1.1 Determinants of vitamin D status in pregnancy Level II studies Study ref Evidence Level Sample size Setting/population Findings Comments () II 50 150 serum samples from women in 1st, 2nd and 3rd trimester of pregnancy in Warsaw. 72.7% of the sera were from women who reported taking multivitamin supplements containing vitamin D3 (71% of that group was taking 400 IU daily). BMI: Mean 250HD concentrations by BMI in 1st trimester differed significantly (p<0.05): BMI <21 (13 patients, 39 samples): 27.3 ng/mL BMI >25 (14 patients, 42 samples): 23.5 ng/mL Optimal 250HD levels (30-80 ng/ml) 30.0% Hypovitaminosis (20-30 ng/ml): 38.7%, Deficiency (10-20 ng/ml): 24.0% Severe deficiency (< 10 ng/ml) 7.3%
() II 60 We consecutively recruited 41 immigrant (originating from Africa, the Middle East, India, Pakistan, Bangladesh and South America) and 19 healthy native Swedish women Migration: Mean+/-SD 25(OH)D in gestational week 12 was 20+/-11 nmol/L among the immigrants and 60+/-17 nmol/L among the Swedish women (p<0.001). Postpartum 25(OH)D was 29+/-18 nmol/L among the immigrants and 53+/-19 nmol/L among the Swedish women (p=0.003). () II 494 Blood samples were taken from 154 African-American, 194 Hispanic, and 146 Caucasian women at <14 weeks of gestation at a southern latitude. Skin phototype: The mean 25(OH)D levels in African-American, Hispanic, and Caucasian pregnant women were 15.5 +/- 7.2 (standard deviation), 24.1 +/- 8.7, 29.0 +/- 8.5 ng/mL, respectively. Ninety-seven percent of 81% of Hispanics, and 67% of Caucasians were deficient or insufficient. Of these pregnant women, 82% had vitamin D levels <32 ng/mL (<80 ng/mL). In logistic regression models, race was the most important risk factor for vitamin D deficiency or insufficiency. African-American women and Hispanic women were more likely to have vitamin D insufficiency and deficiency than Caucasian women. Furthermore, primigravid women were more at risk for vitamin D insufficiency. Deficiency: 25(OH)D <20 ng/mL or <50 nmol/L Insufficiency: 25(OH)D >20 ng/mL or <32 ng/mL or >50 nmol/L or <80 nmol/L matched
() II 346 Women with sufficient stored serum were randomly selected from among all women who delivered between April 2008 and March 2009 in North West London. Sample represented the total population regarding skin tone, quartile, BMI, gestation and parity Skin phototype: Among women with dark skin, only 8% (95% CI: 5-12%) had adequate levels compared with 43% (95% CI: 33-53%) of those with light skin. BMI: Obese women were found to have significantly lower vitamin D levels than non-obese women (47 vs 35% deficiency). Deficiency was defined as <25nmolL(-1) , insufficiency and adequacy >75nmolL(-1) () II 193 Plasma 25(OH)D was determined at 8-20 weeks gestation and following birth. Usual predictors of vitamin D status (BMI, race, season) in addition to prenatal supplemental vitamin D intake and docosahexaenoic acid (DHA) status at delivery were assessed for their interaction on the change on plasma 25(OH)D concentration between the two time points. Season of birth (F = 7.86, P = 0.006) and plasma 25(OH)D concentration (F = 6.17, P = 0.014) were significant variables in the change of vitamin D status while BMI, race, DHA status, and typical vitamin D intake (334 IU/day) from prenatal supplements did not have an effect. Season: Women who delivered in summer and fall had a 1.5-fold greater plasma 25(OH)D concentration than women who delivered in winter and spring (41.1 +/- 23.1 and 40.7 +/- 20.5 nmol/L summer and fall, respectively, versus 27.7 +/- 17.9 and 29.3 +/- 21.4 nmol/L in winter and spring, respectively). Vitamin D status categorized as deficient (<30 nmol/L) or insufficient (30-49.9 nmol/L).
