Akagawa S ,
• Akagawa Y ,
• Yamanouchi S , et al
• Dufault-Thompson K , et al
• Li J , et al
• Zhang W , et al
• Wu L , et al
• Rescigno M ,
• Valzasina B , et al
• Macpherson AJ ,
• Day AS , et al
• Turroni F ,
• Ventura M , et al
• Moubareck CA
• Virmani MD ,
• Rosa F , et al
• Cookson AL ,
• Otter DE , et al
• Santosa I ,
• Itoh S , et al
• Williams NT
• Korpela K ,
• Salonen A ,
• Vepsäläinen O , et al
• Wang T , et al
• Duman N , et al
• Kirpich IA ,
• Solovieva NV ,
• Leikhter SN , et al
• He F , et al
• Kulkarni N ,
• De Preter V ,
• Cloetens L , et al
• Torkaman M ,
• Mottaghizadeh F ,
• Khosravi MH , et al
• Quigley EMM
• O’Hara AM ,
• O’Regan P ,
• Fanning A , et al
• Aslan Y , et al
• Aldemir M ,
• Hosoglu S , et al
• Collado MC ,
• Jalonen L ,
• Meriluoto J , et al
• Aiyegoro OA ,
• Okpeku M , et al
• Sahariah SA ,
• Chopra H , et al
• Purdue-Smithe AC ,
• Schliep KC , et al
• Cruciani F ,
• Baldassarre ME , et al
• Facchinetti F ,
• Pedretti L , et al
• Mastromarino P ,
• Capobianco D ,
• Miccheli A , et al
• Jafarnejad S ,
• Jafarnejad F , et al
• Baldassarre ME ,
• Di Mauro A ,
• Mastromarino P , et al
• Sarangi AN ,
• Goel A , et al
• Astolfi ML ,
• Protano C ,
• Schiavi E , et al
• Halkjær SI ,
• de Knegt VE ,
• Lo B , et al
• Tetzlaff Jm Fau - Altman DG ,
• Altman Dg Fau - Laupacis A , et al
• De-Simone-Formulation
• Atukunda EC ,
• Owembabazi M ,
• Pratt MC , et al
• Mintjens S ,
• van Poppel MNM ,
• Groen H , et al
• McCarthy JS ,
• Yalkinoglu Ö ,
• Odedra A , et al
• Kemper AR ,
• Newman TB ,
• Slaughter JL , et al
• Chiu-Fan LAU ,
• Mohamed M ,
• Ibrahim NR ,
• Ramli N , et al
• Vandermeer B ,
• Campbell S , et al
• Hassan Shabuj M ,
• Hossain J ,
• Chenarani RM ,
• Maamouri G ,
• Khodashenas E , et al
• Kennedy G ,
• Ballard T ,
• Ganpule-Rao AV ,
• Yajnik CS , et al
• Buchner A ,
• Erdfelder E ,
• Faul F , et al
• Sereika SM ,
• ↵ Sample Size Calculator: Determines the minimum number of subjects for adequate study power . Updated July 24, 2019. Accessed June 4, 2024. Available : https://clincalc.com/stats/samplesize.aspx
• Waechter R ,
• Burgen KS ,
• Punch B , et al
• Stiemsma LT ,
• Woodgate P ,
• Mueller NT ,
• Combellick J , et al
• Zheng T , et al
• Palladino V ,
• Amoruso A , et al
• Kumral A Fau - Duman A ,
• Fau - Duman N , et al
• Sun Q , et al

Supplementary materials

Supplementary data.

This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

• Data supplement 1
• Data supplement 2

Contributors SLL is the principal investigator of this trial. CCW and BKA conceived the idea. BKA developed the research question and study design and prepared the protocol for ethical approval submission under the supervision of CCW and YW. WFL and BKA prepared an information sheet, consent form and other logistics before submission to the ethics committee for approval. MBWL and BKA optimised the laboratory sample handling, storage and processing protocol. BKA, CCW and YW established collaboration with the innovation microbiotic company for free supply of the investigational food product. MWL, SLL, CCW, YW, BKA and WFL obtained the funding. CCW is the senior trial supervisor who coordinated the operational delivery of the study protocol. WFL provides support on recruitment. YW and BKA handle the data and analysis. BKA drafted the manuscript and all authors listed provided critical review and approved the manuscript for submission.

Funding The Hong Kong Obstetrical & Gynaecological Trust Fund supported the trial (grant number: N/A). Department of Obstetrics and Gynaecology, Faculty of Medicine, the Chinese University of Hong Kong provided logistics for the laboratory sample storage, processing and analysis.

Competing interests None declared.

Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

Provenance and peer review Not commissioned; externally peer reviewed.

Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

Read the full text or download the PDF:

• Type 2 Diabetes
• Heart Disease
• Digestive Health
• Multiple Sclerosis
• Diet & Nutrition
• Supplements
• Health Insurance
• Public Health
• Patient Rights
• Caregivers & Loved Ones
• End of Life Concerns
• Health News
• Thyroid Test Analyzer
• Doctor Discussion Guides
• Hemoglobin A1c Test Analyzer
• Lipid Test Analyzer
• Complete Blood Count (CBC) Analyzer
• What to Buy
• Editorial Process
• Meet Our Medical Expert Board

Jaundice: Everything You Need to Know

More Than Just Yellow Skin and Eyes

• Complications
• When to Seek Care

Jaundice , also known as icterus , is the yellowish discoloration of the skin and eyes caused by the abnormal buildup of an orangish waste product called bilirubin . Bilirubin is produced by the normal breakdown of red blood cells (RBCs) and processed by the liver , where it is cleared from the body in bile . If too much bilirubin is produced or the liver cannot clear it, jaundice can develop.

Jaundice is not dangerous, but the underlying cause can be. Causes range from relatively benign conditions like Gilbert syndrome to potentially fatal ones like liver cancer . Jaundice can occur at any stage of life, including birth ( neonatal jaundice ). The treatment varies by the underlying cause.

This article describes the causes, symptoms, and diagnosis of jaundice in adults and children. It also explains how jaundice is treated and prevented, including when jaundice is a sign of a medical emergency.

This photo contains content that some people may find graphic or disturbing.

ZayWin Htal / Getty Images

Types and Causes of Jaundice

Jaundice occurs when there is too much bilirubin in the body, referred to as hyperbilirubinemia . There are three main reasons why this might occur, which are:

• Prehepatic jaundice : Too many red blood cells are being broken down, and the liver is unable to handle the overload, causing bilirubin to escape into the bloodstream. ("Hepatic" refers to the liver.)
• Hepatic jaundice : The liver is damaged and doesn't remove enough bilirubin from your blood.
• Posthepatic jaundice : There is an obstruction in the  biliary system (composed of the liver, gallbladder , bile ducts, and pancreas ) that causes bile to back up into your liver.

The other classification of neonatal jaundice is an otherwise normal occurrence in newborns but one that can turn serious in some.

Prehepatic Jaundice

Red blood cells have a life span of around 120 days. They are broken down by the body and replaced by new ones. The process, called hemolysis , produces around 4 milligrams (mg) of unconjugated (free-circulating) bilirubin per day, which the liver usually disposes of in urine and stool.

Prehepatic jaundice is caused when hemolysis is increased, overwhelming the liver with more bilirubin than it can handle.

Possible causes of this include:

• Hemolytic anemia (low numbers of RBCs due to increased destruction)
• Sickle-cell anemia (a hereditary condition of variant hemoglobin-the oxygen-carrying molecule in RBCs)
• Thalassemia (an inherited condition affecting hemoglobin production)
• Spherocytosis (having spherical RBCs rather than biconcave ones)
• Alpha-1 antitrypsin (A1AT) deficiency (an inherited disorder affecting a liver enzyme, a substance that affects chemical reactions)
• Glucose-6-phosphate dehydrogenase (G6PD) deficiency (an inherited disorder affecting an enzyme in RBCs)
• Severe malaria infection (a mosquito-borne parasitic infection affecting RBCs)

Hepatic Jaundice

Once unconjugated bilirubin enters the liver, it is exposed to enzymes that transform it into conjugated bilirubin. This form can be incorporated into a digestive fluid called bile and eliminated from the body as it is carried away in the stool.

