Neonatal hyperbilirubinemia and rhesus disease of the newborn: Incidence and impairment estimates for 2010 at regional and global levels

Background: Rhesus (Rh) disease and extreme hyperbilirubinemia (EHB) result in neonatal mortality and long-term neurodevelopmental impairment, yet there are no estimates of their burden. Methods: Systematic reviews and meta-analyses were undertaken of national prevalence, mortality, and kernicterus due to Rh disease and EHB. We applied a compartmental model to estimate neonatal survivors and impairment cases for 2010. Results: Twenty-four million (18% of 134 million live births ≥32 wk gestational age from 184 countries; uncertainty range: 23-26 million) were at risk for neonatal hyperbilirubinemia-related adverse outcomes. Of these, 480,700 (0.36%) had either Rh disease (373,300; uncertainty range: 271,800-477,500) or developed EHB from other causes (107,400; uncertainty range: 57,000-131,000), with a 24% risk for death (114,100; uncertainty range: 59,700-172,000), 13% for kernicterus (75,400), and 11% for stillbirths. Three-quarters of mortality occurred in sub-Saharan Africa and South Asia. Kernicterus with Rh disease ranged from 38, 28, 28, and 25/100,000 live births for Eastern Europe/Central Asian, sub-Saharan African, South Asian, and Latin American regions, respectively. More than 83% of survivors with kernicterus had one or more impairments. Conclusion: Failure to prevent Rh sensitization and manage neonatal hyperbilirubinemia results in 114,100 avoidable neonatal deaths and many children grow up with disabilities. Proven solutions remain underused, especially in low-income countries. Copyright © 2013 International Pediatric Research Foundation, Inc. Inconsistent use of definitions and management approaches limit the use of available data at both national and global levels. We used the following definitions shown in Figure 1, starting from perinatal risk factors, outcomes in terms of mortality, and then impairments (hearing loss and neurodevelopmental impairment, including choreoathetoid cerebral palsy). Schematic representation of the prenatal and neonatal risk factors for Rhesus (Rh) disease and extreme hyperbilirubinemia and their impact on stillbirths, neonatal death due to kernicterus, and long-term impairment of kernicterus during childhood. In view of the complex confluence of biological risk, interaction with other childhood disease, and social–cultural factors, we did not estimate childhood death due to kernicterus. ABE, acute bilirubin encephalophathy. Rh disease or Rh hemolytic disease is defined by maternal–fetal Rh (D) antigen incompatibility and the consequences associated with maternal sensitization (see Web appendix I-iii for details and references). This was the most common and severe cause of fetal and neonatal hemolysis in Europe and the United States until about 60 y ago; it is now rare in countries where Rh prophylaxis is used. Women whose erythrocytes are Rh (D)-antigen negative are sensitized (develop anti-Rh (D) antibodies) during a previous pregnancy in which the fetus is Rh (D)-positive or by exposure to Rh antigens from blood products/transfusion. Severe hemolytic disease manifests in utero as progressive anemia and hypoalbuminemia, leading to anasarca (edema) and heart failure (hydrops fetalis), resulting in stillbirths or early neonatal deaths. Surviving infants can present with severe jaundice, anemia, and death from kernicterus or brain damage resulting from EHB. These complications can be treated with timely exchange blood transfusions. In most high-income countries, Rh disease has been eradicated by coordinated obstetrical and neonatal care (32). These prenatal interventions require expert assessment, use of Rh immunoprophylaxis, and diagnosis of fetal anemia, early signs of cardiac failure, or hydrops, in addition to the timely use of intrauterine transfusion to correct hemolytic anemia. G6PD deficiency is an X-linked inherited enzymopathy (33,34,35,36,37,38,39,40). G6PD deficiency is widespread (450 million people). There are variable data regarding the distribution of individuals at risk for neonatal hemolytic crisis due to G6PD deficiency, partly due to diverse assay methods for enzyme activity or genetic identification and timing of the assay in relation to postnatal and chronological ages. Recent population migration, sample size, and validity of the surveys also limit the accurate representation of a national prevalence (34). Existing published data highlight important limitations due to the use of summarized national levels that can mask subnational variations. Accurate (phenotypic) quantitative identification of deficient G6PD enzyme activity by spectrophotometry is a measure of the condition soon after birth. However, variations due to both partial phenotypic manifestations of diverse genetic mutations and the high enzyme activity of younger red blood cells are significant confounding factors. DNA/polymerase chain reaction screening for specific mutations is ideal to identify female heterozygotes, but this approach is limited by the diversity of known variants and the occasional mismatch with phenotypic expression of enzyme activity. More recently, Luzzatto et al. (37). have suggested estimation of G6PD deficiency allele frequency to predict and generate population-weighted estimates