Abstract
Background
Gestational weight gain (GWG) is a modifiable risk factor associated with adverse birth outcomes. Studies have shown that the provision of multiple micronutrient supplements to pregnant women reduces the risk of low birth weight. However, the effect of multiple micronutrient supplements on GWG has been understudied.
Objectives
We examined the effect of daily supplementation of pregnant women with multivitamins on GWG in relation to the GWG recommendation by the Institute of Medicine (IOM).
Methods
Pregnant women with gestational age between 12 and 27 wk were randomly assigned to receive daily multivitamins or placebo until delivery. Weight was measured at enrollment and every follow-up visit. Percentage adequacy of GWG was calculated as actual GWG divided by the recommended GWG according to the IOM recommendation. Binary outcomes included severely inadequate (<70%), inadequate (<90%), and excessive GWG (≥125%). The analysis included 7573 women with singleton pregnancies. Multiple linear regression models were used to examine the association between multivitamin supplementation and percentage adequacy of GWG, and log-binomial models were used for binary outcomes.
Results
The mean percentage adequacy of GWG was 96.7% in the multivitamin arm and 94.4% in the placebo arm, with a mean difference of 2.3% (95% CI: 0.3%, 4.2%; P = 0.022). Compared with women in the placebo arm, those who received multivitamins had a lower risk of severely inadequate GWG (RR: 0.90; 95% CI: 0.83, 0.97; P = 0.008) and inadequate GWG (RR: 0.95; 95% CI: 0.91, 0.99; P = 0.018). No significant difference was found in excessive GWG.
Conclusions
Multivitamin supplementation increased GWG and reduced the risk of severely inadequate and inadequate GWG among pregnant women in Tanzania. Together with previously reported beneficial effects of the supplements on birth outcomes in low- and middle-income countries, our findings support scaling up the use of prenatal supplements that include multivitamins in addition to iron and folic acid. This trial was registered at clinicaltrials.gov as NCT00197548.
Key words: prenatal multivitamin supplementation, gestational weight gain, body mass index, Tanzania, Institute of Medicine
Introduction
Maternal weight gain during pregnancy has been associated with adverse maternal and birth outcomes (1, 2). Previous studies have shown that lower gestational weight gain (GWG) increases the risk of low birth weight and small for gestational age at birth, whereas greater GWG was associated with higher risks of large for gestational age and macrosomia (3, 4, 5, 6). Both lower and higher GWG have been associated with increased risk of preterm birth (2, 3). In addition, women who gain excessive weight during pregnancy may experience various adverse maternal outcomes, including complications during labor, increased risk of cesarean delivery, and subsequent maternal obesity and cardiovascular disorders (1, 2).
In 2009, the Institute of Medicine (IOM) re-examined the recommendations for weight gain during pregnancy stratified by prepregnancy maternal BMI (2). These recommendations were entirely based on studies from high-income countries. Data on GWG from low- and middle-income countries (LMICs) are limited (7). A recent analysis using data from Demographic and Health Surveys estimated that the average total GWG in sub-Saharan Africa and south Asia ranged between 6 and 7 kg, only about half the IOM's minimum recommendation for normal-weight women (8). Achieving optimal GWG not only improves immediate birth outcomes but also has many potential long-term benefits. Increasingly, evidence shows that optimal GWG is associated with reduced risks of postpartum weight retention, infant mortality, as well as child overweight and obesity later in life (9, 10).
Provision of multiple micronutrient supplements to pregnant women has been consistently associated with improved birth outcomes, including small-for-gestational-age births and low birth weight, in LMICs (11, 12, 13). However, evidence linking multiple micronutrient supplements and maternal weight gain is limited and inconsistent. Using data from a randomized controlled trial conducted among pregnant women in Tanzania, we aimed to examine the effect of prenatal multivitamin supplements on the adequacy of GWG based on the IOM recommendations. The analysis was based on the current knowledge level that, compared with iron and folic acid only, maternal multiple micronutrient supplements including iron and folic acid might improve birth outcomes among malnourished pregnant women in LMICs (11). The results from the analysis will help us better understand the beneficial effect of the supplements on birth outcomes, which has been observed from the same data in Tanzania (14) as well as other randomized controlled trials (15, 16, 17), and inform the identification of effective prenatal nutritional interventions to achieve optimal GWG in LMICs.
