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Vitamin D supplementation in pregnancy and lactation to promote infant growth

BACKGROUND Causes of early infant growth restriction remain incompletely understood. Where vitamin D deficiency is common, vitamin D supplementation during pregnancy and lactation may improve fetal-infant growth and other birth outcomes. METHODS We conducted a randomized, double-blind, placebo-controlled trial of maternal vitamin D supplementation from 17-24 weeks gestation until birth or 6 months postpartum. Participants were randomly allocated to five vitamin D and/or placebo supplementation groups: (A) 0 IU/week, (B) 4200 IU/week, (C) 16800 IU/week, or (D) 28000 IU/week in pregnancy, all with 0 IU/week postpartum; or, (E) 28000 IU/week in prenatal and postpartum periods. The primary outcome was length-for-age z-score at one year of age according to World Health Organization child growth standards. RESULTS Among 1164 infants assessed at one year of age (90% of 1300 pregnancies), there were no differences across groups in length-for-age z-scores (mean ±standard deviation): A: -0.93 ±1.05, B: -1.11 ±1.12, C: -0.97 ±0.97, D: -1.06 ±1.07, E: -0.94 ±1.00 (p=0.23). Groups were similar with respect to other anthropometric measures, birth outcomes, and morbidity. Vitamin D had dose- dependent effects on maternal and infant serum 25-hydroxyvitamin D and calcium, maternal urinary calcium excretion, and maternal parathyroid hormone concentrations. No clinical adverse events were attributed to the vitamin D intervention. CONCLUSIONS In a population with widespread prenatal vitamin D deficiency and fetal/infant growth restriction, maternal vitamin D supplementation from mid-pregnancy until birth or 6 months postpartum does not influence fetal or infant growth, and has no beneficial or harmful effects on numerous other birth and infant outcomes.

. Supplementation duration and adherence among participants included in the complete case analysis, by supplementation group . 32 Table S11. Raw anthropometric parameters and additional anthropometric indicators for infants at 1 year of age, by supplementation group . 33 Table S12. Pairwise between-group comparisons of the effect of different doses of prenatal and postpartum vitamin D supplementation on lengthfor-age z-score, weight-for-age z-score, weight-for-length z-score, body mass index-for-age z-score, head-circumference-for-age z-score, and midupper arm circumference-for-age z-score at 1 year of age ..  Table S18. Length-for-age z-scores of infants at 1 year of age by supplementation group, using multiple imputation to impute missing 1 year lengthfor-age z-scores ..  Table S19. Effect of prenatal and postpartum vitamin D on anthropometric outcomes at 1 year of age after correcting for gestational age at birth .... 42 Table S20. Per-protocol analysis of the effect of prenatal and postpartum vitamin D supplementation on anthropometric outcomes at 1 year of age.43 Table S21. Effect of prenatal and postpartum vitamin D on length-for-age z-score at 1 year of age by gestational age at birth, infant sex, maternal height, maternal supplement adherence, and maternal baseline serum 25 ( Table S30. Primary diagnoses at clinical encounters and primary discharge diagnoses for hospitalizations among infants up to 6 months of age ........ 60 Table S31. Primary diagnoses at clinical encounters and primary discharge diagnoses for hospitalizations among infants from 6-12 months of age .... 62 Table S32. Additional Methods

Method 1. Detection of outliers and implausible anthropometric values
Data sources Infant length, weight, head circumference, upper-arm length, mid-upper arm circumference, and rump-knee length measurements collected on a trimonthly basis from birth until 2 years of age, with an additional measurement between 2-8 weeks of age.
Implausible values: Anthropometric measurements that were temporally inconsistent with previous measurements. Length, head circumference, upperarm length and rump-knee length were assumed to be constantly increasing through serial measurements, while weight may fluctuate slightly between successive measurements. Any decreases in length, head circumference, upper-arm length and rump-knee length were identified as implausible measurements, whereas any declines in weight ≥10% between two successive measurements were considered implausible.

Statistical analysis
The purpose of identifying outlier was to prompt manual data review and reconciliation. Values were corrected if the review of data forms and study logs provided information that enabled such corrections. However, outliers that could not be reconciled remained in all analyses unless there was sufficient evidence to indicate they were a result of measurement or data entry error.
To identify outliers based on the residual method 1 , linear regression was used to fit a straight line through an individual's age-standardized z-score (Z) as a function of age (t): Zij = β0i + βi tij + εij; where "i" is the i th individual and "j" reflects the j th time point. Based on the model predicted for each individual, jackknife residuals were calculated, and measurements with an absolute jackknife residual ≥5 were flagged as outliers for length, weight, and head circumference, and measurements with an absolute jackknife residual ≥7 were flagged as outliers for mid-upper arm circumference. A similar procedure was applied to raw anthropometric data when z-scores were not available (rump-knee length, upper-arm length), except the raw anthropometric measurement (Y) was regressed on the square root of age (t 1/2 ): Yij = β0i + βi tij ½ + εij; where "i" reflects the i th individual and "j" reflects the j th time point. Based on the model predicted for each individual, jackknife residuals were calculated and measurements with an absolute jackknife residual ≥7 were flagged as outliers.
When implausible values due to temporal inconsistencies between two consecutive measurements were flagged, jackknife residuals for each of the two time points were compared and the measurement with the largest absolute jackknife residual was considered the incorrect measurement. Implausible values were dropped from analysis unless they could be reconciled and corrected through manual review.
All serum 25(OH)D measurements were conducted at the Analytical Facility for Bioactive Molecules (AFBM) at the Hospital for Sick Children (Toronto, Canada). The AFBM participates in Vitamin D External Quality Assessment Scheme (DEQAS) certification. Serum samples of women at baseline, delivery, 3 months postpartum and 6 months postpartum; venous cord; and infants at 3 months, 6 months and 12 months of age were extracted by the AFBM via liquid-liquid using a Zinc Sulfate/Methanol/n-Hexane protocol. Standard curves were prepared in 4% BSA in PBS and the internal standard 25(OH) Vitamin D3-d6 was prepared in methanol.