Maternal outcomes Impaired glucose tolerance and gestational diabetes Study ref Evidence Level Sample size Setting/population Findings Comments () II 1,314 Pregnant women who participated in Project Viva, a birth cohort study. 25(OH)D levels were measured at 26-28 weeks gestation during GDM screening using a 1-hour 50-g glucose challenge test 25(OH)D levels <25 nmol/L were found in: 44 of 1,087 women (4.0%) with normal glucose tolerance 9 of 159 women (5.7%) with impaired glucose tolerance 9 of 68 women (13.2%) with GDM. Analyses that were adjusted for sociodemographics, season, maternal BMI, gestational weight gain, and dietary factors suggested that women with 25(OH)D levels of <25 vs >25 nmol/L may have higher odds of experiencing GDM (OR 2.2; 95%CI 0.8-5.5). Glucose levels after the glucose challenge test were associated inversely with 25(OH)D levels (P<0.01). Second-trimester 25(OH)D levels were associated inversely with glucose levels after 1-hour 50-g glucose challenge test; low 25(OH)D levels may be associated with increased risk of GDM. () II Australian study 5,109 Study was conducted on the basis of a study population of 11,358 women who were attending first-trimester Down syndrome screening in NSW. Cases of each study outcome of interest (SGA, preterm birth, preeclampsia, GD, miscarriage, and stillbirth) were randomly selected from the maternal screening population. In the univariate analysis, women with 25(OH)D concentrations <37.5 nmol/L had increased risk of GD; however, this association was attenuated after adjustment for maternal factors (aOR: 1.08; 95% CI: 0.74, 1.56). Controls were sourced using a method that ensured the random blinded selection of samples.
() IV Australian study 1,550 Among pregnant women in a maternity service that recommends routine antenatal screening and advises supplementation where necessary, Vitamin D serum concentrations were measured in early and late pregnancy. The relationship between initial vitamin D status, maternal factors and pregnancy outcomes were estimated. After adjusting for potential confounders, there was an association between GDM and early pregnancy vitamin D deficiency (OR 6.90 [1.66, 28.7]; p=0.008) or insufficiency (OR 7.6 (1.83, 32.0];p=0.005) compared to replete. Deficient:<50 nmol/L (n=849 [55%]) Insufficient: 50-74 nmol/L (n=571 [37%]) Replete: >75nmol/L (n=130 [8%]) () IV Australian study 399 Pregnant women living in an Australian subtropical environment. All patients underwent a blinded 75-g oral glucose tolerance test at 24-32 (target 28) weeks' gestation. A difference of one standard deviation in maternal 25-hydroxy vitamin D was inversely related to fasting glucose (fasting glucose lower by 0.047 mmol/l, P=0.012) when assessed with multiple linear regression after adjusting for confounders. Maternal 25-hydroxy vitamin D correlated with beta-cell function as estimated by the homeostasis model function equation (r=0.131, P=0.009), but not with the homeostasis model assessment of insulin resistance. An association between mid-gestational 25(HO)D and fasting glucose was confirmed in a largely normoglycaemic and vitamin D-replete pregnant population. The correlation between 25-hydroxy vitamin D and beta-cell function suggests that vitamin D may influence glucose metabolism through this mechanism. Mean (+/- SD) fasting plasma glucose: 4.5 +/- 0.4 mmol/l. Mean (+/- SD) serum 25(HO)D: 132.5 +/- 44.0 nmol/l. cell
() III-3 159 In a nested case-control study of 2,496 pregnant women, we identified 39 women who developed preeclampsia and 120 non-preeclamptic controls Vitamin D levels were similar in women who developed preeclampsia, 52.2 +/- 20.5 nmol/L, and controls, 48.6 +/- 20.5 nmol/L, p = 0.3. In addition, vitamin D deficiency (<50 nmol/L) was found in a similar proportion of control group (51.7%) as those with severe preeclampsia (41.2%). Our data do not support the hypothesis that vitamin D deficiency in early pregnancy is associated with preeclampsia, but we cannot rule out a relation later in gestation. () IV Australian study 1,550 Among pregnant women in a maternity service that recommends routine antenatal screening and advises supplementation where necessary, Vitamin D serum concentrations were measured in early and late pregnancy. The relationship between initial vitamin D status, maternal factors and pregnancy outcomes were estimated. There was no association between early vitamin D deficiency and preeclampsia (p = 0.64). Deficient:<50 nmol/L (n=849 [55%]) Insufficient: 50-74 nmol/L (n=571 [37%]) Replete: >75nmol/L (n=130 [8%])