Methods
Study population
The current analysis used data from pregnant women who were enrolled in a double-blind, randomized, placebo-controlled trial in Dar es Salaam, Tanzania, between 1 August, 2001 and 31 July, 2004 (14). The eligibility criteria for the original trial included a negative test for HIV infection, a plan to stay in Dar es Salaam until delivery and for ≥1 y after delivery, and an estimated gestational age between 12 and 27 wk at enrollment. Eligible women were randomly assigned to receive a daily oral dose of either a multivitamin supplement or placebo from the time of enrollment until 6 wk after delivery. The supplements included 20 mg thiamin, 20 mg riboflavin, 25 mg vitamin B-6, 100 mg niacin, 50 μg vitamin B-12, 500 mg vitamin C, 30 mg vitamin E, and 0.8 mg folic acid. All tablets were commercially manufactured by Tishcon Corp; the supplement tablets and placebo were similar in shape, size, and color. Adherence to the assigned treatment was calculated as the number of tablets that were absent from the returned bottles divided by the total number of tablets the participant should have taken. All women, irrespective of the assigned study regimen, were given daily doses of iron (60 mg elemental iron) and folic acid (0.25 mg) according to Tanzanian antenatal care guidelines. All women were also provided with malaria prophylaxis in the form of sulfadoxine-pyrimethamine tablets at 20 weeks and 30 weeks of gestation. Ethics approval for the trial was obtained from the institutional review boards of Muhimbilli University of Health and Allied Sciences in Dar es Salaam, Tanzania, and Harvard School of Public Health in Boston, MA, USA. Written informed consent was obtained from all women.
Data collection
All women completed a baseline questionnaire that included their sociodemographic characteristics, reproductive and medical history, smoking, and alcohol consumption. We constructed a baseline wealth index based on household asset ownership (e.g., television, refrigerator, radio, sofa, and fan) using principal component analysis (18). Participants had study visits by medical providers monthly until 32 weeks of gestation, then every 2 wk until 36 weeks of gestation, and then weekly until 6 wk after delivery. At baseline, research nurses measured maternal height to the nearest 0.1 cm using a stadiometer with headcovers and shoes removed. Weight was measured at baseline and every follow-up visit to the nearest 100 g using balanced scales with the participant wearing light clothing without shoes.
Estimation of first-trimester weight
Because pregnant women with gestational age between 12 and 27 wk were enrolled in the trial, the majority of study participants (98%) did not have weight measures in the first trimester. For women enrolled after 14 weeks of gestation, we developed a model to impute their weight at 9 weeks of gestation using restricted cubic spline models; we chose this time point because it is the starting anchor used by the INTERGROWTH-21st GWG standards (19). In another study sample where the first-trimester weight was available for each pregnant woman, the correlation coefficient between imputed weight from the model and observed weight at early pregnancy was 0.96, and the absolute difference was within 2 kg for 77% of the women participants. Details of the model's development, selection, and validation have been published elsewhere (20).
BMI (in kg/m2) was calculated as the first-trimester weight (predicted or observed). Women were classified as being underweight (BMI < 18.5), normal weight (BMI = 18.5–24.9), overweight (BMI = 25–29.9), or obese (BMI ≥ 30) based on the WHO criteria (21). For participants who were <20 y of age at enrollment, we used the WHO BMI-for-age growth references to classify adolescents as underweight (<−2 SD), normal weight (−2 SD to <1 SD), overweight (1 SD to <+2 SD), or obese (≥+2 SD) (22).
Outcomes
Percentage adequacy of GWG
First, total GWG for each woman was calculated by subtracting the predicted or observed first-trimester weight from the weight value measured at the last follow-up visit during pregnancy. Second, following the IOM 2009 recommendation (2), we estimated the expected weight gain for each woman at the time of their last observed weight measure using the following formula:
| (1) |
The expected first-trimester total weight gain was assumed to be 2 kg for underweight and normal-weight women, 1 kg for overweight women, and 0.5 kg for obese women; and the recommended rates of GWG for the second and third trimesters were 0.51, 0.42, 0.28, and 0.22 kg/wk for underweight, normal-weight, overweight, and obese women, respectively (2).
Finally, the percentage adequacy of GWG was calculated by dividing the actual GWG by the expected GWG at the last observed weight measurement, multiplied by 100. This is a continuous measure that has been used in a previous study (23). We further categorized percentage adequacy of GWG into binary outcome measures. Inadequate GWG was defined as percentage adequacy of GWG < 90%, severely inadequate GWG as percentage adequacy of GWG < 70%, and excessive GWG as percentage adequacy of GWG > 125%. The cutoffs of 90% and 125% correspond to the lower and upper limits of the recommended total weight gain during pregnancy according to the IOM guidelines. The recommended range is 12.5–18 kg for women who are underweight (BMI < 18.5), 11.5–16 kg for normal weight (BMI = 18.5–24.9), 7–11.5 kg for overweight (BMI = 25–29.9), and 5–9 kg for obese (BMI ≥ 30) (2).
Using a similar strategy we developed trimester-specific outcome measures (e.g., percentage adequacy of GWG within the second and third trimesters) for study participants who had ≥2 weight measures within a specific trimester. Corresponding binary outcomes, including inadequate, severely inadequate, and excessive GWG, were created for the second and the third trimester, respectively, as well.