Specific details on lab techniques
Internal standard was added to silanized glass round-bottom tubes. Sample, standard, or NIST SRM972a quality control was then added, followed by 0.4M ZnSo4.
After a brief vortex, methanol was added and tubes were vortexed again. Next, n-Hexanes were added and tubes were vortexed for 1 minute followed by a 30 second rest. The tubes were vortexed for 1 minute with 30 second rest a total of 3 times. Samples were then centrifuged at 800g for 10 minutes. Hexane supernatants were transferred to a clean conical silanized glass tube. Methanol was added to the original tubes and samples were vortexed thoroughly before a second addition of n-Hexanes. Samples were then vortexed and centrifuged as described above, and the supernatant was combined with the previously transferred hexane supernatant. Samples were taken to dryness under nitrogen and then reconstituted in equal parts water and methanol and transferred into inserts in autosampler vials.
Samples were analyzed by LC-MS/MS using an Aglient 1290 HPLC interfaced with an AB Sciex 5500 Q-Trap mass spectrometer. Samples were injected onto a Kinetex F5 2.6 um 100 x 3.0 mm column (Phenomenex). Chromatographic separation of 25(OH)D2, 25(OH)D3, and the 25(OH)D3 C-3 epimer occurred at retention times of 2.55, 2.40, and 2.54 min, respectively. Analytes were eluted from the Kinetex column at a flow rate of 700 µL/min over a gradient of mobile phases of water and methanol. Data were collected and analyzed using Sciex Analyst v1.6.3.

Quality control
To ensure quality of data, NISTSRM972a quality control and DEQAS standards (451,452,453,454,455) were run with every batch of specimens assayed. DEQAS standards were regularly monitored for accuracy by comparing calculated concentrations with the expected concentrations. In addition, a pooled plasma sample was run in at least duplicate with every batch assayed. Average inter-assay coefficient of variation (CV) was 10%, and average intra-assay CV was 5%.

Statistical analysis
Distributions of maternal serum 25(OH)D concentrations (nmol/L) at baseline, delivery, 3 months postpartum and 6 months postpartum; serum 25(OH)D concentration in cord blood; and infant serum 25(OH)D concentrations at 3 months, 6 months and 12 months of age, stratified by treatment group, were first visualized using boxplots and jittered scatterplots. In addition, graphs of mean 25(OH)D concentrations with 95% confidence interval bands were generated for each of the specified maternal and infant time points, stratified by treatment arm.
Means and standard deviations of maternal serum 25(OH)D concentrations (nmol/L) at baseline, delivery, 3 months postpartum and 6 months postpartum; serum 25(OH)D concentrations in venous cord blood; and infant serum 25(OH)D concentrations at 3 months, 6 months and 12 months of age, were calculated, stratified by treatment arm (Table S23). Comparisons of 25(OH)D concentrations across treatment groups at each of the specified time points were conducted using ANOVA. For those ANOVAs that were statistically significant (p<0.05), pairwise comparisons using t-tests were carried out between each of the treatment groups. The Holm test was used to account for multiple testing.
The number and proportion of women and infants at each of the specified time points with measured 25(OH)D concentrations <30 nmol/L; 25(OH)D concentrations ≥30 nmol/L and ≤50 nmol/L, and >125 nmol/L were also calculated, by treatment group (Table S23). Comparisons across treatment arms at each time point were carried out using Chi-square or Fischer's exact tests. For those tests that were statistically significant, pairwise comparisons were carried out between each of the treatment groups, adjusting for multiple comparisons by using the Holm test.
Primary analyses of 25(OH)D concentrations excluded the C-3 epimer of 25(OH)D3. Since 25(OH)D2 concentrations were undetectable or negligible in a large subset (n=1149) of representative samples that we checked, reported 25(OH)D values represent 25(OH)D3 only (Table S23). Concentrations of the C-3 epimer of 25(OH)D3, as well as total 25(OH)D concentrations (sum of 25(OH)D3 and C-3 epimer of 25(OH)D3) were reported separately as means with standard deviations, and proportions of women and infants at each specified time point, by treatment group (Table S24).

Method 3. Rickets screening and determination
Infants were scheduled for screening for rickets at 6-month clinical visits. Serum calcium, inorganic phosphorous, and alkaline phosphorous (ALP) were measured in venous blood, and results were reported to the study physician. X-rays of wrists and/or knees, additional blood work, and referral to a pediatrician for assessment and treatment were prompted if any of the following criteria were met: ALP>450 U/L; or, ALP>350 U/L and phosphorus <1.56 mmol/L; or, phosphorus <1.00 mmol/L; or, total calcium < 2.10 mmol/L. If infant blood samples were not collected at the 6-month clinical visit, blood collection for rickets screening was offered at a later date. Wrist and/or knee radiographs were interpreted by a pediatric radiologist (J.S.) blinded to clinical and laboratory data to determine the number of infants with x-ray-confirmed rickets.