Hepatic jaundice is caused when liver cells involved in this process, called hepatocytes , are damaged. The damage may be transient (temporary) or permanent, caused by a wide range of infectious, autoimmune, inflammatory, and genetic diseases like:

• Viral hepatitis (most commonly hepatitis A , hepatitis B , and hepatitis C )
• Alcoholic liver disease
• Metabolic dysfunction-associated steatotic liver disease (MASLD) (fat accumulation and inflammation in the liver)
• Liver cirrhosis (extensive scarring in the liver)
• Autoimmune hepatitis
• Drug-induced liver toxicity
• Hemochromatosis (iron overload)
• Wilson’s disease (genetic disorder leading to a buildup of copper)
• Gilbert syndrome (a genetic condition affecting a liver enzyme)
• Liver cancer

Posthepatic Jaundice

Once bile leaves the liver, it is transported to the gallbladder for storage. Whenever food is eaten, it is released into the main duct, called the common duct, where it mixes with digestive fluids from the pancreas. These fluids are then released into the first part of the small intestine , called the duodenum , to break down fats and protein.

Posthepatic jaundice occurs when there is an obstruction in the pathway from the liver to the small intestine. This causes bile to back up into the liver, where bilirubin can escape.

Posthepatic jaundice may be due to an obstruction or a disease that causes bile ducts to become narrow or pinched. Examples include:

• Biliary tract strictures (narrowing of bile ducts)
• Primary biliary cirrhosis (damage to the small bile ducts due to inflammation)
• Primary sclerosing cholangitis (damage to the small bile ducts due to inflammation)
• Pancreatitis (inflammation of the pancreas)
• Cholestasis of pregnancy (slowing of bile flow)
• Liver flukes (parasitic infection)
• Gallbladder cancer
• Bile duct cancer
• Pancreatic cancer

Neonatal Jaundice

Neonatal jaundice is a common occurrence in newborns, affecting 60% of full-term babies and 80% of preterm babies . It usually develops by the second or third day of life and almost always clears on its own without consequence.

Neonatal jaundice is caused when fetal hemoglobin (the protein in red blood cells that carries oxygen) is broken down and replaced with the post-birth form of hemoglobin. This breakdown causes the release of more bilirubin than a newborn's liver can clear.

On rare occasions, neonatal jaundice is not normal. Some of the same conditions that cause jaundice in adults—like G6PD deficiency, spherocytosis, and A1AT deficiency—can also affect newborns, leading to potentially life-threatening complications,

Other serious causes in newborns include:

• Biliary atresia (blocked bile ducts)
• Alagille syndrome (a genetic condition affecting bile flow)
• Rh factor hemolytic disease (a blood type mismatch between the pregnant person and the fetus)
• Familial cholestasis (a genetic condition in which bile builds up in liver cells)

Justin Paget / Getty Images

What Is Breastfeeding Jaundice?

Another relatively benign cause of jaundice is "breastfeeding jaundice," a casual term for suboptimal intake jaundice. This usually occurs in the second week of life when a newborn is not getting enough nutrition.

Inadequate feeding delays the passage of the baby's first poop (called the meconium ), which contains large amounts of bilirubin. Breast milk is also thought to contain substances that can impair the conjugation of bilirubin in the liver.

Increased breastfeeding or supplementation with bottled formula will almost invariably help resolve the condition.

Jaundice Symptoms

Jaundice is characterized by the yellowing of the skin and sclera (white of the eye) due to the buildup of bilirubin into tissues. Depending on the cause, the symptoms can be transient and barely noticeable or long-lasting and severe.

Jaundice symptoms can also differ in newborns.

Reproduced with permission from ©DermNet and ©Te Whatu Ora dermnetnz.org 2023.

Common Symptoms

On its own, jaundice does not cause anything other than yellowish discoloration. In many cases, it is the first sign of a disease and, in some, the only sign.

Jaundice in adults and children is typically pathologic, meaning it is related to a disease. If other symptoms accompany jaundice, it is due to the underlying disease. These symptoms can vary by whether the condition is hepatic, posthepatic, or prehepatic.

Hepatic and posthepatic causes of jaundice often manifest with symptoms of hepatitis (liver inflammation), causing:

• Nausea and vomiting
• Upper-right abdominal pain and swelling
• Dark urine (caused by the buildup of bilirubin in your urine)
• Pale and greasy stool (caused by the lack of bile secretion)

Prehepatic jaundice caused by excessive hemolysis can lead to symptoms of hemolytic anemia , causing:

• Rapid heart rate
• Shortness of breath
• Low exercise tolerance
• Dizziness or light-headedness
• Enlarged liver or spleen
• Blood in urine

Symptoms in Newborns

Neonatal jaundice is most often physiological , meaning it is related to normal bodily functions. Symptoms tend to develop within two to three days of birth, starting at the face and moving downward to the chest, stomach, legs, and feet.

Depending on the severity, there may be other symptoms such as excessive sleepiness, fussiness, and poor feeding, Over time, though, the yellowing will usually dissipate as large amounts of bilirubin are excreted in the baby's stool and urine.

However, in some newborns, jaundice may be pathologic. This is typically the case when bilirubin levels are extremely high or when jaundice occurs immediately after birth or persists for weeks.

Persistent hyperbilirubinemia can lead to a potentially fatal condition called kernicterus , in which bilirubin invades the brain, causing brain dysfunction known as encephalopathy . If not treated immediately, kernicterus can lead to seizures, brain damage, and complications such as:

• Involuntary eye movements ( nystagmus )
• Uncontrollable twitches and spasms ( myoclonus )
• Permanent hearing loss
• Learning disabilities
• Cerebral palsy (a neurological condition due to brain damage)

How Long Does Jaundice Last?

The duration of jaundice varies based largely on whether the underlying condition is acute (sudden and severe) or chronic (persistent or long-lasting). Generally speaking, the discoloration will fade once the underlying cause is resolved—whether it be an acute infection, biliary obstruction, or toxic drug reaction.

Jaundice has a typical course with some diseases (like acute viral hepatitis , which usually peaks in two weeks and starts to fade over two to three weeks). With other diseases, such as liver cancer, jaundice will only clear after a liver transplant .

With neonatal jaundice, the timeline is more consistent. In formula-fed babies, jaundice typically clears within two weeks. In breastfed babies, jaundice may last two to three weeks, sometimes longer.

How Jaundice Is Diagnosed

While jaundice is usually self-evident, a physical exam and lab tests are needed to help narrow the possible causes.

As part of the evaluation, the healthcare provider will perform a urinalysis to check for bilirubin in your urine and liver function tests (LFTs) to measure levels of bilirubin and another byproduct called urobilinogen in your blood.

LFTs also measure liver enzymes called alkaline phosphatase (ALP) , alanine transferase (ALT) , and aspartate transferase (AST), which tend to rise with liver or biliary disease.

These results, paired with the color of your urine and stool, can help determine if the cause is prehepatic, hepatic, or posthepatic.

Other tests and procedures may be ordered based on the initial findings, including imaging studies like ultrasound , computed tomography (CT) , or magnetic resonance imaging (MRI) to check for blockages. A liver biopsy may also be performed to obtain a sample of liver tissue for evaluation in the lab.

Neonatal jaundice is monitored with blood tests that measure bilirubin in milligrams per deciliter of blood (mg/dL). Bilirubin can also be measured with a noninvasive, handheld device called a transcutaneous bilirubinometer , though blood testing remains the gold standard.

With physiological jaundice, newborns typically have unconjugated bilirubin levels between 12 and 15 mg/dL for the first two weeks, gradually decreasing to 2 mg/dL over the next month and eventually settling to a normal adult level of 0.2 to 0.8 mg/dL.

On the other hand, jaundice is considered pathologic if:

• Total bilirubins are over 19.5 mg/dL.
• Total bilirubins increase by 5 mg/dL per day or 0.5 mg/dL per hour.
• Jaundice occurs within the first 24 hours of birth.
• Jaundice persists without letting up for more than two weeks.

Jaundice Treatment

Jaundice is treated by resolving the underlying condition. The treatment varies by the cause.

Treatment may be provided by different specialists, such as:

• Gastroenterologist (digestive system specialist)
• Hepatologist (liver specialist)
• Hematologist (blood disorder specialist)
• Oncologist (cancer specialist)
• Rheumatologist (autoimmune, inflammatory, and musculoskeletal disease specialist)
• Surgical team

If a bile duct is blocked, surgery or procedures like shock wave lithotripsy can help clear the obstruction. Surgery may also be needed for cancer of the liver, pancreas, gallbladder, or bile duct, along with chemotherapy and radiation .