GWG z scores
We also used the INTERGROWTH-21 GWG standards to derive GWG z scores (19). Because the currently available GWG equation for expected weight gain is meant for normal-weight women, we restricted this outcome to normal-weight women only.
Statistical analysis
For the current analysis, we only included women with singleton pregnancies who had ≥1 weight measurement during the pregnancy. We excluded observations (not participants) with implausible weight values (defined as being <30 kg or >120 kg) at any point during pregnancy. Subject characteristics were summarized using mean ± SD for continuous variables and n (%) for categorical variables by intervention arm. We used multiple linear regression models to estimate mean differences and 95% CIs in percentage adequacy of GWG and GWG z score between arms. We used log-binomial models or modified Poisson regression with robust SE to estimate the RRs and 95% CIs of binary outcomes associated with prenatal multivitamin supplements. In univariate analysis, we only included prenatal multivitamin supplements as an independent variable in the models. In multivariable analyses, we adjusted for baseline characteristics including maternal age, gestational age at enrollment, household wealth index, maternal education, parity, maternal stature, maternal anemia, smoking, and hypertension status. All the covariates were selected based on their inclusion in previous analyses from the same trial and from the literature (11, 24). In secondary analyses, we examined whether the aforementioned covariates as well as infant sex and adherence to regimen modified the effects of prenatal multivitamin supplements on GWG. Infant sex was selected as a potential effect modifier based on results from previous studies (11, 15). Two-tailed P values < 0.05 were considered significant. All statistical analyses were performed using SAS version 9.4 (SAS Institute).
Results
Among the 8428 pregnant women randomly assigned in the trial, 7573 were singletons with ≥1 weight measurements before delivery (Supplemental Figure 1). At baseline, more than half (56%) of pregnant women were <25 y old, one-third were enrolled before 20 weeks of gestation, and ∼80% had ≤7 y of education. Pregnant women in the multivitamin and placebo arms did not differ in age, marital status, gestational age, parity, education, household wealth, or nutritional status measured by BMI, maternal stature, or hemoglobin concentrations. The study arms were similar with respect to adherence, with a mean of 88% and median of 96% (Table 1).
TABLE 1.
Characteristics of pregnant women by intervention arms1
| Multivitamins (n = 3797) | Placebo (n = 3776) | |
|---|---|---|
| Woman's age at randomization, y | 25.2 ± 5.1 | 25.0 ± 5.0 |
| <25 | 2102 (55.6) | 2125 (56.6) |
| ≥25 | 1682 (44.4) | 1627 (43.4) |
| Marital status | ||
| Married or cohabiting | 3339 (88.5) | 3302 (88.3) |
| Unmarried | 435 (11.5) | 436 (11.7) |
| Gestational age at randomization, wk | 21.3 ± 3.4 | 21.2 ± 3.5 |
| <20 | 1277 (33.6) | 1286 (34.1) |
| ≥20 | 2520 (66.4) | 2490 (65.9) |
| Parity | ||
| 0 | 1741 (46.0) | 1711 (45.6) |
| ≥1 | 2041 (54.0) | 2039 (54.4) |
| BMI at first trimester (observed or imputed),2 kg/m2 | 22.7 ± 3.9 | 22.7 ± 4.0 |
| Underweight | 407 (10.7) | 391 (10.4) |
| Normal weight | 2499 (65.8) | 2473 (65.5) |
| Overweight or obesity | 891 (23.5) | 912 (24.1) |
| Maternal stature, cm | 155.6 ± 6.0 | 155.4 ± 5.9 |
| <150 | 602 (15.9) | 589 (15.6) |
| ≥150 | 3195 (84.1) | 3187 (84.4) |
| Maternal anemia3 | ||
| Yes | 2205 (67.9) | 2161 (66.5) |
| No | 1045 (32.1) | 1089 (33.5) |
| Household wealth less than median | ||
| Yes | 1850 (48.9) | 1832 (48.7) |
| No | 1937 (51.1) | 1931 (51.3) |
| Education, y | ||
| 0–4 | 434 (11.5) | 409 (10.9) |
| 5–7 | 2479 (65.5) | 2538 (67.6) |
| 8–11 | 667 (17.6) | 623 (16.6) |
| ≥12 | 204 (5.4) | 184 (4.9) |
| Current smoking | ||
| Yes | 6 (0.2) | 14 (0.4) |
| No | 3777 (99.8) | 3743 (99.6) |
| Hypertension | ||
| Yes | 155 (4.1) | 148 (3.9) |
| No | 3642 (95.9) | 3628 (96.1) |
| Adherence to treatment < 95%4 | ||
| Yes | 1587 (45.8) | 1615 (46.3) |
| No | 1881 (54.2) | 1873 (53.7) |
n = 7573. Values are mean ± SD or n (%).