Method 4. Sensitivity and stratified analyses
Sensitivity analyses included: (1) using z-scores assigned based on gestational age (GA)-corrected age instead of chronological age; (2) per-protocol analyses; (3) subgroup and interaction analyses; (4) adjustment for baseline characteristics; (5) marginal effects of supplementation on length-for-age zscore (LAZ) from birth to 1 year; (6) multiple imputation to impute missing length-for-age z-scores of infants at 1 year of age.

Data sources
Gestational age at birth was based on recalled last menstrual period and 2 nd trimester ultrasound reports (see Table S1 in the Supplementary Appendix). Per-protocol analyses were based on adherence data, described in detail in Method 6 of the Supplementary Appendix. Data for subgroup/interaction and adjusted analyses were captured in study questionnaires from baseline and delivery, maternal anthropometry and biochemical measurements (25(OH)D, hemoglobin). Data for the marginal effects analyses used infant LAZ measurements from birth until 1 year of age. In addition to treatment allocation and length-for-age z-score at 1 year of age, infant anthropometric measurements at 6 and 9 months of age, maternal baseline characteristics (asset index, height) and infant sex were used for multiple imputation.

Operational definitions
GA-corrected age: GA-correction was only applied to preterm infants (<37 weeks), and was calculated using the following formula: GA-corrected age = Chronological age -(280 -Gestational age at birth), where gestational age at birth was the difference in days between the date of last menstrual period (LMP) and infant date of birth.
Per-protocol analyses: Per-protocol analyses were restricted to participants who received at least: (1) 90% of all scheduled study supplement doses and (2) had no consumption of non-study vitamin D or calcium from enrolment to 6-months postpartum for the overall test of difference across treatment groups.
For the single pairwise comparison that assessed the effect of postpartum supplementation (28000; 28000 vs. 28000; 0), per-protocol was consumption of at least 90% of postpartum doses and no consumption of non-study vitamin D or calcium in the 0-6 month postpartum period.

Statistical analysis
(1): GA-corrected age analyses: Among preterm infants, z-scores were assigned based on gestational age-corrected age, whereas for term infants z-scores were based on chronological age. The global test of difference across treatment groups using an ANOVA and the 6 pairwise comparisons that assessed the prenatal and postpartum effects of vitamin D supplementation on infant growth using t-tests (with adjustment for multiple comparisons using the Holm test in the prenatal period) were repeated using gestational-age corrected z-scores.
(2) Per-protocol analyses: The global test of difference across treatment groups using an ANOVA was repeated among participants classified as overall perprotocol. Five pairwise comparisons that assessed the effect of prenatal supplementation were repeated among participants classified as per-protocol in the prenatal period using t-tests and the Holm test to adjust for multiple comparisons. One pairwise comparison to assess the effect of postpartum supplementation was repeated among participants classified as per-protocol in the postpartum period using a t-test.
(3) Subgroup/interaction analyses: To test the overall effect of treatment assignment on LAZ at 1 year of age within each subgroup, ANOVA was used. A linear regression model with an interaction term between each treatment group and the respective subgroup was also generated, and contrasts were performed on the interaction term to assess the overall significance of this interaction effect across all treatment groups.
(4) Adjustment for baseline covariates: To adjust for baseline characteristics, separate linear regression models were used to assess the change in the primary inferences upon adjustment for each baseline characteristic. The coefficient estimate (and 95% CI) and the significance of the coefficient was presented for each covariate. Contrasts were conducted to test the difference in LAZ at 1-year of age across treatment groups after adjusting for the covariate included in the model. Two p-values for each covariate were presented: pcovariate which reflects the association between LAZ at 1 year and the covariate of interest, and pgroup which reflects the overall difference in LAZ at 1 year of age after adjusting for the single baseline characteristic.
(5) Marginal effects of supplementation on length-for-age z-score from birth to 1 year: The marginal effects of treatment group on LAZ were assessed using generalized estimating equations to model LAZ trajectories from birth until 1 year of age. A restricted cubic spline model was used, with knots set at 91, 182 and 273 days of age. Knots were selected to align with the data collection schedule. Interaction terms between treatment group and all age terms were included in the model to allow for differences in slopes between treatment arms. The marginal effects of treatment group on LAZ at birth, 3 months, 6 months, 9 months and 12 months of age, and on overall LAZ were assessed. The predicted mean LAZ was presented for the placebo group, and the mean difference (compared to the placebo group) in LAZ was presented for all other treatment groups.
(6) Multiple imputation to impute missing length-for-age z-scores of infants at 1 year of age: Multiple imputation by chained equations (MICE) was used to impute missing LAZ at 1 year of age. The imputation model included the main exposure (treatment assignment), outcome (LAZ at 1 year), and auxiliary variables that helped improve the performance of the missing data procedure (asset index, maternal height, LAZ at 6 months, LAZ at 9 months, and infant sex). Auxiliary variables were selected based on their relationship to missingness or LAZ at 1 year, using a liberal p-value of ≤0.1 or r 2 >0.3 for inclusion in the imputation model, based on Chi-square or Fisher's tests, t-tests or Wilcoxon-rank sum tests, and correlation analyses depending on the nature of the data. Although additional LAZ measurements from different time points were also related to LAZ at 1 year, they were not included in the imputation model due to the high degree of collinearity.
The dataset was arranged in wide format, such that each participant had one row of data. Using a MICE approach, all variables included in the imputation model (treatment assignment, LAZ at 1 year, asset index, maternal height, LAZ at 6 months, LAZ at 9 months, infant sex) were imputed if data were missing. Continuous variables were imputed using linear regression and binary variables were imputed using logistic regression. Fifty imputed datasets were generated.
Missing data was imputed for: (1) All participants with missing LAZ at 1 year except two women who were identified as protocol violations, to generate complete datasets for 1298 mother-infant pairs; and (2) Participants with missing LAZ at 1 year, among live births only and infants who did not die before 1 year of age, and excluding two participants identified as protocol violations, generating complete datasets for 1233 mother-infant pairs.
The estimation model used linear regression to determine the association between treatment group and LAZ at 1 year, with a contrast to test the overall difference in mean LAZ at 1 year of age between treatment groups.

