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. 2021 Apr 12;12:619176. doi: 10.3389/fendo.2021.619176

Table 2.

Table summarizing the outcomes reviewed with GRADE rating for quality of evidence.

Reviewed studies Observations Comments GRADE Rating(Average score)* Level of evidence
Prevalence of B12 deficiency
in pregnancy
B12 deficiency: 50-70% (1721, 23, 24).
Raised Methylmalonic acid: 70-90% (19, 22).
Hyperhomocysteinemia: 28-43% (19, 20, 22).
B12 measurements were lower in the third trimester of pregnancy as compared to early pregnancy.
Prevalence reported from both community and hospital based samples in rural and urban populations. Standardized assay techniques used to measure B12 concentrations with similar cut off values across studies.
Estimates of prevalence rates are reliable
Pregnancy
outcomes
Anemia with macrocytosis Two cross-sectional studies (25, 26) reported 40-50% prevalence of macrocytosis in pregnant women with anemia Small sample size 1.5 Low
Recurrent pregnancy losses Two case control studies
Higher homocysteine (2 studies) (27, 28), low B12 (1 study) (27), low B12-folate ratio (1 study) (28) in women with RPL
These Case control studies have methodological limitations (inadequate control for confounding, sample selection and matching not adequately described) 2.5 Low
Higher risk for pre-eclampsia Two case control studies. Higher maternal homocysteine (2 studies) (29, 30) and low B12 (1 study) (30) in preeclamptic women 2.0 Low
Higher risk for Preterm delivery 2 case control studies. Higher homocysteine and higher B12 levels in mothers delivering preterm due to preeclampsia) (31, 32) 2 Low
Higher risk for GDM One observational study (18) in a prospective birth cohort. Higher risk for gestational diabetes in B12 deficient women. One RCT (33) supplementation with micronutrient snack reduced incidence of GDM by 50% Observations adjusted for confounding. Supported for causality by intervention trial (micronutrient snack of green leafy vegetables and milk powder) 3 Moderate
Congenital
anomalies
Higher risk for NTD in offspring Three singe center case control studies (3436) and one multicenter study (37)
Higher homocysteine in mothers (2 studies) (36, 37), fathers and neonates (1 study) (34), vegetarian diet in mothers (1 study) (35), low maternal b12 status (1 study) (36) and low maternal transcobalamin levels (1 study) (37) was associated with higher risk for NTD.
Maternal 776C>G polymorphism in TCN2 was strongly predictive of NTD in the offspring (1 study) (37)
A large multicenter case control study ~ 700 subjects, NTD detected by fetal ultrasound, maternal blood concentrations measured at time of detection confirmed association of risk of NTD with maternal transcobalamin levels. Supported for causality by associations with genetic polymorphisms of B12 metabolism. 4 High
Increased risk for congenital heart defects 1 case control study (38) Higher maternal homocysteine in cases with congenital heart defects in offspring Maternal concentrations measured 9-15 months after delivery (no temporal correlation between exposure and outcome. Small sample size 1.5 Very low
Risk for orofacial clefts One case control study. Exclusive vegetarianism in mothers associated with higher risk of orofacial clefts in mother (39) Vegetarian diet is a proxy for B12 status. Maternal concentrations or dietary intakes not assessed 1 Very low
Birth
outcomes
Higher Neonatal morbidity One case control study reported higher neonatal morbidity in anemic pregnant women with macrocytosis (26).
In one intervention trial (40) micronutrient supplementation (inclusive of B12) in undernourished mothers reduced neonatal morbidity
Small sample size in case control study. Intervention trial performed in a selected sample of undernourished mothers. Supplementation given in late pregnancy. 2.5 Low
Higher risk
for LBW
Lower consumption of GLV and fruits (1study) (41), lower maternal B12 status (2 studies) (24, 42), lower maternal B12/folate ratio (1 study) (23) and lower cord B12 status (1 study) (43) was associated with lower birth weight. In three studies (24, 42, 44) higher maternal homocysteine was associated with birth weight additionally supported for causal association by Mendelian randomization technique (1 study) (44). A micronutrient food based intervention did not improve birth weight or fetal growth (2 studies) (45, 46). One RCT with 50mcg B12 starting from early pregnancy did not improve birth weight (47). Micronutrient supplementation (inclusive of B12) in late pregnancy in undernourished mothers reduced incidence of LBW (40). Many observational studies with adjustments for confounding.
Mendelian randomization technique supports causal association of high maternal homocysteine (marker of B12 deficiency) with LBW. Inference of causality from RCT is inconclusive.
4 High
Higher risk for IUGR, SGA Lower maternal B12 status associated with higher risk of IUGR (1 study) (48). In a case control study nested within a birth cohort SGA group had higher maternal homocysteine during pregnancy (1 study) (49). Women with lowest dietary intakes of B12 rich foods and higher intake of folic acid supplements during pregnancy had highest risk for delivering SGA babies (1 study) (50) Case control study with matched sample and adjusted for confounders. Systematic assessment of dietary intakes. 3 Moderate
Other neonatal size (smaller length, head circumference) Higher consumption of GLV and milk by mother was associated with higher birth length, head, chest circumference (1 study) (41). Higher maternal folate to B12 ratio was associated with birth length chest circumference and head circumference (1 study) (23). GLV and milk products are a proxy measure of B12 intake. Small sample size of observational study that examined folate/B12 ratio 2.0 Low
Later
life outcomes
Lower vitamin B12 status in offspring Maternal B12 status in pregnancy associated with B12 status in offspring at 6 weeks (1 study) (21), 2 years (1 study) (51) and 9 years of age (52) 3 Moderate
Offspring metabolic outcomes (adiposity, insulin resistance, bone mineral density) Higher dietary intake of GLV milk products during pregnancy associated with higher bone mineral density in childhood but no associations with B12 concentrations (1 study) (53).
Low maternal B12 status and low B12-high maternal folate pattern was associated with higher insulin resistance in offspring at 6 years (1 study) (19) while maternal B12 showed no association at 9 years in another study (54). High maternal folate associated with higher adiposity and insulin resistance in childhood (2 studies) (19, 54). High homocysteine associated with higher glucose concentration in child (1 study) (54).
Observations in cohort studies adjusted for confounding 3 Moderate
Cardiovascular outcomes (Offspring stress response and HRV) Higher maternal B12 deficiency and higher homocysteine in pregnancy associated with greater cortisol and heart response to stress in childhood (1 study) (55). Low maternal B12 status in pregnancy associated with reduction in HRV in child (56) Observations in prospective cohorts with adjustment for cofounders but outcomes examined in smaller subset of participants 2.5 Low
Offspring cognitive functions Low maternal B12 status associated with poorer cognitive function in offspring at 2 years and 9 years (2 studies) (57, 58) and there was no association with B12 in one study (59).
Higher maternal folate associated with better motor development at 2 years (57) and better cognitive functions at 9 years (59). One RCT showed supplementation with 50mcg B12 starting from early pregnancy improved language functions at 30 months (60) but not 9 months (61). Higher maternal homocysteine was associated with poorer cognitive outcomes (60, 61)
Supported for causality by observations from RCT 3.5 Moderate

GRADE ratings (1 – Very low, 2- Low, 3 – Moderate, 4 – High).

*Average of ratings by 2 reviewers.