When a chronic disease like cirrhosis or primary sclerosing cholangitis causes liver failure (meaning that the liver can no longer support the body's needs), the only option may be a liver transplant .

In all other cases, the treatment is largely medical.

While most cases of jaundice in newborns resolve on their own, those with total bilirubins over 21 mg/dL should receive specialized phototherapy (sometimes referred to as "bili lights").

Phototherapy involves exposure to a certain bandwidth of blue light (not ultraviolet light) that converts bilirubin in the skin into a water-soluble form that is more easily passed in urine. Home phototherapy machines allow home treatment outside of the hospital.

In severe cases, a procedure called an exchange transfusion can counteract the effects of kernicterus. Exchange transfusion is performed by slowly removing blood from the infant and replacing it with fresh donor blood or plasma. While potentially lifesaving, risks include blood clots, severe changes in blood chemistry, and shock .

How to Prevent Jaundice

Jaundice can't always be prevented, but there are certain measures you can take to avoid some of the underlying causes, including:

• Eat a healthy, balanced diet low in fat and high in vegetables, fruits, and whole grains. This can reduce your risk of MASLD, gallstones, and acute pancreatitis.
• Limit your alcohol intake to no more than two drinks per day for males and one day per drink per day for females. If you already have liver disease, alcohol may need to be avoided.
• Get vaccinated against hepatitis A and hepatitis B .
• Quit smoking . Smoking causes the constriction (narrowing) of blood vessels that can contribute to liver and biliary disease.
• Avoid the overuse of Tylenol (acetaminophen) , which is associated with a high risk of hepatotoxicity (liver poisoning). Never take Tylenol with alcohol.
• Avoid herbal remedies like kava, ephedra, skullcap, and pennyroyal, all of which have been linked to acute liver failure.
• To reduce the risk of breastfeeding jaundice, newborns should have eight to 12 feedings per day for the first several days of life. Formula-fed infants should have 1 to 2 ounces (30 to 60 milliliters) of formula every two to three hours for the first week.

Complications of Jaundice

Left untreated, the underlying causes of jaundice can turn serious and even life-threatening.

One of the key concerns is acute liver failure—also known as fulminant hepatic failure —which can sometimes develop rapidly in otherwise healthy individuals. This is especially true with severe drug-induced liver injury, in which a single event can cause irreparable damage requiring a liver transplant.

Autoimmune hepatitis and acute hepatitis A and B have also been known to cause acute liver failure.

Another concern is complications of hemolytic anemia, one of the most common causes of prehepatic jaundice. Severe cases have been known to cause life-threatening arrhythmia (irregular heartbeats), heart failure , and even death.

When to Contact a Healthcare Provider

No amount of jaundice is considered "normal." Call a healthcare provider immediately if you develop jaundice for any reason—even if it is mild and you have no other symptoms. Early intervention can help you avoid potentially serious complications.

Seek immediate emergency care if jaundice is accompanied by:

• Sudden, severe sleepiness
• A fruity breath
• Disorientation or confusion
• A swollen, fluid-filled belly ( ascites )

When to Call 911: Neonatal Jaundice

Call 911 or rush to the nearest emergency department if your baby has jaundice accompanied by signs of kernicterus, such as:

• A shrill, high-pitched cry
• Extreme drowsiness
• Poor feeding
• Head and limb loppiness, like a rag doll
• The lack of a startle reflex
• Gaps in breathing

Jaundice is the yellowing of the skin and eyes caused by the abnormal buildup of bilirubin. Bilirubin is a byproduct of the breakdown of red blood cells.

Jaundice can be prehepatic (related to the excessive breakdown of red blood cells), hepatic (related to the liver), or posthepatic (related to the impaired flow of bile from the liver). Neonatal jaundice in newborns is usually normal but can become life-threatening if bilirubin levels are persistently high.

Jaundice is diagnosed with blood tests and will usually clear once the underlying condition is resolved. Infants with very high bilirubin levels may benefit from phototherapy or an exchange transfusion.

MedlinePlus.  Jaundice .

Fargo MV, Grogan SP, Saguil A. Evaluation of jaundice in adults . Am Fam Physician. 2017;95(3):164-168.

National Institute of Health and Care Excellence. Jaundice in babies born under 28 days .

Markovic AP, Lalosevic MS, Mijac DD, et al. Jaundice as a diagnostic and therapeutic problem: a general practitioner’s approach . Dig Dis. 2020;40(3):362–369. doi:10.1159/000517301

Thiagarajan P, Parker CJ, Prchal JT. How do red blood cells die? Front Physiol. 2021;12:655393. doi:10.3389/fphys.2021.655393

Gondal B, Aronsohn A. A systematic approach to patients with jaundice . Semin Intervent Radiol. 2016;33(4):253–258. doi:10.1055/s-0036-1592331

Boyer JL, Soroka CJ. Bile formation and secretion: an update . J Hepatol. 2021;75(1):190-201. doi:10.1016/j.jhep.2021.02.011

Eghbalian F, Hasanpour-Dehkordi A, Raeisi R.  The effects of clofibrate on neonatal jaundice: a systematic review .  Int J Prev Med . 2022;13(3). doi:10.4103/ijpvm.IJPVM_407_20

Ullah S, Rahman K, Hedayat M. Hyperbilirubinemia in neonates: types, causes, clinical examinations, preventive measures and treatments: a narrative review article . Iran J Public Health. 2016;45(5):558–568.

Centers for Disease Control and Prevention. Breastfeeding: jaundice .

American College of Surgeons Division of Education. Jaundice .

Mitra S, Rennie J.  Neonatal jaundice: aetiology, diagnosis, and treatment .  Br J Hosp Med (Lond) . 2017;78(12):699-704. doi:10.12968/hmed.2017.78.12.699

National Institute of Diabetes and Digestive and Kidney Diseases.  Hepatitis A .

Pan JJ, Fontana RJ.  CAQ corner: acute liver failure management and liver transplantation .  Liver Transpl.  2022;28(10):1664–1673. doi:10.1002/lt.26503

March of Dimes. Newborn jaundice .

Kemper AR, Newman TB, Slaughter JL. Clinical practice guideline revision: management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation . Pediatrics. 2022;150(3):e2022058859. doi:10.1542/peds.2022-058859

Wang L, Yu WF. Obstructive jaundice and perioperative management .  Acta Anaesthesiologica Taiwanica . 2014;52(1):22–29. doi:10.1016/j.aat.2014.03.002

Tariq NUA, McNamara MG, Valle JW. Biliary tract cancers: current knowledge, clinical candidates and future challenges . Cancer Manag Res. 2019;11:2623–2642. doi:10.2147/CMAR.S157092

American Liver Foundation.  Liver transplantation .

Storck LJ, Imoberdorf B, Ballmer PE. Nutrition in gastrointestinal disease: liver, pancreatic, and inflammatory bowel disease . J Clin Med. 2019;8(8):1098. doi:10.3390/jcm8081098

National Institute on Alcohol Abuse and Alcoholism. Drinking levels defined .

National Cancer Institute. New insights into why smoking causes fatty liver disease .

National Institute of Diabetes and Digestive and Kidney Diseases.  Clinical and research information on drug-induced liver injury: acetaminophen .

National Institute of Diabetes and Digestive and Kidney Diseases. Herbal and dietary supplements .

Wendon J, Cordoba J, Dhawan A, et al.  EASL clinical practical guidelines on the management of acute (fulminant) liver failure .  J Hepatol . 2017;66(5):1047-1081. doi:10.1016/j.jhep.2016.12.003

National Heart, Lung and Blood Institute.  Hemolytic anemia .

By James Myhre & Dennis Sifris, MD Dr. Sifris is an HIV specialist and Medical Director of LifeSense Disease Management. Myhre is a journalist and HIV educator.

An official website of the United States government

The .gov means it’s official. Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

• Publications
• Account settings

Preview improvements coming to the PMC website in October 2024. Learn More or Try it out now .

• Advanced Search
• Journal List
• Paediatr Child Health
• v.11(10); 2006 Dec

Case 2: Newborn with jaundice and “hyperglycemia”

A nine-day-old boy was admitted to the paediatric ward of a regional hospital after a maternal-newborn clinic appointment, where he was found to be jaundiced with a total serum bilirubin of 400 μmol/L. He had been followed by the public health nurse in the community for poor weight gain in his first week of life. His weight on the day of admission was 2.52 kg, while his birth weight had been 2.81 kg.