Method 5. Graphical representation of longitudinal anthropometric data
Population-average infant anthropometric trajectories (length-for-age z-scores, weight-for-age z-scores, weight-for-length z-scores, body mass index-forage z-scores, head circumference-for-age z-scores) were depicted graphically based on predicted values from regression models of all available measurements (from birth to 1 year of age) as a function of age ( Figure S1-S5 in the Supplementary Appendix). Restricted cubic spline models were used in which knots were set at 91, 182, and 273 days (3, 6 and 9 months). Interactions between treatment group and all age terms were included in the models to allow for differences in slopes among treatment arms. Generalized estimating equations were used to account for the within-child correlation of repeated measures. Overlaying the scatter plots of observed measurements ( Figures S1-S5), coloured lines were used to distinguish predicted means for each treatment group. Missing data was not imputed for participants with an incomplete set of anthropometric measurements (birth, 3 months, 6 months, 9 months, 1 year). Measurements were not dropped from analysis on the basis of missing covariates, as age and treatment assignment were the only covariates in the models. The same models were used to generate estimated marginal effects of treatment group (Table S17).

Data sources
To determine the actual number of supplements consumed by each participant, a manual review of supplementation logs by two independent reviewers was conducted. Any discrepancies in the count of supplements consumed between the two reviews were flagged and a third study team member reviewed the supplementation log to resolve the discrepancy.
To determine the number of scheduled doses in the prenatal and postpartum period for each participant, data from a number of study questionnaires was used, including participant enrolment and discharge dates, weekly prenatal interviews, and labour and delivery records.

Operational definitions
Adherence: Supplementation adherence was calculated from the number of doses received divided by the number of doses scheduled, multiplied by 100 to generate a percentage, stratified by the prenatal and postpartum period for each participant.
Doses administered: The number of directly observed and unobserved doses consumed.
Prenatal scheduled doses: For the majority of participants in which infant date of birth (DOB) was not missing (i.e., excluding participants who died, withdrew from the study, or were lost to follow up prior to giving birth), the number of scheduled doses in the prenatal period was calculated as the number of weeks between enrolment and infant DOB. A subset of infants were born on a day in which a regular prenatal visit was scheduled, such that the prenatal visit may not have occurred if the participant was already in labour. Participants who gave birth on the day of a scheduled prenatal visit and did not complete a prenatal visit on the same day were identified, and scheduled prenatal doses were calculated as the number of weeks between enrolment and infant DOB, minus 1 week. Among women who died or were lost to follow up prior to giving birth, the number of scheduled doses in the prenatal period was calculated as the number of weeks between enrolment and maternal death or date of last contact, respectively.
Postpartum scheduled doses: The number of scheduled doses in the postpartum period was set to 26 for all participants who were included in the complete case analysis. Among participants who exited the study prior to delivery, delivered a stillborn baby, or were lost to follow up and not successfully contacted at least once after delivery, the number of postpartum scheduled doses was set to 0. Among participants who were formally discharged between delivery and 6 months postpartum (due to infant death, loss to follow up), the number of postpartum scheduled doses was calculated as the number of weeks between infant DOB and the date the participant was discharged from the study. For participants who were successfully contacted at least once during the postpartum period but had not been officially discharged from the study before 6 months postpartum, the number of scheduled doses in the postpartum period was determined as the number of weeks between infant DOB and the date in which the participant was last successfully contacted for a weekly postpartum interview.
Total vitamin D administered: The product of the assigned dosage in the treatment group and the number of supplement doses administered, stratified by the prenatal and postpartum period for each participant.

Proportion of tablets consumed under direct observation:
The number of home visits in which a supplement was consumed divided by the total supplementation doses administered.

Statistical analysis
Continuous non-normally distributed variables, including number of completed weekly monitoring visits, total supplementation doses administered, total vitamin D administered, adherence, and proportion of tablets consumed under direct observation, were reported using medians and interquartile ranges. Categorical variables were reported as frequencies and percentages and include the proportion of participants who received 100%, ≥90%, and ≥80% of scheduled doses. All variables were reported for the prenatal and postpartum period separately. To compare continuous non-normally distributed variables, the Kruskal-Wallis test was used, while Chi-square tests were used to compare categorical variables. No statistical test was used to compare total vitamin D administered between the five treatment groups.