of affected population. Howes et al. (33). have used this approach to propose a Bayesian geostatistical model adapted to the gene’s X-linked inheritance that circumvents the above-mentioned limitations to assess national prevalence. There is paucity of data to estimate a neonate’s risk for G6PD deficiency following exposure to aggravating triggers that may cause unpredictable adverse consequences (35). Prematurity: Preterm birth is any birth before 37 completed wk of gestation (<259 d since the first day of the woman's last menstrual period) (41,42). Further subdivisions based on completed GA are as follows: late preterm (34 to <37 wk); moderately preterm (32 to <34 wk); and very preterm (<32 wk). The incidence of kernicterus in 1955, i.e., before the clinical use of phototherapy, was 10.1, 5.7, 3.2, 1.1, and 0.8% for infants at 30, 31–32, 33–34, 35–36, and >36 wk GA, respectively (43). We limited our analysis to the group of preterm births of >32 wk GA because preterm births <32 wk handle hyperbilirubinemia differently, and according to International Classification of Diseases rules, deaths and disability in this group should be allocated to preterm birth as the primary condition to address, so we will not include these here to avoid double counting the burden along with those included in preterm birth direct complications. EHB is defined as total plasma/serum bilirubin >25 mg/dl (428 µmol/l) or those treated with exchange blood transfusion (44). Kernicterus or CBE has been used as a clinical diagnosis that relies on a history of excessive prolonged hyperbilirubinemia and classical abnormalities of muscle tone, movement disorders, and aberrant processing disorders (26,45,46). Acute signs of extrapyramidal dysfunction may precede CBE. Acute bilirubin encephalopathy (31) includes progressive changes in an infant’s mental (behavioral) status, muscle tone, and distinct cry patterns. Acute clinical signs, initially described in 1955 by Crosse et al. (43), are as follows: “the first 24 to 48 hours of life are the most critical. Signs develop in a baby who is jaundiced… and include head retraction, an expressionless facies, usually with oculogyric movements, changes in muscle tone, cyanotic attacks, refusal to suck, vomiting and hemorrhage prior to death. In severe cases these signs are self-evident but in those less affected they are easily missed …. unless specifically sought.” “Several babies who showed minimal signs have proved to be definite cases of kernicterus.” Thus, neonatal mortality is due to respiratory failure and progressive coma or intractable seizures. An increased signal on magnetic resonance imaging of the globus pallidus and other areas prone to bilirubin neurotoxicity is often evidenced in surviving infants. Posticteric clinical sequelae include irreversible, but static, classic signs of athetoid cerebral palsy, generalized dystonia, paralysis of upward gaze, “kernicteric facies,” and sensorineural hearing impairment. Neuromotor impairment secondary to abnormal muscle tone includes dystonia that is characterized by excessive or sustained contraction of opposing muscles during voluntary movements, in addition to hypertonia or hypotonia. Painful muscle cramps, incoordination of sucking, swallowing, and visuomotor function may manifest during early infancy. Cerebral palsy with choreoathetosis is another classic manifestation of kernicterus, which is characterized by involuntary movements or irregular muscle contractions that manifest as writhing or twisting. Paroxysmal movement disorders are often misdiagnosed and labeled as seizures. Hearing impairment is defined by sensorineural abnormalities ascertained by objective tests. Auditory system abnormalities with hyperbilirubinemia primarily involve brainstem nuclei, leading to abnormalities in auditory brainstem responses and detected by referred hearing screens during infancy. Auditory neuropathy, also called ‘‘auditory dyssynchrony,” is often subtler and associated with childhood hearing impairment (47,48,49,50,51,52). Developmental delay or cognitive impairment, ascertained by the Bayley Mental Developmental Index, provides continuous variables to define the extent of aberrations for mental and psychomotor indexes. In addition, infants’ intelligence can be estimated or tested for intelligence quotients of <70 using the Wechsler Intelligence Score for Children (47). Cognitive impairment has been reported and possibly related to associated hearing impairment, neuromotor impairment, or, possibly due to social neglect. Other posticteric sequelae may result from subtle signs either with exposure to TB levels that are lower than EHB or following partial treatment of EHB. These “soft” perturbations of sensory processing disorders have been described as the syndrome of bilirubin-induced neurologic dysfunction or “BIND” (53) but are intentionally not included in this study due to the limited data and consensus in definitions found in the literature. Systematic reviews of the main electronic literature databases (Ovid Medline, Ovid Medline In-Process and Non-Indexed Citations, PubMed, Cinahl, Global Health, Scopus, and Popline) were undertaken using a combination of medical subject heading and free text words. Search terms used were exchange blood transfusion, kernicterus/bilirubin encephalopathy, death (from