For participants who were ≥20 y old, underweight, normal weight, overweight, and obesity were defined as BMI (in kg/m2) <18.5, 18.5–24.9, 25–29.9, and ≥30, respectively. For participants who were <20 y old, WHO BMI-for-age growth references were used to classify adolescents as underweight (<−2 SD), normal weight (−2 SD to <1 SD), overweight (1 SD to <+2 SD), or obese (≥+2 SD).
Anemia was defined as maternal hemoglobin concentrations < 110 g/L.
Adherence to the assigned treatment was calculated as the number of tablets that were absent from the returned bottles divided by the total number of tablets the participant should have taken.
The mean percentage adequacy of GWG was 96.7% in the multivitamin arm and 94.4% in the placebo arm, with a crude mean difference of 2.3% (95% CI: 0.3%, 4.2%; P = 0.022). In multivariate analysis adjusted for potential confounders, the association persisted with a mean difference of 2.1% (95% CI: 0.2%, 4.0%; P = 0.029). Multivitamin supplementation reduced the risks of severely inadequate GWG and inadequate GWG. In the multivitamin arm 910 women (24.0%) had severely inadequate GWG compared with 1005 (26.6%) in the placebo arm. Compared with women who received placebo, those in the multivitamin arm had a 10% lower risk of severely inadequate GWG (RR: 0.90; 95% CI: 0.83, 0.97); the risks of inadequate GWG were 49.5% in the multivitamin arm and 52.3% in the placebo arm (RR: 0.95; 95% CI: 0.91, 0.99). No significant difference was found in excessive GWG between the multivitamin and placebo arms (19.2% in multivitamin compared with 17.8% in placebo; RR: 1.08; 95% CI: 0.98, 1.19). In multivariate analysis after adjusting for the potential confounders, the effect of multivitamin supplements on severely inadequate GWG, inadequate GWG, and excessive GWG did not change appreciably compared with the univariate analyses (Table 2).
TABLE 2.
The effect of prenatal multivitamin supplements on GWG1
| Multivitamins (n = 3797) | Placebo (n = 3776) | P value | |
|---|---|---|---|
| Percentage adequacy of GWG | |||
| Mean ± SD | 96.7% ± 43.4% | 94.4% ± 42.5% | |
| Mean difference (95% CI)2 | 2.3% (0.3%, 4.2%) | Ref. | 0.022 |
| Adjusted mean difference (95% CI)3 | 2.1% (0.2%, 4.0%) | Ref. | 0.029 |
| Inadequate GWG | |||
| n (%) | 1881 (49.5) | 1973 (52.3) | |
| RR (95% CI)2 | 0.95 (0.91, 0.99) | Ref. | 0.018 |
| Adjusted RR (95% CI)3 | 0.95 (0.91, 0.99) | Ref. | 0.021 |
| Severely inadequate GWG | |||
| n (%) | 910 (24.0) | 1005 (26.6) | |
| RR (95% CI)2 | 0.90 (0.83, 0.97) | Ref. | 0.008 |
| Adjusted RR (95% CI)3 | 0.90 (0.84, 0.98) | Ref. | 0.010 |
| Excessive GWG | |||
| n (%) | 729 (19.2) | 672 (17.8) | |
| RR (95% CI)2 | 1.08 (0.98, 1.19) | Ref. | 0.12 |
| Adjusted RR (95% CI)3 | 1.08 (0.98, 1.18) | Ref. | 0.12 |
Inadequate GWG was defined as percentage adequacy of GWG < 90%, severely inadequate GWG as percentage adequacy of GWG < 70%, and excessive GWG as percentage adequacy of GWG > 125%. GWG, gestational weight gain.
Univariate analysis.
Adjusted for maternal age, gestational age at enrollment, household wealth index, maternal education, parity, maternal stature, maternal anemia, smoking, and hypertension status.
We further investigated the effect of prenatal multivitamin supplements on trimester-specific GWG. In the second trimester, women in the multivitamin arm had a greater percentage adequacy of GWG (90.5% compared with 86.5%) than women in the placebo arm, but the difference was not statistically significant (P = 0.12); no significant associations were found between multivitamin supplements and any of the binary outcomes including inadequate GWG, severely inadequate GWG, or excessive GWG in the second trimester. In the third trimester, women in the multivitamin arm were associated with a 4.0% increase in GWG percentage adequacy (92.7% compared with 88.7%; P = 0.09). In addition, multivitamin supplementation was associated with a 6% reduced risk of having severely inadequate GWG (RR: 0.94; 95% CI: 0.89, 1.00; P = 0.042) and a nonsignificant 3% reduction in risk of inadequate GWG (RR: 0.97; 95% CI: 0.92, 1.01; P = 0.11) in the third trimester (Table 3).
TABLE 3.