Method 7. Development of asset index
Data source An asset index was constructed using data collected from a baseline survey on household characteristics. Ownership (yes/no) of the following 19 items was self-reported by trial participants: private toilet, electricity, radio, TV, mobile phone, non-mobile phone, fridge, almirah/wardrobe, table, chair, electric fan, DVD/CD player, autobike, rickshaw/van, bicycle, motorcycle/motor scooter/tempo/CNG, livestock/herds/farm animals/poultry, homestead, and land.

Operational definition
Asset index: a single measure that enables relative comparisons among participants with respect to household wealth by summarizing information regarding ownership of selected items or property.

Statistical analysis
Principal component analysis was used to generate a summary measure of household wealth by reducing multiple variables into a smaller set of uncorrelated variables (or principal components) 4 . The first principal component, which accounts for the largest amount of variance between the original set of variables, is assumed to reflect relative wealth 5 and was used to assign each participant a wealth score. Lower scores reflect ownership of fewer items (i.e., less relative wealth) while higher scores are indicative of greater relative wealth. Using the distribution of asset scores in the study population, quintiles were formed and participants were categorized into 1 of 5 groups. Figure S1. Length-for-age z-scores from birth to 1 year of age. Lines represent predicted means from generalized estimating equations with cubic knots at 91, 182, and 273 days and interactions between treatment groups and all age terms. Darker shading at <-2 LAZ indicates stunting. Figure S2. Weight-for-age z-scores from birth to 1 year of age. Lines represent predicted means from generalized estimating equations with cubic knots at 91, 182, and 273 days and interactions between treatment groups and all age terms. Figure S3. Weight-for-length z-scores from birth to 1 year of age. Lines represent predicted means from generalized estimating equations with cubic knots at 91, 182, and 273 days and interactions between treatment groups and all age terms. Figure S4. Body mass index-for-age z-scores from birth to 1 year of age. Lines represent predicted means from generalized estimating equations with cubic knots at 91, 182, and 273 days and interactions between treatment groups and all age terms. Figure S5. Head circumference-for-age z-scores from birth to 1 year of age. Lines represent predicted means from generalized estimating equations with cubic knots at 91, 182, and 273 days and interactions between treatment groups and all age terms. Tables   Table S1. Participant inclusion and exclusion criteria Inclusion criteria Exclusion criteria  Age 18 years and above;  17 to 24 completed weeks of gestation (i.e., 17 weeks +0 days to 24 weeks + 0 days, inclusive) based on recalled last menstrual period (LMP) and/or ultrasound;

Rules for integrating information from recalled LMP and ultrasound:
 If there is a difference of >10 days between gestational age dated using the LMP and second trimester ultrasound, the estimated date of delivery will be adjusted as per the second trimester ultrasound (SOGC guidelines); otherwise (i.e., if the difference is ≤10 days), the GA date based on LMP will be used.  If there is more than one ultrasound, GA estimation should be based on the earliest of the ultrasounds for which a written report is available. If the earliest ultrasound was performed in the 1 st trimester, and there is a difference of >5 days between gestational age dated using the LMP and 1 st trimester ultrasound, the estimated date of delivery will be adjusted as per the 1 st trimester ultrasound (SOGC guidelines); otherwise (i.e., if the difference is ≤5 days), the GA date based on LMP will be used.
 Intends to reside in the trial catchment area (including Hazaribag, Azimpur, Lalbag, and Kamrangirchar) for at least 18 months;  Provides written informed consent.
 History of any medical condition or medications that may predispose to vitamin D sensitivity, altered vitamin D metabolism, and/or hypercalcemia, including active tuberculosis or current therapy for tuberculosis, sarcoidosis, history of renal/ureteral stones, parathyroid disease, renal or liver failure, or current use of anti-convulsants a .  High-risk pregnancy based on one or more of the following findings by point-of-care testing: o Severe anemia: hemoglobin <70 g/L assessed by Hemocue o Moderate-severe proteinuria: ≥300 mg/dl (3+ or 4+) based on urine dipstick o Hypertension: ≥1 systolic blood pressure reading ≥140 mm Hg and/or ≥1 diastolic blood pressure reading ≥90 mm Hg, in repeat measurements taken at least one minute apart  High-risk pregnancy based on one or more of the following findings by maternal history and/or ultrasound: o Multiple gestation o Major congenital anomaly o Severe oligohydramnios  Unwillingness to stop taking non-study vitamin D or calcium supplements or a multivitamin containing calcium and/or vitamin D.  Currently prescribed vitamin D supplements as part of a physician's treatment plan for vitamin D deficiency.  Previous enrolment in the trial during a previous pregnancy. a Post-trial analysis of screening documents revealed that study physicians also occasionally excluded some women with medical conditions complicating their pregnancy that may have not directly altered vitamin D metabolism (n=84), but who were nonetheless deemed to be unlikely to enrol in the trial or complete trial procedures and follow-up.

Blood pressure
An automated digital blood pressure monitor was used to measure maternal systolic and diastolic blood pressure. Two consecutive readings were recorded and a third measurement was performed if either systolic or diastolic blood pressure differed by >10 mmHg.