() IV Australian study 1,550 Among pregnant women in a maternity service that recommends routine antenatal screening and advises supplementation where necessary, Vitamin D serum concentrations were measured in early and late pregnancy. The relationship between initial vitamin D status, maternal factors and pregnancy outcomes were estimated. There was no association between early vitamin D deficiency and preterm birth (p = 0.11). Deficient:<50 nmol/L (n=849 [55%]) Insufficient: 50-74 nmol/L (n=571 [37%]) Replete: >75nmol/L (n=130 [8%]) Small for gestational age Study ref Evidence Level Sample size Setting/population Findings Comments () II 280 Pregnant women at 11-13 weeks' gestation, of whom 75% used vitamin supplementation. Frequency of SGA neonates was similar in both groups (5.3% – 25OHD <20 ng/ml and 3.9% – 25OHD>20 ng/ml). Deficiency: <20 ng/ml (54%) Insufficiency: 20-30 ng/ml (34%) Sufficiency: >30ng/ml (11%) () II 3,730 Secondary analysis of data derived from a large cohort in The Netherlands (Amsterdam Born Children and their Development (ABCD) cohort), including women with singleton term deliveries. Compared with women with adequate vitamin D levels, women with deficient vitamin D levels had a higher risk of SGA (OR 2.4, 95 % CI 1.9, 3.2). Deficient: ≤29.9 nmol/l Insufficient: 30-49.9 nmol/l Adequate: ≥50 nmol/l ethnic
Macrosomia Study ref Evidence Level Sample size Setting/population Findings Comments () II 2,358 Pregnant women (median weeks of gestation 14.0, range 13.0-15.0) from the INMA (INfancia y Medio Ambiente) cohort (Spain, 2003-2008) Maternal deficit of 25(OH)D3 (<20 ng ml(-1)) was associated with increased risk of fetal overweight defined as AC 90th percentile (OR=1.50, 95%CI: 1.01-2.21; P=0.041) or as EFW 90th percentile (OR = 1.47, 95% CI: 1.00-2.16; P = 0.046). No significant associations were found with rapid growth. Fetal anthropometry Study ref Evidence Level Sample size Setting/population Findings Comments () II 2,358 Pregnant women (median weeks of gestation 14.0, range 13.0-15.0) from the INMA (INfancia y Medio Ambiente) cohort (Spain, 2003-2008) We found no association of maternal 25(OH)D3 concentration with femur length and a weak inverse association with biparietal diameter at 34 weeks. Infant and childhood outcomes Growth in the first year Study ref Evidence Level Sample size Setting/population Findings Comments () II 3,730 Secondary analysis of data derived from a large cohort in The Netherlands (Amsterdam Born Children and their Development (ABCD) cohort), including women with singleton term deliveries. Neonates born to mothers with a deficient vitamin D status showed accelerated growth in weight and length during the first year of life. Deficient: ≤29.9 nmol/l Insufficient: 30-49.9 nmol/l Adequate: ≥50 nmol/l ethnic
ADHD Study ref Evidence Level Sample size Setting/population Findings Comments () II 1,650 pairs Mother-child pairs from five birth cohorts embedded in the INMA Project (Spain, After adjustment, the number of total ADHD-like symptoms in children decreased by 11% per 10ng/ml increment of maternal 25(OH)D3 concentration (incidence rate ratio [IRR] = 0.89; 95% CI = 0.80, 0.98). Similarly, the number of symptoms in the ADHD subscales decreased in relation to higher maternal 25(OH)D3 concentration (IRR per 10ng/ml increment = 0.89; 95% CI = 0.79, 0.99 for the inattention scale; and IRR = 0.88; 95% CI = 0.78, 0.99 for the scale). Using diagnostic criteria, we found an association of increasing maternal 25(OH)D3 with a lower risk of ADHD DSM-IV (relative risk ratio per 10ng/ml increment = 0.87; 95% CI = 0.72, 1.06) and ICD-10 hyperkinetic disorder (relative risk ratio = 0.72; 95% CI = 0.49, 1.04) in children.