The effect of prenatal multivitamin supplements on GWG within the second trimester and the third trimester1
| Second trimester | Third trimester | |||||
|---|---|---|---|---|---|---|
| Multivitamins (n = 2568) | Placebo (n = 2588) | P value | Multivitamins (n = 3150) | Placebo (n = 3137) | P value | |
| Percentage adequacy of GWG | ||||||
| Mean ± SD | 90.5% ± 95.4% | 86.5% ± 92.0% | 92.7% ± 88.5% | 88.7% ± 101.9% | ||
| Mean difference (95% CI)2 | 4.0% (−1.1%, 9.1%) | Ref. | 0.12 | 4.0% (−0.7%, 8.7%) | Ref. | 0.09 |
| Adjusted mean difference (95% CI)3 | 5.0% (−0.5%, 10.5%) | Ref. | 0.08 | 3.6% (−1.5%, 8.8%) | Ref. | 0.09 |
| Inadequate GWG | ||||||
| n (%) | 1330 (51.8) | 1378 (53.3) | 1723 (54.7) | 1778 (56.7) | ||
| RR (95% CI)2 | 0.97 (0.92, 1.02) | Ref. | 0.30 | 0.97 (0.92, 1.01) | Ref. | 0.11 |
| Adjusted RR (95% CI)3 | 0.97 (0.92, 1.02) | Ref. | 0.26 | 0.96 (0.92, 1.01) | Ref. | 0.10 |
| Severely inadequate GWG | ||||||
| n (%) | 999 (38.9) | 1040 (40.2) | 1250 (39.7) | 1324 (42.2) | ||
| RR (95% CI)2 | 0.97 (0.90, 1.04) | Ref. | 0.35 | 0.94 (0.89, 1.00) | Ref. | 0.042 |
| Adjusted RR (95% CI)3 | 0.97 (0.90, 1.04) | Ref. | 0.38 | 0.94 (0.88, 1.00) | Ref. | 0.036 |
| Excessive GWG | ||||||
| n (%) | 778 (30.3) | 734 (28.4) | 865 (27.5) | 847 (27.0) | ||
| RR (95% CI)2 | 1.06 (0.98, 1.16) | Ref. | 0.13 | 1.02 (0.94, 1.10) | Ref. | 0.68 |
| Adjusted RR (95% CI)3 | 1.07 (0.98, 1.16) | Ref. | 0.12 | 1.01 (0.93, 1.10) | Ref. | 0.80 |
Inadequate GWG was defined as percentage adequacy of GWG < 90%, severely inadequate GWG as percentage adequacy of GWG < 70%, and excessive GWG as percentage adequacy of GWG > 125%. GWG, gestational weight gain.
Univariate analysis.
Adjusted for maternal age, gestational age at enrollment, household wealth index, maternal education, parity, maternal stature, maternal anemia, smoking, and hypertension.
Among women with normal BMI at baseline, the mean ± SD GWG z score based on the INTERGROWTH-21 standards was −0.49 ± 0.98 in the multivitamin arm and −0.54 ± 0.96 in the placebo arm; the mean difference was 0.05 (95% CI: −0.01, 0.11; P = 0.08).
The effect of multivitamin supplementation on GWG percentage adequacy, and on the binary outcomes of inadequate GWG, severely inadequate GWG, and excessive GWG, was not modified by any of the following potential effect modifiers: adherence to regimen, maternal age, gestational age at randomization, parity, maternal BMI, maternal stature, maternal anemic status, maternal education, household wealth index, maternal hypertension, smoking status, and infant sex (Table 4, Supplemental Table 1).
TABLE 4.
