Bilirubin in the newborn: Physiology and pathophysiology

Breastfeeding and gestational age

Jaundice and hyperbilirubinaemia are more likely to occur when babies are breastfed, particularly when they are having difficulties establishing effective feeding and when there is weight loss due to inadequate intake (Rankin, 2017). This is thought to result from factors associated with ineffective or suboptimal breastfeeding, including reduced fluid and calorific intake, which can result in increased enterohepatic recirculation of bilirubin, and thus increased bilirubin load (Maisels, 2015; Blackburn, 2017). Encouraging early and frequent feeding is key to enhancing gut motility, promoting the establishment of intestinal bacteria, and ensuring adequate hydration to effect the removal of bilirubin from the intestines, as well as preventing its reabsorption (Maisels, 2015; Mitra and Rennie, 2017). Efficacious breastfeeding support can therefore be essential to mitigate the effects of breastfeeding-associated hyperbilirubinaemia.

Another form of jaundice associated with breastfeeding is breast milk jaundice. This occurs slightly later than physiological jaundice, in the second week, and is thought to be due to factors in the breast milk itself that enhance the enterohepatic circulation of bilirubin. The presence of b-glucuronidase in breast milk is one of the factors implicated in increasing this recirculation of bilirubin, as this enzyme converts bilirubin back to its unconjugated form in the intestine, resulting in its reabsorption (Mitra and Rennie, 2017; Rankin, 2017). Preterm infants are also at increased risk for hyperbilirubinaemia (Amin, 2016), as there are many aspects of preterm physiology that can potentially exacerbate the factors that produce physiological jaundice (Table 2), including a further reduced red blood cell lifecycle, reduced albumin production, and further immaturity of liver conjugating enzymes (Blackburn, 2017). This can result in hyperbilirubinaemia that is earlier in onset, more severe, and more prolonged (Rankin, 2017). Late preterm infants may be at particular risk, as unlike early preterm infants, who will remain in hospital under observation, late preterm infants are more likely to be discharged earlier, leaving them more vulnerable to the effects of potentially inadequate surveillance and lack of sufficient parental and breastfeeding support (Kaplan et al, 2016).

Community care

Many infants are now discharged within 48 hours, and it is therefore often impossible to assess and manage jaundice—or to ensure breastfeeding is properly established appropriate support offered—before discharge (Jing et al, 2017). Early discharge from hospital is associated with readmission for jaundice, and breastfed and late preterm infants are particularly at risk (Lain et al, 2015). In addition, significant hyperbilirubinaemia may be detected later in the community than it would be in hospital, resulting in higher bilirubin levels when infants are readmitted, and poorer outcomes (Battersby et al, 2017). Appropriate and efficacious follow up of all infants in the community is therefore essential, and midwives should be aware of any underlying risk factors or deviations from the norm in order to effect appropriate management and referral. Examination of the baby should be performed in a well-lit room and, if jaundice is suspected, a bilirubin measurement should be taken, either using a transcutaneous bilirubinometer (TCB) or by obtaining a blood sample to measure total serum bilirubin (TSB), since visual assessment of jaundice and/or cephalocaudal progression is not reliable (Ives, 2015; Grace, 2017; Mitra and Rennie, 2017). The National Institute for Health and Care Excellence (NICE) (2016) advise that a bilirubin measurement is obtained rather than assessing jaundice visually, and that all infants with risk factors for hyperbilirubinaemia be reviewed within 48 hours of life. Risk factors include: gestational age under 38 weeks, jaundice that develops within 24 hours, a sibling with jaundice requiring phototherapy, and exclusive breastfeeding (NICE, 2016). However, additional factors that may warrant consideration include Asian ethnicity, significant bruising or cephalohaematoma, blood group incompatibility, and glucose-6-phospahte dehydrogenase (G6PD) deficiency (Maisels, 2015; Ng and How, 2015; Chang et al, 2017). Appropriate follow-up, including thorough consideration of risk factors and universal TCB/TSB monitoring, is essential (McGillivray et al, 2016). An extremely important part of this follow-up is breastfeeding support and parental education on the importance of frequent feeds to mitigate jaundice, and the importance of being aware of frequency of voiding and stooling—as well as any changes to stools—to ensure that the baby is receiving adequate hydration (Ng and How, 2015; Watchko, 2016; Hassan and Zakerihamidi, 2017). In addition, parents should be advised on the signs of jaundice and, importantly, to get help in the presence of signs that indicate a deteriorating condition (such as poor feeding and lethargy) where jaundice is present but is below treatment level (Grace, 2017). Adequate surveillance of jaundice, along with efficacious breastfeeding support and parental education around what is normal and what is not, is key to preventing the raised bilirubin levels that can result in the need for hospital readmission and deleterious harm if not identified and adequately managed.