The pregnancy and family history were unremarkable, and the boy was born at term with an uncomplicated initial stay in the hospital. Breastfeeding had been established before discharge home on the second day of life and was supplemented with formula by bottle after an appointment on the fifth day at the maternal-newborn clinic, where the boy was found to have lost over 10% of his birth weight. His parents reported that he was becoming less and less interested in eating, and by the day of admission, they needed to wake him for most feeds.

On admission, he was jaundiced and moderately dehydrated but otherwise had a normal physical examination. Other than the hyperbilirubinemia, the remainder of the initial blood work was unremarkable. The direct antiglobulin test was negative. The baby was started on double phototherapy and intravenous rehydration, and within 6 h, he had a repeat total bilirubin of 309 μmol/L, with a direct bilirubin of 34 μmol/L. A glucose meter check also performed at the time showed a reading of 26 mmol/L. A serum sample sent to the laboratory showed the glucose to be 2 mmol/L. Repeat glucose meter checks performed overnight were all greater than 20 mmol/L, while laboratory samples were in the low to normal range. After approximately 24 h of phototherapy, the total bilirubin was 250 μmol/L, with a direct bilirubin of 39 μmol/L. The baby developed a bronzed colour (direct hyperbilirubinemia), and liver function tests showed an alkaline phosphatase of 685 U/L, alanine aminotransferase of 83 U/L and aspartate aminotransferase of 155 U/L. A urine test result was able to quickly point to the likely diagnosis.

CASE 2 DIAGNOSIS: GALACTOSEMIA (GALACTOSE-1-PHOSPHATE URIDYL TRANSFERASE DEFICIENCY)

The urine was strongly positive for reducing substances and negative for glucose. Other studies performed as part of the evaluation of the direct hyperbilirubinemia included abdominal ultrasound (to assess liver and biliary anatomy); alpha-1-antitrypsin level; urine for viral culture; thyroid function; metabolic screen; and hepatitis viral serology. A confirmatory red blood cell study of galactose-1-phosphate uridyl transferase (GALT) activity showed markedly reduced quantity. The baby was started on a lactose-free soy formula two days after admission, resulting in a marked improvement in feeding, growth and liver function tests.

The differential diagnosis for a newborn with a direct hyperbilirubinemia (conjugated bilirubin greater than 30 μmol/L or greater than 15% of total bilirubin) is broad. Etiologies can be divided into three general categories ( 1 ): obstruction to biliary flow, hepatic cell injury and chronic bilirubin overload. Obstruction to biliary flow can be secondary to anatomic abnormalities (eg, extrahepatic biliary atresia) or from the production of viscous bile (eg, cystic fibrosis). Hepatic injury can be from numerous sources, such as congenital infections, parenteral nutrition or inborn metabolic errors (eg, galactosemia). Chronic bilirubin overload is less commonly a cause of direct hyperbilirubinemia in the newborn period but can be seen with hemolytic anemias, such as glucose-6-phosphate dehydrogenase (G6PD) deficiency or hereditary spherocytosis.

Initial investigations should confirm a cholestatic picture, establish liver function and detect readily treatable disorders. Secondary investigations should identify a specific diagnosis among the more common etiologies. Preliminary investigations include total and direct bilirubin levels, blood and urine cultures, direct antiglobulin test, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl transferase, serum glucose, albumin, ammonia, coagulation studies and a complete blood count with differential. To further delineate a diagnosis, more specific testing can be done, such as an abdominal ultrasound, alpha-1-antitrypsin, congenital infection screen, metabolic screen (blood gas, serum amino acids and urine organic acids), sweat chloride, urine for reducing substances (see below), thyroid studies or other tests as indicated.

Galactosemia is an autosomal recessive disorder in which galactose is not properly metabolized. Dietary lactose is broken down by lactase into glucose and galactose and then, in a three-step process, galactose is converted to glucose. This metabolic pathway is particularly important for the newborn, whose main carbohydrate source is lactose. Classic galactosemia, by far the most common variant, involves a deficiency of GALT. This results in a buildup of galactose-1-phosphate and other precursors, causing damage to many organs, including the liver, spleen, kidney, ocular lens, cardiac muscle, brain, gonadal tissue and erythrocytes. The earlier the disorder is diagnosed and a galactose-free diet is implemented, the less damage will ensue. Even with optimal dietary treatment, developmental delays and learning disabilities are common, and affected women almost invariably suffer premature ovarian failure ( 2 ).

Galactosemia has an incidence of approximately one in 60,000 in North America ( 3 ). Several countries have universal newborn screening for galactosemia, but the practice is not widespread. In Canada, only a minority of provinces have a newborn galactosemia screening program in place. More common symptoms and signs suggestive of galactosemia are as follows ( 4 ):

• poor feeding or weight gain
• hepatomegaly
• encephalopathy
• full fontanel
• bleeding or easy bruising

There are also several reports of galactosemic infants presenting with Escherichia coli sepsis ( 5 ).

The presence of urinary reducing substances in the absence of glucosuria (as detected by a routine dipstick test) supports the diagnosis of galactosemia. False-positive and false-negative results are not uncommon. Urinary reducing substances will not be present if the infant is not receiving any dietary galactose (ie, infants already switched to a soy-based formula). The Beutler enzyme spot test is not widely available outside of academic centres but is a more sensitive, rapid test for galactosemia due to GALT deficiency. A recent blood transfusion can cause a false-negative result, while G6PD deficiency results in false-positive results. The confirmatory test (red blood cell quantitative GALT assay) may take some time, but in the interim, a galactose-free diet should be instituted. Finally, red blood cell galactose-1-phosphate concentrations are elevated in all causes of galactosemia regardless of the specific enzyme defect, but the test is not widely available.

In the above case, the discordant glucose meter and serum sample glucose concentrations also provided an important clue to the diagnosis. The need to confirm glucose meter checks with serum samples should be emphasized. Some glucose meters will overestimate the serum glucose in the setting of hypergalactosemia due to the lack of specificity of the enzyme used by the assay ( 6 ). As well, untreated galactosemic infants like the one described above may be hypoglycemic because a major source of their dietary glucose is, in effect, not available.

CLINICAL PEARLS

• Conjugated hyperbilirubinemia in the newborn is always pathological and requires a systematic approach to diagnosis. Common and treatable conditions should be ruled out promptly.
• Galactosemia is a relatively rare disorder, but early recognition is key to improving outcome.
• If galactosemia is suspected, a galactose-free diet should be initiated pending confirmatory test results.
• Those caring for newborns need to be aware that some commercially available glucose meters will overestimate serum glucose levels in the setting of galactosemia.

ACKNOWLEDGEMENT

Special thanks for the assistance of Dr Joseph Madden, Paediatrician, North Bay General Hospital.

• Open access
• Published: 12 June 2024

Risk factors for neonatal hypoxic ischemic encephalopathy and therapeutic hypothermia: a matched case-control study

• Suoma Roto 1 ,
• Irmeli Nupponen 2 ,
• Ilkka Kalliala 1 &
• Marja Kaijomaa   ORCID: orcid.org/0000-0003-2180-1483 1  

BMC Pregnancy and Childbirth volume  24 , Article number:  421 ( 2024 ) Cite this article

144 Accesses

2 Altmetric

Metrics details

Peripartum asphyxia is one of the main causes of neonatal morbidity and mortality. In moderate and severe cases of asphyxia, a condition called hypoxic-ischemic encephalopathy (HIE) and associated permanent neurological morbidities may follow. Due to the multifactorial etiology of asphyxia, it may be difficult prevent, but in term neonates, therapeutic cooling can be used to prevent or reduce permanent brain damage. The aim of this study was to assess the significance of different antenatal and delivery related risk factors for moderate and severe HIE and the need for therapeutic hypothermia.

We conducted a retrospective matched case-control study in Helsinki University area hospitals during 2013–2017. Newborn singletons with moderate or severe HIE and the need for therapeutic hypothermia were included. They were identified from the hospital database using ICD-codes P91.00, P91.01 and P91.02. For every newborn with the need for therapeutic hypothermia the consecutive term singleton newborn matched by gender, fetal presentation, delivery hospital, and the mode of delivery was selected as a control. Odds ratios (OR) between obstetric and delivery risk factors and the development of HIE were calculated.