The effect of prenatal multivitamin supplements on percentage adequacy of GWG by potential effect modifiers1
| Percentage adequacy of GWG | Percentage adequacy of GWG during second trimester | Percentage adequacy of GWG during third trimester | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Potential effect modifiers | n | MD (95% CI) | P value | P-int | MD (95% CI) | P value | P-int | MD (95% CI) | P value | P-int |
| Infant sex | ||||||||||
| Female | 3592 | 3.0% (0.2%, 5.8%) | 0.04 | 0.65 | 3.3% (−4.1%, 10.6%) | 0.38 | 0.68 | 5.4% (−0.8%, 11.6%) | 0.09 | 0.55 |
| Male | 3851 | 2.1% (−0.6%, 4.8%) | 0.13 | 5.4% (−1.8%, 12.6%) | 0.14 | 2.5% (−4.6%, 9.6%) | 0.48 | |||
| Gestational age at randomization, wk | ||||||||||
| <20 | 2563 | 2.3% (−1.4%, 6.0%) | 0.23 | 0.99 | 4.4% (−2.0%, 10.8%) | 0.17 | 0.89 | −2.3% (−11.8%, 7.1%) | 0.62 | 0.07 |
| ≥20 | 5010 | 2.2% (0.0%, 4.5%) | 0.05 | 3.7% (−4.2%, 11.5%) | 0.36 | 6.9% (1.6%, 12.2%) | 0.01 | |||
| Maternal adherence to regimen,2 % | ||||||||||
| <95 | 3202 | 2.2% (−0.8%, 5.3%) | 0.15 | 0.68 | 5.3% (−2.5%, 13.2%) | 0.18 | 0.69 | 3.2% (−3.6%, 10.1%) | 0.37 | 0.38 |
| ≥95 | 3754 | 3.0% (0.4%, 5.8%) | 0.03 | 3.2% (−3.8%, 10.2%) | 0.37 | 7.3% (1.2%, 13.4%) | 0.02 | |||
| Maternal age, y | ||||||||||
| <25 | 4227 | 1.8% (−0.7%, 4.3%) | 0.17 | 0.58 | 5.9% (−0.9%, 12.7%) | 0.09 | 0.46 | 6.1% (−0.7%, 13.1%) | 0.08 | 0.33 |
| ≥25 | 3309 | 2.9% (−0.2%, 5.9%) | 0.06 | 2.0% (−5.8%, 9.8%) | 0.62 | 1.5% (−4.8%, 7.8%) | 0.64 | |||
| Parity | ||||||||||
| 0 | 3452 | 1.5% (−1.3%, 4.3%) | 0.29 | 0.44 | 7.3% (−0.2%, 14.7%) | 0.06 | 0.29 | 5.2% (−2.6%, 12.9%) | 0.19 | 0.65 |
| ≥1 | 4080 | 3.0% (0.3%, 5.7%) | 0.03 | 1.7% (−5.4%, 8.7%) | 0.64 | 3.0% (−2.8%, 8.8%) | 0.32 | |||
| BMI at first trimester (observed or imputed)3 | ||||||||||
| Underweight | 798 | 3.4% (0.1%, 6.7%) | 0.05 | 0.49 | 7.4% (−3.7%, 18.5%) | 0.19 | 0.26 | 6.6% (−1.9%, 15.2%) | 0.13 | 0.40 |
| Normal weight | 4972 | 1.8% (0.2%, 3.5%) | 0.03 | 0.9% (−4.4%, 6.2%) | 0.74 | 2.0% (−3.4%, 7.3%) | 0.47 | |||
| Overweight or obesity | 1803 | 4.3% (−1.3%, 9.9%) | 0.13 | 10.7% (−4.0%, 25.5%) | 0.15 | 9.3% (−2.9%, 21.5%) | 0.13 | |||
| Maternal stature, cm | ||||||||||
| <150 | 1191 | 0.0% (−4.5%, 4.5%) | 1.00 | 0.32 | 3.3% (−8.6%, 15.3%) | 0.58 | 0.90 | 3.0% (−6.5%, 12.5%) | 0.54 | 0.84 |
| ≥150 | 6382 | 2.7% (0.6%, 4.8%) | 0.01 | 4.2% (−1.5%, 9.8%) | 0.15 | 4.2% (−1.1%, 9.5%) | 0.12 | |||
| Maternal anemia4 | ||||||||||
| Yes | 4366 | 1.2% (−1.2%, 3.6%) | 0.32 | 0.12 | 3.3% (−3.5%, 10.2%) | 0.35 | 0.41 | 2.3% (−4.1%, 8.7%) | 0.48 | 0.40 |
| No | 2134 | 4.8% (0.7%, 8.9%) | 0.02 | 8.1% (−1.1%, 17.3%) | 0.08 | 7.0% (−1.5%, 15.4%) | 0.11 | |||
| Education, y | ||||||||||
| ≤7 | 5860 | 2.3% (0.2%, 4.5%) | 0.04 | 0.75 | 2.0% (−3.7%, 7.7%) | 0.50 | 0.13 | 5.4% (0.4%, 10.3%) | 0.03 | 0.25 |
| ≥8 | 1678 | 1.6% (−2.6%, 5.8%) | 0.46 | 11.4% (−0.3%, 23.0%) | 0.06 | −1.2% (−13.5%, 11.1%) | 0.85 | |||
| Wealth index < median value | ||||||||||
| Yes | 3682 | 2.4% (−0.2%, 5.0%) | 0.07 | 0.89 | −0.5% (−7.6%, 6.6%) | 0.90 | 0.10 | 8.3% (2.3%, 14.4%) | 0.007 | 0.08 |
| No | 3868 | 2.1% (−0.7%, 5.0%) | 0.14 | 8.0% (0.8%, 15.4%) | 0.03 | 0.0% (−7.0%, 7.2%) | 0.98 | |||
| Hypertension | ||||||||||
| Yes | 303 | 1.6% (−10.4%, 13.6%) | 0.74 | 0.89 | −4.5% (−32.5%, 23.5%) | 0.74 | 0.50 | 5.2% (−22.9%, 33.3%) | 0.72 | 0.92 |
| No | 7270 | 2.3% (0.3%, 4.2%) | 0.02 | 4.4% (−0.8%, 9.6%) | 0.10 | 4.0% (−0.8%, 8.7%) | 0.10 | |||
| Current smoking | ||||||||||
| Yes | 20 | 20.2% (−16.0%, 56.4%) | 0.26 | 0.39 | 28.6% (−78.2%, 135.4%) | 0.57 | 0.63 | −8.4% (−89.2%, 72.5%) | 0.83 | 0.83 |
| No | 7520 | 2.1% (0.2%, 4.1%) | 0.03 | 3.9% (−1.2%, 9.1%) | 0.14 | 3.9% (−0.9%, 8.6%) | 0.11 | |||
GWG, gestational weight gain; MD, mean difference.
