Prenatal supplementation can positively influence birth outcomes by addressing and improving the nutritional status of infants in resource-poor settings. Nevertheless, evidence from historical disasters such the Dutch Famine and the Great Chinese Famines suggest that early life nutritional adversity can have spill-over, intergenerational, effects when an affected girl becomes pregnant. Little is known on whether early life nutritional adversity in the context of historical droughts in Malawi result in intergenerational effects on offspring’s birth outcomes, whether the timing of the early life nutritional adversity (in utero vs. early childhood) matters, and whether prenatal supplements could offset any intergenerational effects.
In Malawi, some of the women who lived in Mangochi District as young children were exposed to one of the droughts of 1981/82, 1987/88, or 1992/93, in utero or at age 0-5 yr, for up to 12 months in each drought period, and to varying degrees of drought severity. This research took advantage of a natural experiment to explore the effects of maternal exposure to drought in early life on offspring’s birth outcomes. In this natural experiment, there was no pre-determined randomization of exposure and non-drought exposure and, as such, assignment of pregnant women into the two groups was simply determined by date of birth (DoB). The outcomes of interest were infant length-for-age Z score (LAZ), weight-for-age Z score (WAZ), and birthweight (either actual birthweight where available, or imputed, where newborns were weighed within 3-5 days of birth). Additionally, this research assessed the impact of a novel prenatal supplement on the hypothesized intergenerational effects of maternal exposure to drought in Malawi compared to the standard of care prenatal supplement.
This research also took advantage of the existence of a unimodal weather pattern in Malawi which is divided into three parts, with a single rainy season and harvest: the cold and dry season (coincides with the harvest and post-harvest months), the hot and dry season (coincides with the pre-lean [“hunger”] months), and the hot and wet season (coincides with the lean “[hunger”] months). The literature cites the importance seasonality on birth outcomes. The exposures of interest were offspring’s birth in the pre-lean months or lean months compared to birth in the harvest/post harvest months (based on known DoB). The outcomes of interest were measured birthweight – measured within 72 hours of birth – and imputed birthweight, if measured more than 3 days after birth, measured infant LAZ and infant WAZ. Weight and length data were expressed as Z-scores (WAZ, LAZ) relative to the 2006 WHO growth standards.
The primary objective of study #1 was to estimate the direct effects of in utero maternal exposure to the pooled droughts of 1981/82, 1987/88, and 1992/93 on infant LAZ, infant WAZ, and imputed birthweight [measured close to the time of birth depending on where the infant was born (i.e., clinic vs. non-clinic setting)]. The secondary objective of study #1 was to assess the effects of prenatal supplements to offset the impact of maternal exposure to drought in utero on infant LAZ and WAZ, and imputed birthweight.
The primary objective of study #2 was to estimate the direct effects of maternal exposure to drought in 1981/82, 1987/88, or 1992/93 at age 0-5 yr and maternal exposure to the pooled droughts in the narrower age groups of 0-2 yr and 3-5 yr on infant LAZ, infant WAZ, and imputed birthweight. The secondary objective of study #2 was to assess the effects of prenatal supplements to offset the impact of maternal exposure to drought in early childhood on infant LAZ, child WAZ, and imputed birthweight.
The primary objective of study #3 was to estimate the seasonality effects of month of birth on selected birth outcomes (measured birthweight and LAZ), for infants whose weight was measured within 72 hours of birth. The secondary objective of study #3 was to estimate the seasonality effects of month of birth on birth outcomes (imputed birthweight, LAZ, and child WAZ) for the whole sample, including imputed birthweight for children weighed more than 3 days after birth.
From 2010-2012, the iLiNS-DYAD-M (a registered clinical trial, #NCT01239693 at clinicaltrials.gov) enrolled 1391 women with gestation age < 20 weeks and randomized them to receive a prenatal supplement called a small-quantity, lipid-based nutrient supplement (SQ-LNS: a peanut-paste fortified with milk fats, 19 vitamins and minerals, and essential fatty acids), or to receive a multiple-micronutrients tablet, or to receive the standard ante-natal care - an iron-folic acid (IFA) tablet. In the main trial, the women were only supplemented if they signed an informed consent form. Ethical approval was obtained from the University of Waterloo Research Ethics Committee (ORE #22443) for the present research.