Urine dipstick test
Participants urinated in a urine collection container and a test strip was immersed and quickly removed from the urine within 1 hour of collection. The test strip was compared to the coloured legend provided by the manufacturer to evaluate the amount of protein in urine.

Venous blood collection
Blood was collected by a trained phlebotomist and centrifuged at a low speed for 15 minutes. Plasma or serum was transferred into 0.25 mL aliquots. One serum aliquot was stored at 2-8 °C for same-or

30-weeks gestation
Weekly Delivery Weekly 2 to 8 weeks 3 months 6 months 9 months 12 months next-day analysis of serum calcium. Additional aliquots were stored at -70 °C for future analyses.

Urine collection for biochemistry
Participants urinated in collection containers and samples were stored in 1.5 mL aliquots. One aliquot from the sample collected at delivery was stored at 2-8 C for same or next-day analysis of urine calcium:creatinine ratio. Additional aliquots were stored at -70 C for future analysis.

Height, weight
Maternal height and weight were measured using a stadiometer and a digital floor scale. Two measurements were obtained for each parameter (height and weight) by one study worker, and third measurements were done if the difference in paired measurements was greater than 0.5 kg for weight or 2 cm for height.

30-weeks gestation
Weekly Delivery Weekly 2 to 8 weeks 3 months 6 months 9 months 12 months techniques. If paired measurements differed by more than 7 mm for length, 5 mm for head circumference, and 50 g for weight, a second set of measurements was performed. If the second set of measurements differed by more than the specified thresholds, measurements were repeated a third time.

Mid-upper arm circumference, upper-arm length, rumpknee length
Infants were measured independently by two study personnel using standardized techniques. If paired measurements differed by more than 5 mm, a second set of measurements was performed. If the second set of measurements differed by more than 5 mm, measurements were repeated a third time.

Venous blood collection
Blood was collected by a trained phlebotomist and centrifuged at a low speed for 15 minutes. Plasma or serum was then transferred in 0.25 mL aliquots into microfuge tubes. One serum aliquot was stored at 2-8 °C for same-or nextday analysis of serum calcium. The aliquot at 6 months of age was also analyzed for serum phosphate and alkaline phosphatase. Additional aliquots were stored at -70 °C for future analyses.

30-weeks gestation
Weekly Delivery Weekly 2 to 8 weeks 3 months 6 months 9 months 12 months Urine collection Infant urine was collected using urine collection bags that adhered to the perineum. One aliquot was stored at 2-8 C for same or nextday analysis of urine calcium:creatinine ratio. Other 1.5 mL aliquots were stored at -70 °C for future analysis.  a Methods are described in detail elsewhere 6 . b Blood pressure measured at 24 and 30 weeks gestation, and weekly from 36 weeks gestation to delivery c Only weight was measured. d Only upper-arm length and rump-knee-length were measured.  , where d is the difference between paired measurements, and n is the number of observations at a given measurement time point. b Linear regression was used to fit a straight line through an individual's age-standardized z-score (Z) as a function of age (t): Zij = β0i + βi tij + εij ; where "i" is the i th individual and "j" is the j th time point. Based on the model predicted for each individual, jackknife residuals were calculated, and measurements with an absolute jackknife residual ≥5 were flagged as outliers for length, weight, and head circumference, and measurements with an absolute jackknife residual ≥7 were flagged as outliers for mid-upper arm circumference. c An individual's raw anthropometric measurement (Y) was regressed on the square root of age (t 1/2 ) to model a curvilinear relationship: Yij = β0i + βi tij ½ + εij ; where "i" is the i th individual and "j" is the j th time point. Based on the model predicted for each individual, jackknife residuals were calculated and measurements with an absolute jackknife residual ≥7 were flagged as outliers.

