Maternal vitamin D status and its implications on the newborn – A narrative review

INRODUCTION

Vitamin D is a fat-soluble vitamin which is necessary for bone mineral homeostasis. Vitamin D status is assessed by serum 25-hydroxyvitamin D [25(OH)D] levels due to its longer half-life of 21 days. About 95% of circulating 25(OH)D is endogenously produced in the skin by the action of ultraviolet rays from sunlight. The pandemic of hypovitaminosis D affects all ages, including pregnant women and their newborns with varied prevalence depending on the cutoffs used.^[1-5] Two different cutoffs are currently in use.^[4,5] The Endocrine Society, USA recommends circulating 25(OH)D levels >30 ng/mL as sufficient and <20 ng/mL as deficient, whereas Institute of Medicine, USA recommends >20 ng/mL as sufficient and <12 ng/mL as deficient, respectively.^[4,5]

CASE SCENARIOS

Vitamin D is often overlooked as a potentially treatable parameter in various neonatal conditions and resultant outcomes. The relationship between vitamin D status and small for gestational age (SGA) is postulated to be mediated by placental vascularization. The impact of vitamin D status on fetal growth is often confounded by perinatal risk factors. Furthermore, the pleiotropic role of vitamin D in immune regulation is often linked to the risk of development of neonatal sepsis. Herein, we describe two babies where hypovitaminosis D was observed in the setting of neonatal sepsis and SGA.

VITAMIN D STATUS IN INDIAN PREGNANT WOMEN AND NEWBORN DYAD

The exposure of sunlight in India ranges from approximately 3–4 h in winters to 7 h in summer.^[6] However, rapid urbanization with prolonged indoor work hours and traditional cultural attire where people cover most body surface have possibly led to further diminutive exposure of sunlight resulting in significant prevalence of hypovitaminosis D in native Indians.^[6,7] Vitamin D deficiency is a concern, especially in pregnancy as it potentially affects both mother and fetus. Several studies have shown widespread prevalence of vitamin D deficiency during pregnancy in India.^[3-6,8-10] Some of the salient studies are summarized in Table 1. Briefly, Goswami et al., assessed vitamin D status in 29 pregnant women in a public hospital of New Delhi. The mean maternal and cord blood 25(OH)D was 8.8 ± 4.3 and 6.7 ± 2.0 ng/mL, respectively.^[6] Subsequently, Sachan et al., reported similar findings for 117 mother and newborn dyads from Lucknow.^[8] With increased awareness about hypovitaminosis D, calcium and vitamin D supplementation is being commonly prescribed in India. Recently, Gowtham et al., reported hypovitaminosis D in 65% of mothers and 68.6% newborns in 121 cases from Puducherry, India.^[9] A 5-fold higher risk of hypovitaminosis D was observed in newborns of vitamin D deficient mothers. Similar findings were reported from the Middle East, African, and Western countries.^[11,12] Goswami et al., in 2016, showed that mother with twin pregnancy had higher vitamin D deficiency with 25(OH)D <12 ng/mL in 89% cases.^[13]

FUNCTIONAL SIGNIFICANCE OF MATERNAL VITAMIN D DEFICIENCY

Global and Indian data on maternal and newborn vitamin D deficiency and its functional significance are limited.^[6-9,13,14] The fetus, deprived of sunlight, depends entirely on maternal supply of calcium and vitamin D. Neonatal hypovitaminosis D has been linked with preterm birth, alteration in bone mineral content, neonatal respiratory distress syndrome (RDS), seizures, sepsis, acute gastroenterocolitis and increased risk of hospitalization.^[15,16] Various anthropometric parameters including BW, birth length, head circumference, femur length, and fontanelle size are also being assessed for their relationship with vitamin D.^[17,18] Maternal vitamin D status may have long-term implications on the health of offsprings.^[14] Vitamin D deficiency during pregnancy causes various manifestations such as childhood obesity and increased risk of recurrent wheeze in early childhood. In a longitudinal follow-up study involving 198 children born in UK, children of vitamin D deficient mothers had reduced whole body and lumbar spine bone mineral density at 9 year of age.^[14] Recently, El-Heis et al., showed that vitamin D supplementation reduced the risk of infantile atopic eczema.^[19] However, the effect of maternal vitamin D supplementation on neonatal and childhood bone health is variable. In a large randomized placebo-control trial on vitamin D supplementation, there was no difference in neonatal whole body bone mineral content assessed by dual-energy X-ray-absorptiometry.^[15] Figure 1 provides the brief depiction of role of vitamin D in various neonatal outcomes.

Close

Figure 1:

Salient manifestations of maternal and newborn vitamin D deficiency.