Eighty-eight cases with matched controls met the inclusion criteria during the study period. Maternal and infant characteristics among cases and controls were similar, but smoking was more common among cases (aOR 1.46, CI 1.14–1.64, p  = 0.003). The incidence of preeclampsia, diabetes and intrauterine growth restriction in groups was equal. Induction of labour (aOR 3.08, CI 1.18–8.05, p  = 0.02) and obstetric emergencies (aOR 3.51, CI 1.28–9.60, p  = 0.015) were more common in the case group. No difference was detected in the duration of the second stage of labour or the delivery analgesia.

Conclusions

Smoking, induction of labour and any obstetric emergency, especially shoulder dystocia, increase the risk for HIE and need for therapeutic hypothermia. The decisions upon induction of labour need to be carefully weighed, since maternal smoking and obstetric emergencies can hardly be controlled by the clinician.

Peer Review reports

Peripartum asphyxia, generally referred to as birth asphyxia, is one of the main causes of neonatal mortality worldwide [ 1 ]. Approximately three to five newborns per 1000 live births in developed countries are affected by birth asphyxia [ 2 ]. This condition of hypoxia and acidemia can develop gradually during pregnancy and lead to an emergency cesarean section when detected. It can also develop abruptly when complications during labour occur [ 3 ].

The pathophysiology of birth asphyxia and its multifactorial antecedents are well studied and recognized: An increased risk is associated with maternal health problems such as diabetes mellitus, cholestasis of pregnancy, anemia, and hypertension, as well as fetal conditions like intrauterine growth restriction and infections [ 4 , 5 ]. Extensive effort is made to screen and follow-up these mothers and pregnancies with known obstetric risk factors for development of birth asphyxia.

The clinical signs associated with birth asphyxia may be transient and reversible or lead to permanent neurological impairment or death [ 6 ]. A condition called hypoxic-ischemic encephalopathy may follow and, if diagnosed, can further be divided in mild, moderate, and severe [ 7 ]. A quick recovery, normal level of consciousness, mild neurological signs and absence of seizures are typical to a mild HIE, whereas moderate and severe HIE include presence of seizures, multiorgan failure, primitive reflexes and altered level of consciousness and tone [ 7 ]. The diagnosis of severe birth asphyxia is set when the neonate presents with a five-minute Apgar score of 0 to 3 and a pH of 7.0 or less in the umbilical artery blood sample [ 4 ].

In the severe cases of birth asphyxia, HIE predisposes the resuscitated neonate to permanent neurologic morbidities such as cerebral palsy, epilepsy, and developmental delays. The medical intervention to reduce brain damage in term neonates with moderate and severe HIE is therapeutic hypothermia, i.e., cooling of the neonates to around 33 °C for three days [ 8 ].

Despite the high-quality maternal care and the recognition of antenatal risks, birth asphyxia and HIE remain a challenge in perinatal care. Due to the multifactorial nature of fetal distress [ 9 , 10 ], the adverse outcome is not always predictable in risk pregnancies. In addition, many cases of HIE occur unanticipated in low-risk pregnancies.

The aim of this study was to assess the importance of different obstetric risk factors associated with moderate and severe HIE and the need for therapeutic hypothermia in term neonates delivered at the hospitals of Helsinki University Hospital area. We particularly focused on the management protocols of pregnancy and delivery.

This was a retrospective, matched case-control study concerning pregnancies and deliveries in the Helsinki University Hospital area. The same guidelines for follow-up and treatment of pregnancy and delivery are used in all Helsinki University area hospitals. The neonatal intensive care is centralized at the Neonatal Intensive Care Unit (NICU) in Helsinki University Hospital Women’s Clinic. The study period was from January 1, 2013, to December 31, 2017. The treatment of deliveries in the Helsinki University Hospital area was re-organized after a closure of one delivery hospital in late 2017 and the patient record systems was changed in early 2020. Due to the possible bias caused by these factors, years after 2017 were excluded from the study.

The study group consisted of patients who gave birth to asphyxiated singleton neonates with aforementioned symptoms of moderate or severe HIE. Each neonate was born term (one case of 36 6/7 gestation weeks), was admitted to the NICU and offered therapeutic hypothermia for neuroprotection. The indications for hypothermia were admitted from the international guidelines and previous research [ 2 ].

After each delivery with an asphyxiated newborn, the consecutive term singleton, matched by the delivery hospital, fetal gender, presentation (occipital vs. breech), and the mode of delivery (vaginal, assisted vaginal, elective, emergency, and crash cesarean delivery), was selected as a control. An emergency cesarean was defined as a decision-to-delivery-interval of 30 min and a crash cesarean as an immediate delivery after the decision to deliver. Subgroups were formed based on the mode and onset (spontaneous vaginal delivery, induced vaginal delivery, failed induction and cesarean, cesarean) of delivery.

The data for the study was collected from the hospital database (Siemens Obstetrix). All available information concerning fetal and maternal well-being during pregnancy and delivery was collected. This included maternal age and health (pregestational body mass index (BMI), chronic illnesses, medication), gestation at delivery, parity and previous births, and information concerning hospital visits during the ongoing pregnancy. Data on the time of hospital admission and the time of birth in relation to midwife work shifts was also obtained. We considered and tested multiple previously suggested risk factors for HIE or birth asphyxia [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 ] and analyzed their possible interactions.

Statistics/analyses

SPSS version 25.0.0 (IBM SPSS Statistics, Armonk, New York) was used to analyze the data. Independent samples t-test and Chi-square test were used for comparing continuous and categorical variables within subgroups, and for testing the independence of variables. Interactions between variables were further assessed with a stratified analysis. ( S10 )

Crude and adjusted odds ratios (OR and aOR respectively) were calculated using logistic regression to estimate associations between different independent variables and the outcome. From the univariate logistic regression, variables with a p  < 0.1 were exported to the multivariable logistic regression analysis. A forward stepwise logistic regression analysis was used to suggest multivariable models. Statistical significance was declared at p  < 0.05 and the CIs were set to 95%. Due to the novel study design and small sample sizes, we saw fit to try out and present two different approaches to the multivariate logistic regression analysis.

We used Benjamini-Hochberg corrected p -values (q-values) in the univariate logistic regression to account for multiple testing [ 25 ]. Missing values of > 5% per category were imputed using the fully conditional specification method and with maximum iterations of 10.

During the study period, 98 355 deliveries took place in Helsinki University area hospitals, the average being 19 671 per year. One hundred and twelve term neonates (including one case of 36 + 6 gestational weeks) presented with moderate to severe HIE and were admitted to the NICU to receive therapeutic hypothermia. The study period incidence of therapeutic hypothermia for signs of moderate to severe HIE in our obstetric population was 1.0/1000.

After excluding twin pregnancies, ninety-seven singleton pregnancies with neonatal HIE and therapeutic hypothermia made up the primary study group. Due to the failure to find matched controls, nine more pregnancies were excluded, leaving us with the final study group of eighty-eight cases.

Altogether, 45.5% of the neonates (40/88) in the study group were born vaginally and 65% (26/40) of them were ventouse-assisted. Two neonates were vaginally born in breech position. Cesarean deliveries constituted 54.5% (48/88) of study group deliveries, including elective, emergency, and crash procedures with the proportion of 2.0% (1/48), 29.2% (14/48), and 68.8% (33/48) respectively. Four emergency cesarean sections were preceded by a failed instrumental delivery. Due to the matching by delivery mode, the proportions were equal in the control group (Fig.  1 : The mode of delivery among cases of HIE and therapeutic hypothermia). The mortality in the study group was 10.2% (9/88). There were no neonatal deaths in the control group.

The mode of delivery (%) among cases of hypoxic ischemic encephalopathy and therapeutic hypothermia

Approximately the same proportion of patients in the groups were nulliparous (62.5% vs. 59.1%, p  = 0.576), and no difference was observed in mean maternal age (31.99 vs. 32.96, p  = 0.239) and BMI (24.20 vs. 23.96, p  = 0.467). The mean number of daily cigarettes (1.9 vs. 0.4) was higher ( p  = 0.001) in the study group. No difference was detected in the mean gestational age at delivery (38.89 vs. 40.21 gestational weeks, p  = 0.160) and newborn weight (3458.61 vs. 3472.33 g, p  = 0.898). Post term pregnancy was more common (3.41% vs. 13.64%, p  = 0.024) in the control group (Table  1 ).

