A six-year study of nearly 100,000 women in Botswana showed that inexpensive daily diet supplementation of iron, folic acid and vitamin supplementation in pregnancy can reduce complications at birth.
The researchers found that iron and folic acid supplementation (IFAS), as well as iron and folic acid plus essential vitamins and trace minerals (multiple micronutrient supplementation, or MMS), are associated with significantly lower rates of babies born at low birthweight and other complications at birth, compared with iron or folic acid alone. For example, the rate of low-birthweight birth was under 10.5% for women supplementing their diets with multiple micronutrients, the lowest rate of any comparison group.
Published in Lancet Global Health, the study was led by Ellen Caniglia, ScD, an assistant professor of epidemiology in the Department of Biostatistics, Epidemiology, and Informatics at the Perelman School of Medicine at the University of Pennsylvania, as well as investigators at the Botswana-Harvard Aids Institute Partnership and Harvard TH Chan School of Public Health.
The results represent a broad, real-world confirmation of earlier clinical trial results. The study, the largest ever of its kind, also included a substantial cohort of pregnant women with HIV, and found that IFAS and MMS appeared to have even larger benefits in this group.
“Our results support the current World Health Organization (WHO) recommendation that pregnant women should take iron and folic acid supplementation daily, but also provide compelling evidence that multiple micronutrient supplementation has further advantages over IFAS,” Caniglia said.
About 15% to 20% of children born annually worldwide have low birthweight, defined as weighing under 2.5kg at birth. Commonly occurring with preterm birth, low birthweight is associated with significantly increased risks of childhood illnesses and death, and diseases later in life, like diabetes and cardiovascular disease.
The highest rates of of these births occur in South Asia and sub-Saharan Africa.
To help reduce the rate of babies born at low birthweight and related complications at birth, the WHO recommends daily IFAS throughout pregnancy, in all settings, based on substantial clinical trial evidence. There is also clinical trial evidence that daily prenatal MMS, which includes iron and folic acid plus vitamins (A, C, D, E, B1, B2, B3, B6, B12) and minerals/metals (iodine, selenium, zinc, copper), may be superior to IFAS.
However, there has been a need for more evidence for MMS’s benefits, especially with respect to IFAS, in real-world settings, and in high-risk women such as women with HIV. This latest study provides proof that the approach can help.
Caniglia and colleagues examined supplement use and birth outcomes among 96,341 women who were seen between 2014 and 2020 in a group of government hospitals in Botswana. The sample patients studied represents a large proportion of all births in Botswana in the time period. Supplement initiation was relatively easy to track in the sample because the pills were prescribed and provided free of charge by the participating hospitals.
The researchers analysed how the rates of low-birthweight and other complications at birth, such as preterm or very preterm delivery, stillbirth, and neonatal death, varied according to the supplements each woman began taking during her pregnancy.
Women who initiated IFAS had clearly lower rates of most adverse birth outcomes, compared with women who took only iron or folic acid. Rates of low-birthweight births, for example, were 16.92% in the folic acid-only group and 12.70% in the iron-only group, but only 11.46% in the IFAS group.
Compared with IFAS, women who initiated MMS use saw significantly lower rates of preterm delivery, very preterm delivery, low birthweight, very low birthweight, and Caesarean delivery.
The rate of low-birthweight birth, for example, was 10.48% for women on MMS. Similarly, the rate of preterm birth was 12.68% for the women taking IFAS, and 11.63% for those taking MMS.
HIV infection is unusually prevalent in Botswana, and nearly a quarter of the pregnant women in the study were living with the virus. The analysis revealed that among them, the differences in rates of adverse outcomes between MMS and IFAS, and between IFAS and folic acid or iron alone, were generally larger than those seen in HIV-negative women – suggesting that supplementation has greater benefits for this population.
“We don't really know why this is. Possibly, pregnant women with HIV are more likely to be micronutrient deficient,” Caniglia said.
The data suggested that women over 35 also seemed to derive greater benefit from IFAS or MMS, compared with younger women.
While the study illuminated the comparative benefits of prenatal supplements, it also highlighted the problem of supplement shortages or “stock-outs”. Throughout the study period, IFAS was universally recommended by the WHO for pregnant women, yet more than 43% of the women in the study received iron alone, folic acid alone, or no supplement at all, apparently due to these stock shortages.
“This highlights the need for new strategies to improve prenatal supplementation coverage among pregnant women,” Caniglia said.
She and her colleagues plan to conduct further studies in Botswana, aimed at understanding barriers to the use of prenatal supplements and demonstrating the value of these supplements in improving birth outcomes.
Study details
Iron, folic acid, and multiple micronutrient supplementation strategies during pregnancy and adverse birth outcomes in Botswana.
Ellen Caniglia, Rebecca Zash, Sonja Swanson, Emily Smith, Christopher Sudfeld, Julia L Finkelstein, Modiegi Diseko, Gloria Mayondi, Mompati Mmalane, Joseph Makhema, Wafaie Fawzi, Shahin Lockman, Roger Shapiro.
Published in The Lancet Global Health in June 2022.
Summary
Background
Antenatal multiple micronutrient supplementation (MMS) with iron, folic acid, and other micronutrients might improve birth outcomes, but it is not currently universally recommended by WHO.
Methods
In this observational cohort study, we surveyed pregnancies for adverse birth outcomes at eight hospitals from July, 2014, to July, 2018, and 18 hospitals from August, 2018, to December, 2020, in Botswana to assess four routine supplementation strategies in women presenting before 24 weeks’ gestation: folic acid only, iron only, iron and folic acid supplementation (IFAS), and MMS. Women with singleton pregnancies; a known HIV status, age, and delivery site; haemoglobin measured within 7 days of presenting to antenatal care; and weight measured within 31 days of presenting to care were included in our analysis. Data were abstracted from the maternity obstetric record (a record of antenatal care) at the time of birth from all women giving birth at selected hospitals throughout the country. We estimated risk differences overall and in key subgroups, adjusting for demographic and clinical factors.
Findings
Between July 6, 2014, and Dec 8, 2020, 96 341 eligible women (21 659 [22·5%] of whom had HIV) were included in the study. 36 334 (37·7%) women initiated iron only supplementation, 1133 (11·8%) initiated folic acid only supplementation, 23 101 (24·0%) initiated IFAS, and 31 588 (32·8%) women initiated MMS. Women who initiated iron only and folic acid only supplementation had higher risks of stillbirth, preterm birth, very preterm birth, low and very low birthweight, and neonatal death compared with women who received IFAS (adjusted risk differences for iron only supplementation vs IFAS ranged from 0·22% [95% CI 0·04 to 0·40] for neonatal death to 2·39% [1·78 to 3·00] for preterm birth; and adjusted risk differences for folic acid only supplementation vs IFAS ranged from 0·77% [–0·80 to 2·34] for neonatal death to 5·75% [1·38 to 10·13] for preterm birth), with greater difference in women with HIV and those aged 35 years and older. Compared with IFAS, women who initiated MMS had lower risks of preterm and very preterm births, and low and very low birthweight (adjusted risk differences ranged from –0·50% [–0·77 to 0·23] for very preterm birth to –1·06% [–1·69 to –0·42] for preterm birth).
Interpretation
Nationwide data from Botswana support improved birth outcomes with MMS compared with IFAS.
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