jaundice), phototherapy, G6PD deficiency, ABO incompatibility, Rh incompatibility, admission/readmission (for jaundice), sequelae, impairment, and outcomes. Reference lists of all the relevant studies were scanned to further identify studies of interest. We excluded case reports, nonhuman studies, those that did not have the relevant population or age group, those that did not focus on the relevant condition (jaundice, hyperbilirubinemia, and encephalopathy), and those that did not provide relevant primary data (e.g., for prevalence/risk). In addition, we conducted a retrospective review of the historic Rh disease literature, commencing from identification as a clinical disease to the period Rh disease was considered “conquered.” Pivotal studies, cited in Appendix I, allowed for estimation of mortality and disease among survivors. We also identified population-based studies before the use of phototherapy, which reported on the outcome of systematic use of phototherapy. Due to rapid improvement in the access to and quality of specialized/intensive newborn care in countries with low-mortality settings, for mortality, encephalopathy, and long-term impairment risk, we decided to focus on recent literature only and extracted data from studies with birth cohorts having median year of 2005 or later. Where sufficient data were available, standard meta-analysis techniques were used to obtain pooled estimates of the relevant parameter's risk, which included EHB-related neonatal mortality and bilirubin encephalopathy (acute and/or chronic). Heterogeneity across studies was evaluated using I2 and χ2 tests, and where evidence of heterogeneity was present (I2 > 70% or P < 0.05), a random-effects model was used. A systematic review of the published literature using PubMed was performed to establish the prevalence of Rh-negative blood groups by country for all countries with NMR >5. Countries with NMR <5 were presumed to have good Rh prophylaxis and strong health systems, with very low number of cases of Rh disease in these countries. Search terms included “rh, rh blood-group system” (medical subject heading term), “Rhesus,” and “Blood group.” Reference lists of all the relevant studies were scanned to further identify studies of interest and Web-based resources were searched using Internet search engines. For countries with no available data, the prevalence of Rh-negative blood groups was estimated using the regional median prevalence (Web appendix I-iii). A further systematic review using PubMed (search terms included combinations of “Rhesus,” “rhesus disease,” “erythroblastosis fetalis,” “rhesus h(a)emolytic disease of the newborn,” “outcome,” “neonatal death,” and “stillbirth”) was undertaken to estimate the outcome of Rh disease in the absence of effective treatment and limited to primary studies published before 1960 and to reviews without date limitations. Data were not available to estimate every parameter for every country. Hence, we sought to use pooled data from countries that are similar in their access to and quality of care as these are closely linked to outcomes. Outcomes of EHB depend on a systematic approach to prevention and management of hyperbilirubinemia. We grouped countries into three NMR bands (NMR/1,000 live births) as follows: Group 1 (NMR <5), Group 2 (NMR 5 to <15), and Group 3 (NMR ≥15), which approximate to high-, middle-, and low-income countries, respectively. Where data were available, we sought to further distinguish the outcomes between those with access to specialized neonatal care if required (including phototherapy and exchange blood transfusion) and those with basic/limited care only at home or in a facility with no access to these specialized services because this will affect the mortality and kernicterus outcomes. A three-step compartmental model was constructed for each country with at least 10,000 live births for the year 2010 (54,55) as follows: Step 1) estimation of the number of cases based on the prevalence of G6PD deficiency, late-preterm birth, and other causes of EHB, not due to Rh disease, in addition to estimating the prevalence of Rh disease; Step 2) estimation of the number of stillbirths, neonatal deaths, and cases of kernicterus by applying the risk data to the estimated cases; and Step 3) estimation of the numbers of survivors with neurodevelopmental impairment (Figure 2). All results are presented by regional grouping according to the Global Burden of Disease Study Group superregions (56,57) (Appendix II). We quantified the uncertainty surrounding these estimates by taking 1,000 random draws of the input parameters at each step, assuming a normal distribution with mean equal to the point estimate of the parameter and SD equal to the estimated SE of the parameter (55). We summed the data at the worldwide or regional level for each draw and present the 2.5th and 97.5th percentiles of the resulting distributions as the uncertainty range. Schematic representation of the three-compartmental model. This model delineates the serial steps toward input of country-specific parameters, processes, and outputs to estimate prevalence, burden of Rhesus (Rh) disease and extreme hyperbilirubinemia–related mortality, and the number of postneonatal survivors with kernicterus and long-term impairment. A/CBE, acute/chronic bilirubin encephalophathy.