Export to PPT

VITAMIN D DEFICIENCY AND NEONATAL SEIZURES

Maternal vitamin D deficiency leads to poor placental transfer of calcium resulting in reduced stores and decreased intestinal calcium absorption in newborns. Decreased serum ionized calcium, in turn, increases the risk of neonatal hypocalcemic seizure.^[20-24] The serum total calcium cutoff to define neonatal hypocalcemia ranges from <7.0 to <8.0 mg/dL.^[21] Serum ionized calcium cutoff of <4 mg/dL has also been used in disorders affecting albumin levels.^[20,21] Immature parathyroid hormone (PTH) response and hyperphosphatemia have been reported in neonatal hypocalcemia.^[22] Neonatal hypocalcemia manifests as increased neuromuscular excitability, irritability, tetany, laryngospasm, cardiac arrhythmias, seizures, apnea, cyanosis, and feeding problems.^[24]

The prevalence and characteristics of neonatal hypocalcemic seizures have been reported by various investigators. These seizures, occur more commonly in males, and in South Asian or African ethnicity, can be generalized or focal and can occur early at birth, or later, at 4–8 days.^[20,23,25] Huang et al., assessed 1029 Taiwanese newborns admitted in intensive care unit and observed neonatal hypocalcemic seizures in 16 cases.^[26] Nearly 50% of these seizures were attributed to vitamin D deficiency and remaining to various etiologies including DiGeorge syndrome and hypoparathyroidism. Unlike syndromic cases, those neonates with vitamin D deficiency-related seizures recovered completely with no long-term neurodevelopmental sequelae.^[26] SeymenKarabulut et al. assessed 96 Turkish newborns with late-onset neonatal hypocalcemia, occurring at a median age of 5 days with a male preponderance of 60%.^[25] The median cord blood 25(OH)D was 6.3 ng/mL with vitamin D deficiency (<12 ng/mL) in 86% and neonatal seizures in 18%. Interestingly, 54.2% of these neonates had low or normal intact PTH (iPTH).^[25] Soliman et al. reported cases of neonatal seizures occurring within 10 days of birth.^[27] Mothers of affected neonates had 25(OH)D values <10 ng/mL. The seizures were generalized, eight newborns had craniotabes and serum iPTH was normal in 40% of the cases. Treatment with alphacalcidiol and calcium lead to resolution of symptoms within 2 days.^[27] Thomas et al. described 78 cases of neonatal hypocalcemia at a children’s medical center in USA.^[28] Median age at admission was 8 days, 72% were male, and median duration of hospital stay was 3 days. Majority had hypomagnesemia and low iPTH. The seizures responded to supplementation with calcium, calcitriol, low phosphorus formula, and magnesium.^[28]

Although hypovitaminosis D is common in India, the prevalence of neonatal hypocalcemia and seizures is not clear. Mehrotra et al., evaluated vitamin D deficiency in 60 neonates with seizures and their mothers and compared them with healthy neonate-mother pairs in New Delhi, India.^[21] Serum 25(OH)D levels were below 10 ng/mL in 90% of newborns with seizures versus 42% in healthy neonates. Around 85% mothers with affected neonates had vitamin D deficiency when compared to 50% in mothers of healthy neonates.

Thus, up to 50% of all neonatal hypocalcemic seizures could possibly be attributed to vitamin D deficiency with a greater risk in males than females. Serum total calcium level <8.0 mg/dL should alert about possibility of a vitamin D deficiency-related seizure. PTH response is often blunted despite severe hypocalcemia due to inadequate maturation. Appropriate treatment leads to complete recovery without long-term neurodevelopmental sequelae.

VITAMIN D DEFICIENCY AND NEONATAL INFECTIONS

Neonatal sepsis manifests within the first 4 weeks of birth. It can occur early within 72 h, or late beyond 72 h of life.^[29] Bloodstream infections, meningitis, and pneumonia are common causes of neonatal septicemia. Sepsis results in about 20% of neonatal mortality.^[29] Neonatal respiratory diseases also have long-term sequalae, predisposing to respiratory dysfunction, asthma, chronic obstructive disease, and increased mortality at adult age. The burden of neonatal sepsis is high in low-income Asian and African countries.

Several studies have demonstrated possible association between vitamin D and RDS, wheezing, and infections of respiratory tract in infancy.^[30] Novel mechanisms are being proposed to explain increased susceptibility to neonatal infections in hypovitaminosis D.^[16,31-34]