() RCT II 42 Aim: to evaluate the effects of calcium plus Vitamin D administration on metabolic status and pregnancy outcomes in healthy pregnant women Setting: Kashan, Iran Population: Pregnant women aged 18-40 years at week 25 of gestation Intervention: 500 mg calcium-200 IU cholecalciferol supplements (n=21) versus placebo (n=21) for 9 weeks. Subjects also consumed 400 μg folic acid daily from the beginning of the pregnancy and 50 mg ferrous sulfate from the second trimester. Outcomes: Secondary outcomes included birth size, gestational age, and mode of delivery. Supplementation had no significant effect on birth weight (p=0.88). High risk of bias; see Section 2.7
Neonatal serum calcium Study ref Design LoE N Intervention/observation/comparison population Results Limitations () SLR I 76 studies (11 RCTs; 65 observational studies) A modest positive relationship was identified between maternal 25(OH)D and offspring cord blood or postnatal calcium concentrations in a meta-analysis of six intervention studies (all found to be at high risk of bias; mean difference 0.05mmol/l, 95% CI 0.02 to 0.05mmol/l). NB of studies not included in the Cochrane review, one compared vitamin D plus calcium vs no supplement and found a significant difference in serum calcium in cord blood (p<0.25). Study methodology varied widely in terms of study design, population used, vitamin D status assessment, exposure measured and outcome definition.
Hypertensive disorders of pregnancy Study ref Design LoE N Intervention/observation/comparison population Results Limitations () Analysis of 2 RCTs II 504 Analysis of NICHD trial () (included in HTA review) and Thrasher Research Fund trial (). Aim: To assess the safety and health effects of vitamin D supplementation during pregnancy Setting: United States Population: NICHD women with a singleton pregnancy <12–16 wk gestation; Thrasher women at <16 wk gestation Intervention: In the NICHD trial, women were randomized to 400, 2000, or 4000 IU vitamin D3/day, stratified by race. In the Thrasher Research Fund trial, participants were randomized to 2000 or 4000 IU vitamin D3/day. Outcomes: [1] maternal and neonatal 25(OH)D achieved, and [2] maternal comorbidities of pregnancy (COP). While not reaching statistical significance, there was a trend of a lower rate of hypertensive disorders of pregnancy in the 4000 IU group compared to the Control and 2000 IU groups (2.1 vs 8.2 vs 4.5%) Low risk of bias; see Section 2.7
Gestational diabetes Study ref Design LoE N Intervention/observation/comparison population Results Limitations () Analysis of 2 RCTs II 504 Analysis of NICHD trial () (included in HTA review) and Thrasher Research Fund trial (). Aim: To assess the safety and health effects of vitamin D supplementation during pregnancy Setting: United States Population: NICHD women with a singleton pregnancy <12–16 wk gestation; Thrasher women at <16 wk gestation Intervention: In the NICHD trial, women were randomized to 400, 2000, or 4000 IU vitamin D3/day, stratified by race. In the Thrasher Research Fund trial, participants were randomized to 2000 or 4000 IU vitamin D3/day. Outcomes: [1] maternal and neonatal 25(OH)D achieved, and [2] maternal comorbidities of pregnancy (COP). While not reaching statistical significance, there was a trend of a lower rate of gestational diabetes in the 4000 IU group compared to the Control and 2000 IU groups. (5.2 vs 7.3 vs 8.0%) Low risk of bias; see Section 2.7
Low birth weight Study ref Design LoE N Intervention/observation/comparison population Results Limitations () SLR I 76 studies (11 RCTs; 65 observational studies) A modest positive relationship was identified between maternal 25(OH)D and offspring birthweight in meta-analysis of three observational studies using log-transformed 25(OH)D concentrations after adjustment for potential confounding factors [pooled regression coefficient 5.63g/10% change maternal 25(OH)D, 95%CI 1.11 to 10.16g], but not in those four studies using natural units, or across intervention studies. Study methodology varied widely in terms of design, population, vitamin D assessment, exposure measured and outcome definition.