The DoBs of the study participants were self-reported. The data were collected during screening at four study clinics. Other pertinent data on demographic and socioeconomic status (SES) were mainly collected at the homes of the study participants by trained data collectors. Birthweight and length were measured by midwifery-nursing staff unless babies were born in non-clinical settings (e.g., at home). Thus, home births or births outside of study area clinics without accompanying measurements elicited infant measurements by trained field study staff. The data for the 1262 women with known DoBs were included in the main analyses for studies #1 and #2 if the dataset for the covariates was complete. Study #3 analyzed outcomes of singleton births with known infant DoBs.
Multiple regression analyses were conducted using ordinary least square (OLS) methods with birth outcomes as the dependent variables, maternal exposure to drought at various times in early life as well as covariates (maternal effects and sociodemographic variables) and dummy variables for type of prenatal supplement received.
Summary statistics: The average age of the study women was 24 years old with a range of 14 to 48 years. Of the 1262 out of the 1391 participants from the main trial with known DoBs, in study #1, 206 women in total were exposed to drought in utero. In study #2, 831 women were exposed to drought in early childhood (age 0-5 yr). In study #3, of the 1295 infants who could have been assessed, about 28% of infants were born during the lean “hunger” season (n = 368), about 41% of infants were born during the pre-lean season (n = 391), and about 30% were born during the harvest/post-harvest season (n = 536).
Regression results: Some of the more notable results were as follows: among infants born to women exposed to drought in utero during the second-third trimester, there was a positive and somewhat significant effects on imputed birthweight [+88.497g, 95% CI (11.572: 165.422), n = 1074] and when trial supplements were added to the models, only maternal first trimester exposure to drought interacted with MMN (compared to IFA) yielded quite strong and significant results on infant LAZ [-0.853 SD, 95% CI (-1.446: -0.259), n = 980]. In Study #2, among women not exposed to drought postnatally at age 0-5 yr, positive and quite large, significant effects of prenatal supplementation with SQ-LNS compared to prenatal supplementation with IFA were observed for infant LAZ, infant WAZ, and imputed birthweight, with stronger effects observed for infant LAZ and imputed birthweight (p < 0.01) [+0.403 SD, 95% CI (0.099: 0.708), n = 980; +0.372 SD, 95% CI (0.053: 0.691), n = 991; +125.900 g, 95% CI (2.901: 248.899), n = 1074, respectively]. In study #3, after controlling for year of birth and other covariates, birth in the lean season compared to the harvest/post-harvest season was negatively associated with measured birthweight (p < 0.01) and reduced-sample LAZ. The results for imputed birthweight, infant LAZ and infant WAZ, which were consistently significant (p < 0.01), repeated the pattern of previously reported associations in study #3.
For study #1, there was no evidence that maternal exposure to drought in utero adjusted for baby’s sex, maternal effects and socio-economic variables decreased birth length and weight in offspring of rural Malawian mothers. Also, prenatal supplementation with SQ-LNS did not moderate the hypothesized intergenerational effects of maternal exposure to drought in utero by not improving rural Malawian offspring’s birth size compared to prenatal supplementation with IFA. For study #2, maternal exposure to the 1981/82 drought at ages 0-5 yr, 0-2 yr, or 3-5 yr vs. non-drought exposure postnatally appeared to improve birth outcomes although not significantly, in rural Malawian offspring, adjusted for covariates. However, prenatal supplementation with SQ-LNS appeared to improve infant weight and length compared to prenatal supplementation with IFA, among infants of mothers not exposed to drought in early childhood. For study #3, the results showed that birth during the lean season led to a significantly lower weight and length for the sample for which actual birthweight was available compared to birth during the harvest/post-harvest season. When imputed birthweight, WAZ and LAZ in the larger samples were regressed against the exposure variables and covariates, the results were still significant and did not change.
Overall, among the three studies, the clinical significance of the effect sizes was markedly larger in the interactions between maternal drought-exposure in early life and prenatal supplements but were marginally smaller in the seasonality of birth assessments despite the sample sizes being larger in the latter assessments.
Finally, studies #1 and #2 were underpowered to detect the hypothesized intergenerational effects from the interacted variables due to limitations with sample sizes and the nature of natural experiments’ inability to optimize sample sizes a priori. Also, the lack of a positive response to SQ-LNS supplementation in the nutritional status of infants may indicate that the relatively small 20g daily-dose of SQ-LNS was inadequate to overcome the hypothesized intergenerational effects of maternal exposure to drought in early life. Nonetheless, there may be a case for prenatally supplementing women from food insecure households with SQ-LNS (compared to IFA) who were not exposed to drought postnatally, in resource-poor settings.||en