There was no difference in the incidence of the most common antenatal complications, such as hypertension or preeclampsia (10.23% vs. 12.50%, p  = 0.797), intrauterine growth restriction (5.68% vs. 7.95%, p  = 0.552), gestational (13.64% vs. 15.91, p  = 0.671) diabetes, type I diabetes (4.55% vs. 3.41%, p  = 0.701) or suspected chorionamniotis (7.95% vs. 6.82%, p  = 0.773). There were no cases of diabetes type II in the study group (0% vs. 2.27%, p  = 0.497) and cholestasis of pregnancy in the control group (3.41% vs. 0%, p  = 0.246) (Table  2 ).

We detected a higher incidence of labour induction in the study group (21.59% vs. 9.09%, p  = 0.025), but no difference was detected in the incidence of cesarean after a failed induction (4.55% vs. 11.36%, p  = 0.106) or the phase II duration of delivery (35.44 min vs. 46.38 min, p  = 0.098). The overall incidence of any obstetric emergency, i.e., shoulder dystocia, placental abruption, or uterine rupture, was higher ( p  = 0.038) in the study group (20.45% vs. 10.23%), driven by a markedly higher incidence of shoulder dystocia (6.82% vs. 0%, p  = 0.029).

There was no difference in the use of epidural (56.82% vs. 68.18%, p  = 0.121), spinal (31.82% vs. 29.55%, p  = 0.744) or oral opioid (20.45% vs. 23.86%, p  = 0.586) anesthesia of deliveries, whereas the use of oxytocin augmentation (27.27% vs. 57,95%, p  < 0.001) and nitrous oxide (38.64% vs. 53.41%, p  = 0.050) was more common in the control group.

Midwife shift change during the active phase of delivery (45.45% vs. 60.23%, p  = 0.051) was somewhat more frequent in the control group and the incidence of delivery during the night shift insignificantly more common in the study group (48.86% vs. 37.50%, p  = 0.070) (Table  2 ).

The univariate analysis showed that nine independent variables were associated ( p  < 0.1) with either the presence or absence of moderate to severe HIE: Smoking, post term pregnancy, induction of delivery, duration of phase II, any obstetric emergency, augmentation of delivery by oxytocin (all stages of labour, including induction), use of nitrous oxide, shift change of midwives during active delivery, and delivery during night shift (10 pm. to 8 am.).

In the multivariate regression model with four to eight variables in the same model, obstetric emergencies, labour induction and smoking significantly increased the odds of HIE (Table  3 , Supporting information Tables S1 - S9 ). We were able to repeat these results in most of the tried models. Induction of labour had a significant association with HIE ( p  = 0.02) in all tried models, but there was no significant association with HIE and the subgroups of induction methods (balloon catheter, vaginal misoprostol, amniotomy followed by oxytocin-infusion), when entered separately to the regression analysis. In fact, in just 33% of cases only one induction method was used.

In the stratified analysis, the association of induction of labour with HIE was even stronger when oxytocin augmentation was used, OR 9.2 (2.71–31.21). Also, the midwife shift change in induced labours resulted in higher OR for HIE (4.5, 1.73–12.20) (Supporting information, Table S10 ). When adjusted with other variables in logistic regression, the significant association of oxytocin use and HIE was still strong, while shift change, duration of the second phase of delivery, and delivery during night shift lost their statistical significance (Table  3 ).

To reveal any common features in different modes of delivery, results were further analyzed in four subgroups: spontaneous and assisted vaginal delivery, and emergency and crash cesarean (Supporting information, Table S11 ). Mothers without preceding active labour or medical intervention, were omitted from the crash cesarean subgroup.

We also made efforts to deeper analyze the cases of shoulder dystocia and induced labours.

There were six cases of shoulder dystocia in the study group, but none in the control group, which made the regression analysis inapplicable for this specific variable. However, the analyses of all obstetric emergencies (placental abruption, uterine rupture, shoulder dystocia) as a surrogate variable showed a statistically significant association with obstetric emergencies and HIE. The increase in odds of HIE with placental abruption and uterine rupture was insignificant or nonexistent. Aforementioned obstetric emergencies altogether presented an OR of 2.57 and aOR of 3.51 ( p  < 0.05) (Table  3 ). Other obstetric emergencies, such as cord prolapse and eclampsia, were not present in our data. The analysis of induced labours showed that even though newborns in the study group were heavier (3790 g vs. 3314 g, p  = 0.030), they were more often born vaginally (84.2% vs. 37.5%, p  = 0.027) (Supporting information, Table S12 ).

When analyzed by the mode of delivery, induction was more common in the study group in vaginal (OR 2.75, 95% 1.13–6.68, p  = 0.016) and assisted (ventouse) vaginal deliveries ( p  = 0.017) (Supporting information, Table S11 ). The midwife shift change was more common in the control groups of the emergency ( p  = 0.008) and crash ( p  = 0.044) caesarean sections and smoking was more common ( p  = 0.039) in the study group of the crash cesarean subgroup. Five of the six study group cases with shoulder dystocia occurred in the ventouse delivery subgroup ( p  = 0.051) (Supporting information Table S11 ).

In this study, maternal smoking, induction of labour and obstetric emergencies appeared to be independent risk factors for HIE. There was a clear dose-dependent association with maternal smoking and HIE. This finding prevailed in the multivariate analysis, although the increase in odds remained quite small. There were more induced labours in the study group and the association with labour induction was most pronounced in the subgroup that received oxytocin, accounting for the use during and after induction. Also shoulder dystocia, a poorly predictable obstetric emergency, increased the risk for HIE. Other previously stated antecedents, e.g., nulliparity, gestational age, maternal weight [ 22 ], prematurity [ 15 ] and chorionamnionitis [ 6 ] appeared mostly not to associate with HIE in this study. Furthermore, post term pregnancy, nitrous oxide, and the use of oxytocin as an independent variable had a seemingly opposite association with HIE.

Smoking is known to be a major risk factor for birth asphyxia and HIE. It is strongly associated with antecedents for asphyxia, i.e., fetal growth restriction [ 26 ] and the risk of placental abruption [ 6 , 27 , 28 ]. Smoking increases oxidative stress and reduces endogenous defenses in the fetus, which may play a role in the pathogenesis [ 29 ]. Even though the harmful effect of smoking is quite indisputable, some bias in the results has to be recognized. The proportion of missing data was substantial, and the imputed data may have skewed the results towards HIE. Also, the frequency, cessation and continuity of smoking was self-reported and susceptible to social desirability bias. It may be, however, safe to assume that the effect of smoking is at least what is presented by the unimputed data (OR 1.21, 95% CI 0.99–1.46, p  = 0.06).

The association between labour induction and HIE requires careful analysis. Significant multicollinearity between induction of labour and other supposed risk factors (obstetric emergency, oxytocin augmentation, shift change, nitrous oxide, and gestational diabetes) was noticed (Supporting information, Table S13 ). The induced labours in the study group ended more frequently in vaginal delivery than in the control group. There were no differences in the indications of labour induction. When these factors are weighed in, the independence of induction of labour as a risk factor for HIE can be considered a complex issue.

The role of induction is, however, worth serious consideration, since these pregnancies may include mothers or fetuses with multiple risk factors. In Finland the rate of induced labours has increased from 17.5% in 2007 to 33.9% in 2021 [ 30 ]. In addition, the proportion of elective inductions without a medical indication are also increasing [ 31 ]. In this study, the risk for HIE was most pronounced among patients with induction of labour together with the use of oxytocin during labour. The oxytocin associated increase in the incidence of encephalopathy was also described in the recent review and meta-analysis by Burgod et al. [ 32 ]. It is also worth noticing that even though newborns in the study group of induced labours were heavier, they were more often born vaginally and the number of ventouse deliveries was twice the proportion in the control group. Compared to zero cases in the study group, in approximately one third of control group cases, a crash cesarean followed a failed ventouse delivery. It can be speculated whether some anchoring bias in decision making is involved and the higher proportions of ventouse and vaginal deliveries in the study group and crash cesareans following ventouse trials in the control group reflect the clinicians’ decisions that are associated with the outcome of the newborn. The number of cases is however too small to draw conclusions.