Adherence to the assigned treatment was calculated as the number of tablets that were absent from the returned bottles divided by the total number of tablets the participant should have taken.
For participants who were ≥20 y old, underweight, normal weight, overweight, and obesity were defined as BMI < 18.5, 18.5–24.9, 25–29.9, and ≥30, respectively. For participants who were <20 y old, WHO BMI-for-age growth references were used to classify adolescents as underweight (<−2 SD), normal weight (−2 SD to <1 SD), overweight (1 SD to <+2 SD), or obese (≥+2 SD).
Anemia was defined as maternal hemoglobin concentrations < 110 g/L.
Discussion
In the current analysis, we found that ∼50% of the study participants experienced inadequate GWG and 25% experienced severely inadequate GWG during pregnancy. This finding is consistent with a recent meta-analysis of studies from sub-Saharan Africa, in which the authors reported that the percentage of inadequate GWG, defined according to the IOM recommendation, was >50% in 9 of the 16 studies (5). Another study from Bangladesh reported that 74% of pregnant women had inadequate GWG (6). We also found that pregnant women who received multivitamin supplementation had greater GWG and reduced risks of inadequate GWG and severely inadequate GWG compared with those who were in the placebo arm. Multivitamin supplementation during pregnancy had no effect on excessive GWG.
Limited information has been reported on the effect of prenatal multiple micronutrient supplements on GWG among pregnant women, and when this question was examined the results were not consistent. A trial from Ghana found that there was no difference in GWG measures between pregnant women who received multiple micronutrient supplements and those who received iron and folic acid supplements (23). Another trial conducted in Mexico similarly reported that multiple micronutrient supplements did not increase weight gain during pregnancy compared with iron supplements only (25). However, results from 2 trials in Tanzania conducted among HIV-negative women (26) and HIV-infected women (27) demonstrated that prenatal multiple micronutrient supplements were associated with greater weight gain during pregnancy. The discrepancy could be due to differences in study population and intervention doses. The doses of multiple micronutrient supplements used in both trials conducted in Tanzania were much higher, containing 6–10 times the RDA for vitamin C and B vitamins, and twice the RDA for vitamin E, compared with only 1–2 RDA in the trials conducted in Ghana and Mexico. Results from trials in Nepal and Bangladesh have brought up the concern that single RDA regimens may be suboptimal in settings of widespread malnutrition and have not resulted in correction of micronutrient deficiencies (28, 29).
The current study aimed to examine the effect of multivitamin supplements on GWG according to the IOM recommendation. Compared with the previous analysis in which direct weight measures were used, the current analysis focused on GWG percentage adequacy, which was imputed based on actual weight gain and the IOM recommendation. Specifically, noting that in most prenatal cohorts in low- and middle-income settings (including our study population) most women do not have a record of prepregnancy weight, we have imputed gestational weight in the first trimester by applying a method that our team has developed (20), and that allowed us to estimate GWG. We used this GWG estimate to compare against the IOM guidelines and our outcomes are independent of gestational age at the time of weight measurement. We then classified the continuous outcome into severely inadequate, inadequate, and excessive GWG, further examined the effect of multivitamin supplements on these binary outcomes, and assessed effect modifiers of the supplements. Furthermore, we used the INTERGROWTH-21 GWG standards that were published in 2016 to derive GWG z scores and re-examined the effect of the supplements on GWG among normal-weight women.
Our current results that multivitamin supplementation was associated with a greater GWG are consistent with the previous findings on birth outcomes in the same trial (14). Several meta-analyses have been conducted to summarize the effect of prenatal multiple micronutrient supplements on birth outcomes (11, 12, 30, 31, 32), and it has been consistently concluded that the provision of multiple micronutrient supplements including iron and folic acid reduced the risks of low birth weight, compared with provision of iron and folic acid only, or provision of iron alone. In response to the accumulating evidence from LMICs on the beneficial effect of multiple micronutrient supplements during pregnancy on low birth weight, in 2020, the WHO changed their recommendation on multiple micronutrient supplements in pregnancy from “not recommended” to “recommended in the context of rigorous research” (33).