Recently, Treiber et al., assessed 402 Slovenian mother and newborn dyads.^[16] Cord blood 25(OH)D was <10 ng/mL in 18% of newborns. Risk of neonatal RDS, hospitalization, and acute gastroenterocolitis was high in vitamin D deficient state, with odd ratio ranging from 3.9 to 5.9.^[16] Similar findings have been reported across India [Table 2]. Dhandai et al., observed significantly low serum 25(OH)D in 60 neonates with late-onset sepsis from a tertiary care center in New Delhi.^[35] Singh and Chaudhari examined 70 cases with and without sepsis each, from Surat.^[36] Cord blood 25(OH)D was low in 80% of newborns with sepsis unlike in 52% of cases without sepsis, with increased mortality in those with 25(OH)D level <11 ng/mL. Similar observations have also been reported by Behera et al., in culture-positive neonatal sepsis from Odisha^[37] and by Agrawal et al., in 225 term neonates from Bhopal.^[38] Cases of neonatal sepsis associated with vitamin D deficiency have associated high CRP and longer hospital stay, especially in those with raised serum iPTH.^[39,40]

Workneh Bitew et al., reported meta-analysis of 14 observational studies (four from India), which included 748 neonates with sepsis and 573 neonates without sepsis and their respective mothers. About 80% of neonates with sepsis had vitamin D deficiency compared to 44% without sepsis. The mean cord 25(OH)D levels were lower by 8.78 ng/mL in neonatal sepsis. The forest plot showed association of neonatal sepsis with hypovitaminosis D in 13 of the 14 studies.^[29]

Information on the maternal vitamin D supplementation and newborn infections is scarce. Loddo et al., in 2023, assessed the effect of antenatal administration of a single dose of 100,000 IU of cholecalciferol.^[30] The supplemented cohort of 54,596 subjects with supplementation had 3.0% lower odds of term infants with perinatal asphyxia, respiratory distress, and meconium aspiration syndrome.

While these studies highlight the role of vitamin D deficiency in neonatal sepsis, underlying pathogenetic mechanisms are not completely understood. Tayel et al., observed a high prevalence of FokI TT polymorphism of vitamin D receptor in vitamin D deficient infants with neonatal sepsis, indicating a possible defect in vitamin D action.^[31] The effect of vitamin D deficiency on the immune system is being elucidated in both experimental and clinical studies.^[32-34] In a mouse model of lung injury, prenatal vitamin D supplementation reduced monocytes/macrophage migration and transforming growth factor–beta-mediated inflammatory pathway activation at the injured site.^[32] Wang et al., observed that winter-born neonates had higher risk of vitamin D deficiency, pneumonia, sepsis, cytomegalovirus infection, and low circulating serum CD3+, CD4+, and IgA.^[33] Youssef et al. observed similar alterations in effector T-cells in 52 Egyptian neonates with hypovitaminosis D.^[34] Zhang et al. observed an association between maternal vitamin D deficiency, placental inflammation, and neonatal sepsis in Chinese women.^[41] Intrauterine infection (15.6 vs. 5.7%) and neonatal sepsis (2.4% vs. 0.5%) were higher in mothers with placental inflammation than in those without inflammation. Marsubrin et al., in 2024, assessed the association of vitamin D deficiency with intestinal dysbiosis in 43 preterm infants below 32 weeks.^[42] The ratio of fecal commensal Lactobacillaceae to pathogenic Enterobacteriaceae was lower in those with vitamin D deficiency.

Thus, neonates with vitamin D deficiency, especially those with high iPTH, are possibly at higher risk of neonatal sepsis, RDS, wheezing, and prolonged hospital stay. Potential postulated mechanisms include effect of vitamin D receptor polymorphism, defect in immune effector cells, placental inflammation, and gut dysbiosis. Randomized-control trials would help to substantiate the role of prenatal vitamin D supplementation in the prevention of neonatal infections. The ongoing double-blind “D-Kids” trial involving weekly supplementation with 14,000 IU of cholecalciferol in 300 Australian pregnant women will probably help understand the effect of antenatal vitamin D supplementation in neonatal infections.^[43]

VITAMIN D AND ANTHROPOMETRY

Anthropometric parameters such as BW, length, head circumference, and anterior fontanelle size reflect the general health and nutritional status of the newborn. The concept of fetal origin of adult onset illnesses suggests that BW is significantly linked to several adult-onset diseases including diabetes mellitus, hypertension, insulin resistance, polycystic ovarian disease, and cardiovascular diseases.^[44,45] However, evidence on possible association between maternal and cord blood vitamin D status with anthropometry is conflicting [Table 3].

CONCLUSION

Thus, current evidence indicates that Vitamin D deficiency may be associated with adverse neonatal outcome in the perspective of hypocalcemic seizures, sepsis, and anthropometry. The guidelines from the Indian Academy of Pediatrics (IAP) which recommend physiological maintenance dose of 400 IU of 25-hydroxycholecalciferol in all asymptomatic neonates till 1 year of age should be followed. Neonates with hypovitaminosis D should be managed with daily doses of 2000 IU of vitamin D for a period of 3 months along with calcium supplementation. However, further prospective studies with vitamin D supplementation are required to assess its role in neonatal seizures, infection, and anthropometry.