Blood group incompatibility and haemolytic disease of the fetus and newborn

Rhesus incompatibility occurs when a rhesus-negative mother is carrying a rhesus-positive baby, and as a result can produce antibodies (alloimmunisation) against the rhesus antigens on the fetal red blood cells if they enter the maternal circulation. There are many types of fetal antigens that can cause maternal alloimmunisation, but the Rh-D antigen is associated with the most severe cases. Rh-D can lead to anaemia and hydrops in the fetus, and hyperbilirubinaemia and kernicterus in the newborn (Ree et al, 2017). Usually, the amount of fetal blood that enters the maternal circulation in pregnancy is too small to trigger an immune response (Blackburn, 2017); however, alloimmunisation can occur during the third stage of labour when the placenta separates from the uterine wall, or due to other sensitising events during pregnancy that result in feto-maternal haemorrhage, such as external cephalic version, miscarriage, or a blow to the abdomen as a result of a fall or domestic violence (Kent et al, 2014; Hutchon, 2016). When this occurs, fetal red blood cells carrying the rhesus antigen are recognised as foreign by the maternal immune system, which mounts an immune response against them. This involves the formation of immunoglobin-G (IgG) antibodies, which are able to cross the placenta; and the formation of memory cells, which can mount a rapid and intense immune response upon future recognition of this antigen (Rankin, 2017). However, the first pregnancy is usually complete by the time these antibodies have been produced (McBain et al, 2015). It is therefore the subsequent pregnancy that is usually of concern, as exposure to even a small amount of fetal blood can stimulate the production of a large amount of IgG antibodies, which are actively transported across the placenta. Here, they bind to antigens on fetal red blood cells, causing haemolysis (Blackburn, 2017) (Figure 2). This process of haemolysis continues after birth, as antibodies remain in the newborn's circulation. Treatment can involve intrauterine blood transfusions for fetal anaemia, postnatal phototherapy, and/or exchange transfusion when required (Ree et al, 2017).

The postpartum administration of anti-D immunoglobulin to prevent sensitisation following birth has been available for approximately 30 years and has been successful in reducing the incidence of haemolytic disease of the fetus and newborn (HDFN) (McBain et al, 2015; Ree et al, 2017). Prophylactic anti-D is now also offered to all rhesus-negative women, to prevent the occurrence of ‘silent’ sensitisations, as well as following any potential sensitising events as described above (McBain et al, 2015). The administration of anti-D is thought to result in the destruction of any fetal red blood cells that enter the maternal circulation before her immune system has a chance to recognise them and mount an immune response (Blackburn, 2017). It is argued that there are ethical issues around this, however, as one third of rhesus-negative women will be carrying a rhesus-negative baby and will thus receive this blood product unnecessarily (Kent et al, 2014). If maternal blood tests to determine fetal rhesus status were made available to rhesus-negative mothers, this would allow them to make fully informed choices around whether to receive anti-D (Kent et al, 2014). In many low-income countries, HDFN and kernicterus are still a pervasive problem, due to fragile and insufficient healthcare systems that result in a lack of antibody screening and anti-D availability for rhesus-negative mothers (Zipursky and Bhutani, 2015).