Table S4. List of secondary outcomes
Secondary outcome Pre-specified in protocol or post-hoc Anthropometric outcomes a Length-for-age z-score<-2 (stunting) at 1 year Pre-specified in protocol Weight-for-age z-score at 1 year Pre-specified in protocol Weight-for-length z-score at 1 year Pre-specified in protocol Body mass index-for-age z-score at 1 year Post-hoc Head circumference for age z-score at 1 year Pre-specified in protocol Mid-upper arm circumference-for-age z-score at 1 year Post-hoc Weight-for-length z-score<-2 (wasting) at 1 year Pre-specified in protocol Head circumference-for-age z-score <-2 at 1 year Pre-specified in protocol Weight-for-age z-score <-2 at 1 year Pre-specified in protocol Weight-for-age z-score at birth Pre-specified in protocol Length-for-age z-score at birth Pre-specified in protocol Head circumference for age z-score at birth Pre-specified in protocol Length-for-age z-score <-2 at birth Pre-specified in protocol Weight-for-age z-score <-2 at birth Pre-specified in protocol Head circumference-for-age z-score <-2 at birth Pre-specified in protocol Small-for-gestational age Pre-specified in protocol Low birth weight Pre-specified in protocol Term low birth weight Post-hoc Placental weight Pre-specified in protocol Length-for-age z-score, weight-for-age z-score, weight-for-length z-score, body mass index-for-age z-score, and head circumference for age z-score trajectories from birth to 1 year Pre-specified in protocol for length; post-hoc for other standardized anthropometric parameters b Raw anthropometric measurements at 1 year (length, weight, head circumference, upper arm length, mid-upper arm circumference, rump-to-knee length) Pre-specified in protocol c Raw length, head circumference, and weight at birth Pre-specified in protocol Pre-specified in protocol Maternal referral to a specialist or hospital up to one-month postpartum Pre-specified in protocol i Rickets (x-ray confirmed) Post-hoc Infant neurological disabilities Post-hoc Infant death  Any time point, and stratified by the neonatal period, 29 days-< 6 months, and 6-12 months Pre-specified in protocol a The protocol referred to anthropometric outcomes up to 2 years of age; however, reported measurements are those obtained up to and including the one-year visit (at which the primary outcome was ascertained). b The protocol stated that "linear growth velocity" would be reported but the analytical approach was not pre-specified; therefore, longitudinal trajectories were modeled using regression cubic splines to reflect between-group differences in interval growth. Data beyond 1 year are not reported. c The protocol stated that raw weight, length, limb length, mid-upper arm circumference, and head circumference would be reported at all discrete measurement time points; however, given the null findings at one year, all raw measurements are only summarized at the 1 year time point. Raw weight, length and head circumference are also reported at birth. d The protocol stated that the 25(OH)D "change in concentration during pregnancy" would also be reported. This is depicted visually in Figure 2, and mean differences can be derived from the Table S23. e Only maternal serum calcium was pre-specified as a safety endpoint; however, summaries of infant serum calcium data are also reported. f These biochemical measurements were described in the Protocol, but were not pre-specified as secondary outcomes. g The protocol specified mean gestational age at delivery would be reported. Median (min, max) gestational age at delivery was instead reported because this variable is not normally distributed. The protocol referred to the sub-category of "early preterm" as < 34 weeks; however, this category was defined as <32 weeks in the main analyses, in which a new category of moderate to late preterm (≥32 weeks to <37 weeks) was also generated. Additional analyses were performed using <34 weeks to define early preterm births. h Only infant morbidity was pre-specified in the protocol. However, summaries of all maternal and infant clinical encounters with physicians and hospitalizations are reported. Also, the protocol specified the "occurrence of episodes of skin infection, sepsis, diarrhea or acute respiratory infection (ARI)" in infants. These outcomes are reported in the primary diagnoses and discharge diagnoses tables; however, the term "skin rash" is used instead of "skin infection" as it was unfeasible to determine whether skin conditions were caused by infections based on the data collected. i The protocol referred to "maternal referral for obstetric care" in the "prenatal period, and up to 1 month postpartum." The reported outcome includes all referrals of women in this time frame, since criteria for defining an "obstetric complication" were unspecified. 105.6 ± 11.3 106.3 ± 12.0 106.0 ± 11.1 106.1 ± 10.9 106.8 ± 11.8 a One participant excluded due to a protocol violation. b N0; 0 = 257, N4200; 0 = 258, N16800; 0 = 253, N28000; 0 = 256, N28000; 28000 = 256. Higher scores indicate greater household asset ownership relative to other participants. See Method 7 in the Supplementary Appendix for a description of the construction and interpretation of the asset index.   0.869 a P-value from Kruskal-Wallis tests for continuous variables and Chi-square or Fischer's tests for categorical variables. b N0; 0 = 209, N4200; 0 = 215, N16800; 0 = 221, N28000; 0 = 205, N28000; 28000 = 208 c The number of continuous weeks from birth in which an infant was classified as exclusively breastfed (breastmilk only), excluding the first week of life. d 3 months of age refers to feeding patterns from birth to 13 weeks of age. Each child-week was classified as exclusively breastfed (breastmilk only); predominantly breastfed (breast milk with water, sugar water, honey, or other non-milk, non-formula liquid); partially breastfed (breast milk with animal, powdered or condensed milk, and solid or semi-solid foods); and not breastfed. Classification of each infant was defined according to the lowest breastfeeding category achieved in any observed week from birth to 3 months of age. Infants with missing data for weeks 12 and 13 were deemed not able to be classified. e 6 months of age refers to feeding patterns from birth to 27 weeks of age. Feeding patterns were classified using the same method used in the birth to 3 month interval, except infants with missing data for weeks 25 and 26 were deemed not able to be classified. f A participant must have had at least 13 weekly visits completed in order to be classified as never having been given infant formula during the first six months of age. Minimum data requirements did not apply if the participant was ever given infant formula. g N0; 0 = 223, N4200; 0 = 229, N16800; 0 = 230, N28000; 0= 220, N28000; 28000 = 223      S12. Pairwise between-group comparisons of the effect of different doses of prenatal and postpartum vitamin D supplementation on length-forage z-score, weight-for-age z-score, weight-for-length z-score, body mass index-for-age z-score, head-circumference-for-age z-score, and mid-upper arm circumference-for-age z-score at 1 year of age     P-value for association between length-for-age z-score and the listed covariate from a linear regression model. b P-value for overall differences in length-for-age z-scores across supplementation groups after adjustment for the single listed covariate from a linear regression model. c Estimates represent mean difference in length-for-age z-score for a 1-unit increase in the covariate.  .173 a Generalized estimating equations were used to model length-for-age z-score as a function of age. A restricted cubic spline model was used, in which knots were set at 91, 182 and 273 days of age (corresponding to 3, 6 and 9 months of age). Interaction terms between treatment group and all age terms were included in the model to allow for differences in slopes between treatment groups, and the marginal effects of treatment group on length-for-age z-scores at specified time points, as well as on overall length-for-age z-scores were assessed. N= 1211 infants contributed at least 1 observation to the model. b Test of overall difference in means across treatment groups.