Shoulder dystocia is an obstetric emergency, that results in prolongation of head-to-body delivery, traction of the brachial plexus, and possible birth trauma [ 33 , 34 ]. The shoulder dystocia incidence reported in studies is approximately 0.7% [ 35 ]. Fetal macrosomia is known to increase the risk of shoulder dystocia more than tenfold [ 35 ] and in these situations, a planned delivery at early term has been demonstrated to reduce the risk of shoulder dystocia [ 34 ]. In this study, six cases of shoulder dystocia were detected in the study group (6.8%) compared to none in the control group. This made the regression analysis inapplicable for this variable. Even though the analysis of all obstetric emergencies (placental abruption, uterine rupture, shoulder dystocia) as a surrogate variable was associated with HIE, the association of HIE with placental abruption and uterine rupture alone was less clear.

As stated, the use of oxytocin in general (irrespective of induction) and nitrous oxide was significantly more common in the control group. However, as shown in the stratified analysis (supplementary information Table S10 ), in the subgroup of induced labours, oxytocin use was more common in the study group. As the need for induction of labour itself may indicate increased risks in the pregnancy, these variables together increase the risk for adverse outcome. In contrast, spontaneous deliveries with oxytocin augmentation were more frequent in the control group. We suggest that the seemingly protective association of oxytocin augmentation in relation to HIE in the regression models could be explained by the asymmetric distribution of these different subgroups. The same can be speculated for the negative association of the administration of nitrous oxide.

The higher incidence of post-term pregnancies in the control group also needs additional attention. It can be speculated that the need for interventions in control group pregnancies was lower and post term was reached more often. It is also of note, that there was significant collinearity between post term pregnancy and oxytocin administration, midwife shift change and delivery during night shift.

In our study population, 54.5% of patients had a cesarean section and the incidences of emergency and crash cesarean were 15.9% and 37.5%. This describes the underlying existence of ante- and intrapartum complications in the study cohort, since the overall incidences of cesarean sections in the Finnish population were 16.7%, 9.2% and 0.9%, respectively [ 30 ]. For example, the rates of pre-eclampsia and pregnancy-induced hypertension in the study were 10.2% and 12.5% compared to our national and worldwide incidences of 5% and 7% [ 36 ].

The purpose of this study was to find HIE risk factors that could be anticipated and avoided in the antenatal care and treatment of delivery. For some patients in the study group, the active labour surveillance, and early obstetric interventions, were never at hand. Our efforts in prevention of HIE should be targeted to patients, that during labour are under constant care and observation.

Compared to previous studies, the selection criteria for this study group were different. Although a similar approach with therapeutic hypothermia as surrogate outcome for severe birth asphyxia (and sequential HIE) has been used before [ 19 ], most case-control studies rest on a study group of neonates diagnosed with neonatal asphyxia, or with signs of birth asphyxia (low Apgar score and/or signs of acidemia in the peripartum blood samples) [ 16 , 18 , 20 , 21 , 24 , 27 , 37 ]. In this study, we chose to use the application of therapeutic hypothermia as the study group inclusion criteria, since it is a clearly defined clinical intervention and in our clinic the indications for use are standardized. The incidence of our inclusion criteria, therapeutic hypothermia (1.1/1000), is slightly higher than the incidence of moderate and severe HIE (0.67/1000) in the study by Liljeström et al. [ 22 ]. Although moderate and severe HIE are the main indications for therapeutic hypothermia, the direct comparison of these incidences should be done with caution. Since the exact severity of HIE may still be uncertain immediately after birth (which may have occurred in another hospital) and the decision concerning this undeniably beneficial treatment has to be made within six hours, the incidence of therapeutic hypothermia treatment may be somewhat higher than the exact incidence of diagnosed moderate and severe HIE.

The study setting could be considered a strength of this study. To the best of our knowledge, this was the first case-control study pairing the groups by the mode of delivery, sex, hospital, and fetal presentation at birth. This could partially explain the differences in our results compared to previous similar studies.

The limitations of this study were its retrospective nature and small sample sizes. It is also likely that the matched case control setting together with a small number of cases failed to show the risks associated with previously described risk factors like hypertension, diabetes, and intrauterine growth restriction. These limitations, as well as coincidence, may also explain the higher incidence of post term pregnancies in the control group. The multicollinearity of some studied risk factors also set limitations when interpreting the data.

There were also some restrictions regarding obtaining data. We didn’t have access to primary health care and antenatal outpatient data, and we relied on the history information of the maternity card and database information upon mothers’ admission to the hospital. Chronic illnesses, obstetric complications and infections were not always structurally recorded. Some information such as substance abuse may be underrepresented but unlikely affects our results.

Demographic risk factors, such as social and marital status, are not collected and had to be excluded. Some previously identified risk factors (urinary tract and viral infections) [ 17 , 23 , 38 , 39 ] had to be excluded because they are treated at the primary health care level.

After controlling for multiple testing, only two of the univariate logistic regression results (maternal smoking and use of oxytocin) remained statistically significant. When studying rare outcomes in limited sample size, one must be careful not to reject the null hypothesis too readily, while minding possibly important findings that fail to reach nominal statistical significance. We considered both these pitfalls and considered clinical applicability as best we could while interpreting these results, but conclusions based on the findings should still be done with caution.

According to our results, induction of labor may be an independent risk factor for HIE, and it should only be used in situations where it evidently improves the outcome of labour. Special vigilance is required from the obstetric team when deciding upon induction and when managing these patients during labour. The increased risk of HIE associated with smoking and obstetric emergencies is unfortunately mostly out of the clinician’s reach.

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Abbreviations

• Hypoxic-ischemic encephalopathy

Neonatal Intensive Care Unit

Lawn JE, Cousens S, Zupan J. 4 Million neonatal deaths: When? Where? Why? Vol. 365, Lancet.2005;365(9462):891–900.

Jacobs SE, Berg M, Hunt R, Tarnow-Mordi WO, Inder TE, Davis PG. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev. 2013;2013(1):CD003311.

PubMed   PubMed Central   Google Scholar  

Yli BM, Kjellmer I. Pathophysiology of foetal oxygenation and cell damage during labour. Best Pract Res Clin Obstet Gynaecol. 2016;30:9–21.

Article   PubMed   Google Scholar  

Igboanugo S, Chen A, Mielke JG. Maternal risk factors for birth asphyxia in low-resource communities. A systematic review of the literature. J Obstet Gynaecol. 2020;40(8):1039–55.

Rossi AC, Prefumo F. Antepartum and intrapartum risk factors for neonatal hypoxic-ischemic encephalopathy: a systematic review with meta-analysis. Curr Opin Obstet Gynecol. 2019;31(6):410–17.

Sarnat HB, Sarnat MS. Neonatal Encephalopathy following fetal distress: a clinical and electroencephalographic study. Arch Neurol. 1976;33(10):696–705.

Article   CAS   PubMed   Google Scholar  

Morales P, Bustamante D, Espina-Marchant P, Neira-Peña T, Gutiérrez-Hernández MA, Allende-Castro C et al. Pathophysiology of perinatal asphyxia: can we predict and improve individual outcomes? EPMA J;2(2). p. 211–30.

Shankaran S, Laptook AR, Ehrenkranz RA, Tyson JE, McDonald SA, Donovan EF, et al. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med. 2005;353(15):1574–84.

Westgate JA, Gunn AJ, Gunn TR. Antecedents of neonatal encephalopathy with fetal acidaemia at term. Br J Obstet Gynaecol. 1999;106(8):774–82.

Seikku L, Gissler M, Andersson S, Rahkonen P, Stefanovic V, Tikkanen M, et al. Asphyxia, neurologic morbidity, and perinatal mortality in early- term and postterm birth. Pediatrics. 2016;137(6):e20153334.

Locatelli A, Incerti M, Paterlini G, Doria V, Consonni S, Provero C, et al. Antepartum and intrapartum risk factors for neonatal encephalopathy at term. Am J Perinatol. 2010;27(8):649–54.

Torres-Muñoz J, Rojas C, Mendoza-Urbano D, Marín-Cuero D, Orobio S, Echandía C. Risk factors associated with the development of perinatal asphyxia in neonates at the Hospital Universitario del Valle, Cali, Colombia, 2010–2011. Biomedica. 2017 1;37(0):51–6.

Lundgren C, Brudin L, Wanby AS, Blomberg M. Ante- and intrapartum risk factors for neonatal hypoxic ischemic encephalopathy. J Matern Fetal Neonatal Med. 2018;18(12):1595–601.