The components of weight gain in early pregnancy are primarily maternal fat deposition, total body water accretion, and placental and other tissue development, whereas weight gain in later pregnancy is thought to be more closely related to fetal growth (2). Previous studies have suggested that GWG during the first and second trimesters had a stronger effect on birth weight than GWG that occurred in the third trimester (1, 34). In the current analysis, we examined the effect of multivitamin supplementation on cumulative GWG by trimester and most of our results were not statistically significant except for severely inadequate GWG in the third trimester. This may be because of limited statistical power of these trimester-specific analyses because women participants had to have ≥2 weight measures within a specific trimester to be included in the analysis for that trimester.
We did not find that the effect of prenatal multivitamin supplements on GWG was modified by adherence to the regimen; this is perhaps because the overall adherence was high (median: 96.4%; IQR: 84%–100%). The low variance in adherence resulted in a small difference in effect size between women with adherence < 95% and those with adherence ≥ 95%, and we perhaps lacked enough power to detect that small difference. The prevalence of hypertension and smoking was very low in the study population, and we were likely underpowered to detect any effect modification by these factors.
There are several plausible mechanisms through which multivitamins could improve GWG. First, multivitamin supplementation may improve maternal immune function, leading to reduced risk of infections, and any adverse effects of these on maternal weight (35, 36). Second, multivitamins may increase food intake by influencing peptide hormone concentrations and neurotransmitters that affect satiety and appetite (37, 38). Third, micronutrients included in the supplements, such as vitamin C, B-vitamins, and iron, are involved in protein and energy metabolism, DNA and RNA synthesis, and cell division, which may directly improve fetal development and growth leading to higher GWG (39, 40, 41, 42). Antioxidants, including vitamins C and E, protect against free radical generation and damage caused by the increased oxidative stress associated with pregnancy (43), which have also been associated with low birth weight and preterm birth (44).
There are several strengths in the current study. First, it aimed to examine the effect of multiple micronutrient supplements on GWG in relation to IOM recommendations. Previous epidemiologic studies of GWG often used total GWG in kilograms or average rate of GWG, which may be biased owing to their correlation with gestation duration (45, 46). By using percentage adequacy of GWG which is independent of gestational duration, our findings could be explained as the effect of multivitamin supplementation on GWG beyond its possible effect on gestation duration. Furthermore, because prepregnancy BMI is one of the main determinants of GWG (3, 47), findings on total weight gain or rate of weight gain from different studies might not be comparable if there were large differences in prepregnancy BMI across studies. Finally, the current analysis has a large sample size with maternal weight measures during pregnancy compared with prior studies, although our statistical power for trimester-specific analyses and assessment of effect modification of supplements was possibly limited. Other limitations of this study should be noted as well. Because participants were enrolled after their pregnancies were confirmed, prepregnancy BMI was not available in the current study. However, because prepregnancy BMI is required to calculate the recommended weight gain based on IOM and INTERGROWTH-21st recommendations, we used BMI measured in the first trimester as a substitute for prepregnancy BMI given that weight gain during the first trimester is minimal. For women who did not have their weight measured during the first trimester we developed and validated a statistical modeling approach to estimate weight at 9 weeks of gestation using weight measures later during the second trimester. The methodological approach has been published (20).
In conclusion, our results demonstrate that the provision of multivitamin supplementation to pregnant women improves GWG in relation to the IOM recommendation. This finding provides additional evidence to support the recently updated WHO guidelines on prenatal multiple micronutrient supplements. Future studies should focus on implementation research to evaluate the acceptability, feasibility, and cost-effectiveness of switching to multiple micronutrient supplements from iron and folic acid supplements only in the target pregnant women population.
Acknowledgments
he authors’ responsibilities were as follows—WWF, AMD, EL, DW, MW, and NP: designed the research; WWF, AP, and WU: conducted the research; EL, DW, and MW: performed data computations and analysis; EL: drafted the manuscript; EL and WWF: have primary responsibility for the final content; and all authors: read and approved the final manuscript.
Data Availability
Data described in the article, code book, and analytic code will be made available upon request pending application and approval.
Footnotes
Supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the NIH (NICHD R01 37701 to WWF) and the Bill and Melinda Gates Foundation (OPP1204850 to WWF).
Author disclosures: the authors report no conflicts of interest.
Supplemental Figure 1 and Supplemental Table 1 are available from the “Supplementary data” link in the online posting of the article and from the same link in the online table of contents at https://academic.oup.com/jn/.
Supplementary Material
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Data described in the article, code book, and analytic code will be made available upon request pending application and approval.