Infantile Developmental Regression, Asymptomatic Abnormal Newborn Screen, and a Shared Diagnosis

A 2-day-old full-term male neonate with mild facial dysmorphisms and unilateral talipes equinovarus transfers to our hospital for metabolic work-up for elevated C3 on newborn screening. Work-up is described in Table 1. The mother reports a benign pregnancy course; she had a precipitous vaginal delivery at home. With elevated C3 on newborn screening, there is initial concern for organic acidurias (eg, propionic acidemia, methylmalonic acidemia). However, biochemical testing narrows the differential to disorders of intracellular cobalamin metabolism or acquired B12 deficiency; confirmatory laboratory results are obtained.A 7-month-old former full-term exclusively breastfed female infant presents with hypotonia, excessive sleepiness, poor feeding, and developmental regression (Table 1). Brain magnetic resonance imaging (MRI) shows diffuse cerebral and cerebellar volume loss with mild myelination delay. The mother reports a history of gastric bypass surgery; she received iron infusions in pregnancy but otherwise had an uncomplicated antenatal course and delivery. The initial differential diagnosis for this infant includes multiple genetic, metabolic, and acquired causes of infantile hypotonia and developmental regression. Biochemical testing and MRI findings similarly narrow this differential to disorders of intracellular cobalamin metabolism or acquired B12 deficiency; confirmatory laboratory results are obtained.Both cases are diagnosed with acquired B12 deficiency with distinct maternal etiologies.A review of maternal laboratory results revealed macrocytic anemia that started before conception (Table 1). Postpartum work-up reveals positive intrinsic factor auto-antibodies consistent with pernicious anemia. Neonatal molecular testing (rapid trio whole genome sequencing) is negative. The final diagnosis is acquired B12 deficiency secondary to asymptomatic antenatal maternal pernicious anemia. The neonate is initially treated with metabolic formula, then switched to regular formula after the diagnosis is confirmed. He receives intramuscular (IM) hydroxocobalamin and oral betaine and then is transitioned to oral cyanocobalamin outpatient. He continues to have normal growth and development. His mother is treated with high-dose oral B12.In this case, a similar review of maternal laboratory results demonstrates persistent microcytic anemia throughout pregnancy and a low postpartum B12 level that was not treated (Table 1). Infant molecular testing (panel for cobalamin and remethylation disorders) was negative. The final diagnosis is acquired B12 deficiency secondary to exclusive breastfeeding in the setting of suspected maternal malabsorption related to previous gastric bypass. The infant initially requires nasogastric tube feeds and IM hydroxocobalamin and is later transitioned to fortified breastmilk bottle feeds and oral cyanocobalamin. At an outpatient follow-up visit, she shows excellent growth and developmental progression. This mother is also treated with high-dose oral B12.Vitamin B12 is an essential cofactor for biochemical pathways instrumental in fetal neurodevelopment and postnatal brain growth and myelination.1,2 B12 deficiency can disrupt critical catabolic pathways, leading to accumulation of toxic metabolites like methylmalonic acid and homocysteine, and depletion of the essential amino acid, methionine. In neonates, this can manifest as poor growth, hypotonia, cerebral atrophy, delayed myelination and developmental delays. Etiologies of neonatal B12 deficiency include inborn errors of metabolism, such as cobalamin disorders and acquired nutritional deficiencies.3The mainstay of pediatric treatment is high-dose B12 supplementation starting parenteral hydroxocobalamin until an inborn cobalamin disorder is ruled out; oral cyanocobalamin is ineffective for treating cobalamin C disorder.3 For elevated homocysteine, betaine can be considered to help lower homocysteine and prevent vascular events. When diagnosed and treated promptly, initial symptoms improve quickly and there can be a regression of brain atrophy; however, neurocognitive symptoms or delays may persist depending on the severity of the initial presentation.1,4There are two-time points at which the child of a B12-deficient mother is especially vulnerable: third trimester and immediately after birth. During the third trimester, in B12-deficient mothers, the levels of B12 transported to the fetus from the placenta decline by up to 30%.5 Postpartum, B12 is more tightly bound to haptocorrin in maternal breastmilk, which reduces bioavailability to breastfed neonates.6Vitamin B12 deficiency has a high global incidence in reproductive age and pregnant women, especially those with malnourishment, secondary malabsorption (eg, inflammatory bowel disease, gastric bypass, gastrectomy, chronic gastritis), pernicious anemia, or strict vegetarian/vegan diets.4,7 Unfortunately, there is a paucity of clear guidelines directed at obstetricians regarding B12 deficiency.The American College of Obstetricians and Gynecologists “Anemia in Pregnancy” and “Bariatric Surgery and Pregnancy” practice bulletins highlight a very small subset of at-risk populations for B12 deficiency and provide no B12 screening recommendations.8,9 Furthermore, although they recommend “close surveillance” postpartum for pregnant women with a history of bariatric surgery, the neonatal risks and type of surveillance is not described.10–13 However, the Center for Disease Control does advise that pregnant women with a history of bariatric surgery have B12 checked every trimester and provides guidance on B12 dosing for normalizing low levels.14 Furthermore, there are clear consensus society guidelines for B12 screening and supplementation for general adult patients with a history of bariatric surgery; this includes annual postoperative B12 screening, standard postoperative B12 supplementation, as well as supplementation dosing recommendations for B12 deficiency.15Given the prevalence of maternal obesity and the associated increase in bariatric surgical procedures performed in reproductive-aged women, it is important that obstetricians have access to better resources for approaching prenatal B12 screening.16 In Figure 1, we propose an evidence-based screening and management approach.17–19 This proposed algorithm is not without limitations; there are limited data on vitamin B12 supplementation in pregnancy or trimester-specific ranges of B12 and what degrees of severity of deficiency should be addressed by oral vs IM routes of supplementation. More research is needed to expand on our knowledge in this realm and guide future recommendations from governing obstetric organizations.The prevalence of B12 deficiency in reproductive-age women will likely continue to grow with the increasing prevalence of bariatric surgeries, vegetarian and vegan diets, and the chronic use of medications that can cause B12 deficiencies, among other causes.20 Given the severe potential perinatal sequelae, obstetricians must engage in their critical role of screening for, diagnosing, and treating maternal B12 deficiency.Acquired vitamin B12 deficiency, which can be secondary to a maternal deficiency in either the prenatal or postpartum setting, has severe sequelae, including failure to thrive, lethargy, hypotonia, developmental regression, cerebral atrophy, and delayed myelination.Pregnant women who are at risk of B12 deficiency including but not limited to those with strict vegetarian or vegan diets, a history of gastric bypass or other gastro-intestinal surgeries, inflammatory bowel disease, pernicious anemia, evidence of macrocytic anemia, or a maternal metabolic disorder involving B12 metabolism, should be screened every trimester and postpartum with a blood count and B12 level, counseled about the perinatal risks, and treated if indicated.SummaryWe present 2 cases of acquired B12 deficiency. These cases and a review of the current literature and society guidelines underscore the lack of standardized screening practices and work-up for antenatal and postnatal maternal vitamin B12 deficiency. Obstetricians must be aware of their critical role in the preconception, prenatal, and postpartum settings to screen for maternal B12 to reduce the incidence of preventable adverse neonatal and infantile outcomes.American Board of Pediatrics Neonatal-Perinatal Content SpecificationRecognize maternal medical disorders and medications affecting the fetus and newborn infant.