Article   Google Scholar  

Itoo BA, Al-Hawsawi ZM, Khan AH. Hypoxic ischemic encephalopathy. Incidence and risk factors in North Western Saudi Arabia. Neurosciences. 2003;8(2):113–9.

PubMed   Google Scholar  

Ayuk Widiani NN, Yuli Kurniati DP, Trisna Windiani IGA. Maternal and infant risk factors on the incidence of neonatal asphyxia in Bali: Case Control Study. Public Health Prev Med Arch. 2016;4(2):120–6.

Hall DR, Smith M, Smith J. Maternal factors contributing to asphyxia neonatorum. J Trop Pediatr. 1996;42(4):192–5.

Badawi N, Kurinczuk JJ, Keogh JM, Alessandri LM, O’Sullivan F, Burton PR, et al. Intrapartum risk factors for newborn encephalopathy: the western Australian case-control study. Br Med J. 1998;317(7172):1549–53.

Article   CAS   Google Scholar  

Blume HK, Loch CM, Li CI. Neonatal encephalopathy and socioeconomic status: Population-based case-control study. Arch Pediatr Adolesc Med. 2007;161(7):663–8.

Nelson DB, Lucke AM, Mcintire DD, Sánchez PJ, Leveno KJ, Chalak LF. Obstetric antecedents to body cooling treatment of the Newborn Infant. Am J Obs Gynecol. 2014;211(2):155–6.

Nayeri F, Shariat M, Dalili H, Bani Adam L, Zareh Mehrjerdi F, Shakeri A. Perinatal risk factors for neonatal asphyxia in Vali-e-Asr hospital, Tehran-Iran. Iran J Reprod Med. 2012;10(2):137–40.

Heinonen S, Saarikoski S. Reproductive risk factors of fetal asphyxia at delivery: a population based analysis. J Clin Epidemiol. 2001;54(4):407–10.

Liljestrom L, Wikstrom AK, Agren J, Jonsson M. Antepartum risk factors for moderate to severe neonatal hypoxic ischemic encephalopathy: a Swedish national cohort study. Acta Obstet Gynecol Scand. 2018;97(5):615–23.

Martinez-Biarge M, Madero R, Gonzlez A, Quero J, Garca-Alix A. Perinatal morbidity and risk of hypoxic-ischemic encephalopathy associated with intrapartum sentinel events. Am J Obstet Gynecol. 2012;206(2):148.e1-148.e7.

Ellis M, Manandhar N, Manandhar DS, De L, Costello AM. Risk factors for neonatal encephalopathy in Kathmandu, Nepal, a developing country: unmatched case-control study. Br Med J. 2000;320(7244):1229–36.

Benjamini Y, Hochberg Y. Controlling the false Discovery rate: a practical and powerful Approach to multiple testing. J R Stat Soc Ser B. 1995;57(1):289–300.

Abraham M, Alramadhan S, Iniguez C, Duijts L, Jaddoe VWV, Den Dekker HT, et al. A systematic review of maternal smoking during pregnancy and fetal measurements with meta-analysis. PLoS ONE Public Libr Sci. 2017;12(2):e0170946.

Tikkanen M, Surcel HM, Bloigu A, Nuutila M, Ylikorkala O, Hiilesmaa V, et al. Self-reported smoking habits and serum cotinine levels in women with placental abruption. Acta Obstet Gynecol Scand. 2010;89(12):1538–44.

Downes KL, Shenassa ED, Grantz KL. Neonatal outcomes Associated with placental abruption. Am J Epidemiol. 2017;186(12):1319–28.

Article   PubMed   PubMed Central   Google Scholar  

Gitto E, Reiter RJ, Karbownik M, Tan D-x, Gitto P, Berberi S, et al. Causes of oxidative stress in the pre- and Perinatal Period. Neonatology. 2002;81(3):146–57.

Perinataalitilasto. – synnyttäjät, synnytykset ja vastasyntyneet - THL [Internet]. [cited 2020 Aug 6]. https://thl.fi/fi/tilastot-ja-data/tilastot-aiheittain/seksuaali-ja-lisaantymisterveys/synnyttajat-synnytykset-ja-vastasyntyneet/perinataalitilasto-synnyttajat-synnytykset-ja-vastasyntyneet .

Kruit H, Nuutila M, Rahkonen L. Lääkärilehti - Synnytyksen käynnistäminen, Kun raskaus on täysiaikainen. Lääkärilehti. 2016;71(25–32/2016):1845–51.

Google Scholar  

Burgod C, Pant S, Morales MM, Montaldo P, Ivain P, Elangovan R, et al. Effect of intra-partum oxytocin on neonatal encephalopathy: a systematic review and meta-analysis. BMC Pregnancy Childbirth. 2021;21(1):1–7.

Collins KA, Popek E. Birth Injury: Birth Asphyxia and Birth Trauma. Academic Forensic Pathology. Volume 8. SAGE Publications Inc.; 2018. pp. 788–864.

Farrar D, Simmonds M, Bryant M, Sheldon TA, Tuffnel D, Golder S, et al. Treatments for gestational diabetes: a systematic review and meta-analysis. BMJ Open. 2017;7(6):e015557.

Hartiadystokia. - Duodecim Oppiportti [Internet]. [cited 2020 Aug 18]. https://www-oppiportti-fi.libproxy.helsinki.fi/op/njs15507/do?p_haku=hartiadystokia#q=hartiadystokia .

Rana S, Lemoine E, Granger J, Karumanchi SA, Preeclampsia. Pathophysiology, challenges, and perspectives. Circ Res. 2019;124(7):1094–112.

Milsom I, Ladfors L, Thiringer K, Niklasson A, Odeback A, Thornberg E. Influence of maternal, obstetric and fetal risk factors on the prevalence of birth asphyxia at term in a Swedish urban population. Acta Obstet Gynecol Scand. 2002;81(10):909–17.

Hayes BC, McGarvey C, Mulvany S, Kennedy J, Geary MP, Mattherws TG et al. A case-control study of hypoxic-ischemic encephalopathy in newborn infants at > 36 weeks gestation. Am J Obstet Gynecol. 2013;209(1):29.e1-29.e19.

Kapaya H, Williams R, Elton G, Anumba D. Can obstetric risk factors predict fetal acidaemia at Birth? A retrospective case-control study. J Pregnancy. 2018;2018:2195965.

Download references

Acknowledgements

We gratefully acknowledge the assistance of Paula Bergman, biostatistician at Biostatistics consulting, University of Helsinki, Finland, for her biostatistical advice.

Helsinki University State Research Funding.

Open Access funding provided by University of Helsinki (including Helsinki University Central Hospital).

Author information

Authors and affiliations.

Department of obstetrics and gynecology, Helsinki University Women’s Hospital, Haartmaninkatu 2, Helsinki, 00029, Finland

Suoma Roto, Ilkka Kalliala & Marja Kaijomaa

Children’s Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland

Irmeli Nupponen

You can also search for this author in PubMed   Google Scholar

Contributions

SR contributed to the literature search, figures, study design, data collection, data analysis, data interpretation and writing. IN contributed to the study design, data collection data interpretation and writing. IK contributed to the data interpretation and writing. MK contributed to the study design, data collection, data analysis, data interpretation, figures, and writing.

Corresponding author

Correspondence to Marja Kaijomaa .

Ethics declarations

Ethical approval.

The study was approved by the Helsinki University Hospital Institutional Review Board. (March 3, 2018, 1/2018).

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note.

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Material 1

Rights and permissions.

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ . The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/ ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Cite this article.

Roto, S., Nupponen, I., Kalliala, I. et al. Risk factors for neonatal hypoxic ischemic encephalopathy and therapeutic hypothermia: a matched case-control study. BMC Pregnancy Childbirth 24 , 421 (2024). https://doi.org/10.1186/s12884-024-06596-8

Download citation

Received : 31 May 2023

Accepted : 20 May 2024

Published : 12 June 2024

DOI : https://doi.org/10.1186/s12884-024-06596-8

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

• Birth asphyxia
• Induction of labour
• Oxytocin treatment
• Shoulder dystocia
• Therapeutic hypothermia

BMC Pregnancy and Childbirth

ISSN: 1471-2393

• Submission enquiries: [email protected]
• General enquiries: [email protected]