1000–1200 IU versus 2000 IU per day Maternal and neonatal 25(OH)D Study ref Design LoE N Intervention/observation/comparison population Results Limitations () RCT II 226 Setting: Greater Vancouver Canada Population: Healthy pregnant women aged y Intervention: 400 IU/d, 1000 IU/d or 2000 IU/d vitamin D3/d from 13 to 24 wk of gestation until 8 wk postpartum, with no infant supplementation. Mother and infant blood was collected at 8 wk postpartum. Outcome: prevalence of infant serum 25(OH)D cutoffs (>30, >40, >50, and >75 nmol/L) by dose at 8 wk of age. Fewer infants born to mothers in the 2000 IU/d group had a 25(OH)D concentration <30nmol/L than infants in the 1000 IU/d and 400 IU/d groups, respectively (2% vs 16% and 43%; P < 0.05). Fewer than 15% of infants in the 400 or 1000/d groups achieved a 25(OH)D concentration >75 nmol/L compared with 44% in the 2000 IU/d group (P<0.05). Almost all infants (~98%, n = 44) born to mothers in the 2000 IU/d group achieved a 25(OH)D concentration >30 nmol/L. At 8 wk postpartum, mean maternal 25(OH)D concentration was higher in the 2000 IU/d [88 (84, 91)] than in the 1000 IU/d [78 (74, 81)] or 400 IU/d [69 (66, 73)] groups (P < 0.05). Unclear risk of bias; see Section 2.7
() RCT II 75 at 2 wk 44 at 2 wk and 2 mth Aim: to examine the effect of vitamin D supplementation during pregnancy on vitamin D activity (VDA) in the first 2 mo of lactation Setting: Auckland, New Zealand Population: Women who were enrolled in a randomized, double-blinded, trial of vitamin D supplementation during pregnancy. Intervention: Pregnant women were enrolled at 27 wk of gestation and randomly assigned to the following 3 groups: placebo, one dosage of daily oral vitamin D3 (1000 IU), or 2 dosages of daily oral vitamin D3 (2000 IU). Outcomes: Serum 25(OH)D was measured at enrollment, at 36 wk of gestation, and in cord blood at birth. Study participants who were breastfeeding were invited to provide breast-milk samples for VDA measurement [concentration of vitamin D2, vitamin D3, 25(OH)D2, and 25(OH)D3] at 2 wk and 2 mo postpartum. Mean (95% CI) VDA at age 2 wk was: 52 IU/L (12, 217 IU/L) in the placebo group, 51 IU/L (17, 151 IU/L) in the 1000-IU group, and 74 IU/L (25, 221 IU/L) in the 2000-IU group. Mean (95% CI) VDA at 2 mo was: 45 IU/L (16, 124 IU/L), 43 IU/L (18, 103 IU/L), and 58 IU/L (15, 224 IU/L), respectively. There was no significant interaction in VDA between the sample-collection time and treatment (P=0.61), but there was a difference between lower- and treatment groups (P = 0.04). Low risk of bias; see Section 2.7
() cohort study III-2 104 Low-risk pregnant women had a 25[OH]D serum level drawn at the first prenatal visit (mean 10.7 [SD6.17] weeks). Supplementation was recommended with either 2000 or 4000 units of vitamin D3 for women who had vitamin D insufficiency (20-29 ng/mL) or deficiency (<20 ng/mL). There were no significant demographic differences between women who were deficient (n=23) or insufficient (n=49) and those whose serum levels were in the sufficient range (>30 ng/mL)(n=32). Among women who had a repeat measure of 25(OH)D after supplementation (n=20), there was a significant rise in vitamin D level (P<0.001). Mean rise: Insufficiency — 2000 units (n=11) 6.72 ng/mL; 4000 units (n=1) 0 ng/mL Deficiency — 2000 units (n=3) 16.3 ng/mL; 4000 units (n=5) 15.8 ng/mL Although there was a not a significant difference, women who took 4000 units had a higher mean rise (13.17 ng/mL) than those taking 2000 units (8.79 ng/mL). Twelve of the women (60%) were still insufficient after supplementation with 2000 units of vitamin D3. Unclear how women were allocated to different doses. Adherence to was questioned as one woman had no change and 2 had a negative change. on
() III-2 275 cases 548 controls 2- to 4-month-old cases with positional skull deformation were compared with controls. A questionnaire was used to gather information on background characteristics and vitamin D intake (food, time spent outdoors and supplements). In a multiple variable logistic regression analysis, insufficient vitamin D supplement intake of women during the last trimester of pregnancy [aOR 1.86, 95% (CI) 1.27-2.70] and of children during early infancy (aOR 7.15, 95% CI 3.77-13.54) were independently associated with an increased risk of skull deformation during infancy.