Alloimmunisation can also occur when the fetus is of a different ABO blood group to the mother and most often occurs when the mother is type-O and the fetus is type-A or type-B (Blackburn, 2017). In this situation, antibodies directed against fetal red blood cells are already present in maternal blood, as type-O blood groups already possess antibodies directed against both type-A and type-B antigens (Rankin, 2017). The effects produced, however, are relatively mild as, usually, antibodies produced by ABO incompatibility are immunoglobin-M (IgM) antibodies that do not cross the placenta. However, type-O mothers more often produce IgG antibodies, which do cross the placenta and can therefore attack fetal red blood cells (Blackburn, 2017). Due to the success of anti-D administration in the prevention of rhesus alloimmunisation, ABO incompatibility now represents an important cause of hyperbilirubinaemia in high-income countries (Chang et al, 2017).

Glucose-6-phosphate dehydrogenase deficiency

G6PD deficiency is a genetic disorder that results in a deficiency in the enzyme glucose-6-phosphate dehydrogenase (G6PD), which has various functions, including protecting cells from oxidative stress (Cunningham et al, 2016; Luzzatto et al, 2016). Because red blood cells transport oxygen, and because this enzyme plays a crucial role in protecting against oxidative stress in this cell type in particular, when oxidative stress does occur, red blood cells cannot produce the extra buffering capacity needed to protect themselves, so become damaged and are destroyed by haemolysis (Wong and Stevenson, 2015; Luzzatto et al, 2016). G6PD deficiency mainly affects individuals of Asian, African, Middle Eastern and Mediterranean origin; however, due to travel and migration, this is now a worldwide problem (Maisels, 2015; Kaplan et al, 2016). Because it is an X-linked disorder, it is more common in men, but female heterozygotes can also be affected. Individuals are usually asymptomatic until they are exposed to an oxidative stress, which can include ingestion of broad or fava beans; infection; antimalarial drugs, such as primaquine; sulphonamide antibiotics; and henna. These products should therefore be avoided by breastfeeding mothers if their infant has this condition (Wong and Stevenson, 2015; Kaplan et al, 2016). Exposure, which can be unpredictable, can result in acute haemolytic anaemia, leading to a sudden and exponential increase in bilirubin to hazardous levels, resulting in bilirubin-induced neurotoxicity and potentially leading to kernicterus (Cunningham et al, 2016; Watchko, 2017).

G6PD deficiency also increases the risk for bilirubin-induced toxicity because bilirubin itself is a major source of oxidative stress (Watchko, 2016). Thus, G6PD deficiency results in the sudden, acute production of bilirubin with which the body is less able to cope (Cunninham et al, 2016) (Figure 2). This two-way attack may be partly why G6PD deficiency is still an important cause of kernicterus worldwide (Watchko, 2015). Furthermore, in order to avoid its potentially deleterious effects, exposure to known triggers must be avoided, and when exposure does occur, quick recognition and treatment of jaundice must ensue to prevent bilirubin reaching neurotoxic levels (Kaplan et al, 2016). However, as exposure and its effects often occur well after neonatal hospital discharge, and exposure to potential stressors cannot always be predicted, G6PD deficiency remains a major risk factor for hyperbilirubinaemia and kernicterus (Cunningham et al, 2016; Watchko 2017). This risk is particularly high in developing countries, where high rates of G6PD deficiency, low birth weight, underfeeding, infection, and lack of access to treatment severely compound the risk of hyperbilirubinaemia and lead to a relatively high incidence of kernicterus (Cunningham et al, 2016). Tests for G6PD-related hyperbilirubinaemia are available, and screening has been carried out successfully in some areas, such as Greece and Hong Kong. However, the value of such screening elsewhere is unclear (Watchko et al, 2013).