Infants at 12 Months
x Urinary calcium:creatinine ratio >1 mmol/mmol in one sample and ≤1 mmol/mmol in a repeat sample; or calcium:creatinine ratio >1 mmol/mmol in one sample when no repeat sample was available. y Urinary calcium:creatinine >2.42 mmol/mmol in two repeat samples. z Urinary calcium:creatinine >2.42 mmol/mmol in one sample and ≤2.42 mmol/mmol in a second repeat sample; or calcium:creatinine >2.42 mmol/mmol in one sample when no repeat sample was available.    -0.023, 0.040) d a Post-hoc analysis undertaken due to differences in maternal calcium at baseline and in cord blood. b Mean is presented for placebo group; mean difference versus placebo presented for all other groups, unless otherwise indicated. Coefficients in bold reflect values that were significantly different (p<0.05) from reference group. c Adjusted for serum calcium at baseline. d Mean difference (95% CI) versus group receiving a prenatal; postpartum dose of 28000; 0 IU/week. e Adjusted for cord blood serum calcium.   Only clinical encounters and hospitalizations during the intervention phase (prenatal period and up to 6 months postpartum) are reported. c Proportions are presented using number of mother-infant pairs assigned to the treatment group as the denominator. d Includes outpatient and emergency room visits and inpatient admissions (i.e., hospitalizations). e Women were classified as having gestational hypertension if at least one of the following two criteria were met: (1) Elevated blood pressure ever detected in routine prenatal monitoring: blood pressure was measured in duplicate (and measured a third time if the difference in paired systolic or diastolic measurements was ≥10 mmHg) at routine prenatal visits (see Table S2 for schedule). Hypertension was defined as ≥2 systolic blood pressure readings ≥140 mmHg, and/or ≥2 diastolic blood pressure readings ≥90 mmHg at the same visit; if only one set of measurements was available, a single systolic reading ≥140 mmHg or a single diastolic reading ≥90 mmHg was used to define gestational hypertension; (2) Prenatal clinical encounter or serious adverse event (hospitalization or death) with documentation of hypertension and/or management of hypertension. f Both deaths were considered to be maternal deaths (death while pregnant or within 42 days termination of pregnancy, irrespective of the duration and site of the pregnancy, from any cause related to or aggregated by the pregnancy or its management but not from accidental or incidental causes). For the participant in the placebo group, cause of death was cardiac respiratory arrest at 35 weeks gestation. For the participant in the 4200;0 group, cause of death at 34 weeks gestation was unconfirmed, but with clinical signs of sepsis/meningitis. g Proportions are presented using number of live births in the treatment group as the denominator, unless otherwise indicated. N0; 0 = 247, N4200; 0 = 254, N16800; 0 = 252, N28000; 0 = 252, N28000; 28000 = 249 h Proportions are presented using number of infants screened for rickets as the denominator. N0; 0 = 165, N4200; 0 = 161, N16800; 0 = 154, N28000; 0 = 155, N28000; 28000 = 152 c Definition of early preterm specified in the protocol. d Post-hoc pairwise comparisons using Chi-square tests showed no significant differences between groups after adjusting for multiple comparisons using the Holm test. e Limited to measurements obtained within 48 hours of birth. f Weight <2500 g and born at ≥37 weeks gestational age. g N0; 0 = 149, N4200; 0 = 160, N16800; 0 = 156, N28000; 0 = 148, N28000; 28000 = 158 h N0; 0 = 164, N4200; 0 = 169, N16800; 0 = 166, N28000; 0 = 160, N28000; 28000 = 165 i N0; 0 = 167, N4200; 0 = 168, N16800; 0 = 169, N28000; 0 = 159, N28000; 28000 = 167 j N0; 0 = 166, N4200; 0 = 171, N16800; 0 = 168, N28000; 0 = 161, N28000; 28000 = 169 k N0; 0 = 168, N4200; 0 = 175, N16800; 0 = 175, N28000; 0 =163, N28000; 28000 = 172       3 Nutritional/feeding concern 7 (2.9) 3 (1.      a The second and third trimester of pregnancy refer to >13 to <27 weeks gestation and ≥27 weeks gestation, respectively. b Proportion of number of times the symptom was reported was calculated using the total number of completed weekly visits within each treatment arms in the specified time period as the denominator. c Greatest absolute difference in proportion of women ever having reported the symptom between placebo and any treatment group supplemented with vitamin D. d Greatest absolute difference in proportion of number of times the symptom was reported between placebo and any treatment group supplemented with vitamin D.  a Proportion of infants ever having been reported as having the symptom by the caregiver was calculated using the number of live births as the denominator. b Proportion of number of times the symptom was reported was calculated using the total number of times the symptom was reported across all treatment arms as the denominator. c Greatest absolute difference in proportion of women ever having reported the symptom between placebo and any treatment group supplemented with vitamin D. d Greatest absolute difference in proportion of number of times the symptom was reported between placebo and any treatment group supplemented with vitamin D.