() () Random sequence generation Low risk ‘Stratified blocked randomization was used to balance by ethnicity and also to balance by enrollment (as a cautionary measure against a potential temporal or seasonal bias). A randomization scheme was developed separately for each of the three groups (ie, the strata). Within each stratum, the treatments were assigned within blocks. Because there were three treatment groups, the block size had to be divisible by 3; the data team selected a block size of six, which was unknown to the investigators or the pharmacists. In this way, at the end of each block (ie, enrollment of six subjects), each group was balanced in the number randomly assigned to the 400-, 2000-, and 4000-IU treatment groups.’ Allocation concealment Unclear risk Not described. Blinding Low risk ‘Double blind’ Incomplete outcome data Low risk Explanation for loss to follow-up (30% from allocation to analysis) explained. Analysis was by intention to treat. Selective reporting Low risk Prespecified outcomes reported. Other limitations Low risk No significant difference in baseline characteristics between groups () Random sequence generation Low risk Randomization lists were generated by computer prior to the start of the study. Allocation concealment Low risk Randomization assignment was blinded to all participants and to the investigators except for the study biostatistician. Dose groups were identified for logistical purposes using 6 letters (3 per dose group) as an additional measure against inadvertent unblinding. Blinding Low risk ‘Double blinded’ Incomplete outcome data Low risk Explanation for loss to follow-up (38% from allocation to analysis) explained. Analysis was by intention to treat. Selective reporting Low risk Prespecified outcomes reported. Other limitations Low risk After controlling for race and study site, no characteristics differed significantly between groups.
Study ref Evidence Level Sample size Setting/population Findings Comments () IV 116 Pregnant women booking for antenatal care in Cairns Base Hospital, Queensland (latitude 16.87°S). There were no significant differences overall in the women’s vitamin D concentrations based on their indigenous status, diabetes status or parity. However, within the range of 50–100 nmol/L, Indigenous women’s median serum vitamin D concentrations (78) were significantly lower than the median concentrations of nonindigenous women (89) P=0.05, but were above the level at which insufficiency is diagnosed. Australian study Vitamin D level (nmol/L): 50–74.9: n=8 (6.9%) 75–99.9: n=28 (24.2%) 100–150: n=68 (58.6%) 151–200: n=12 (10.3%) () II 200 Comparison of vitamin D levels in Aboriginal women attending for antenatal care in Kalgoorlie ((latitude 30.7489°S, longitude 121.4658°E) at either the antenatal clinic at Bega Garnbirringu Health Service (n=100) (BG) or antenatal care with a local GP obstetrician (n=100) (LC). Aboriginal patients from the Aboriginal Community Controlled Health Service (ACCHS) had lower serum vitamin D levels (mean 46.7, SD 21.7 nmol/L), compared with non-Aboriginal women (mean 65.4, SD 18.4 nmol/L, P <0.0001). The difference was 11.5 nmol/L (P = 0.0078) after controlling for confounding variables. 18% of Aboriginal patients had vitamin D deficiency (<25 nmol/L) at measurement, compared with 2% of non-Aboriginal patients