Effects of Maternal Nutritional Supplements and Dietary Interventions on Placental Complications: An Umbrella Review, Meta-Analysis and Evidence Map

Abstract

The placenta is a vital, multi-functional organ that acts as an interface between maternal and fetal circulation during pregnancy. Nutritional deficiencies during pregnancy alter placental development and function, leading to adverse pregnancy outcomes, such as pre-eclampsia, infants with small for gestational age and low birthweight, preterm birth, stillbirths and maternal mortality. Maternal nutritional supplementation may help to mitigate the risks, but the evidence base is difficult to navigate. The primary purpose of this umbrella review is to map the evidence on the effects of maternal nutritional supplements and dietary interventions on pregnancy outcomes related to placental disorders and maternal mortality. A systematic search was performed on seven electronic databases, the PROSPERO register and references lists of identified papers. The results were screened in a three-stage process based on title, abstract and full-text by two independent reviewers. Randomized controlled trial meta-analyses on the efficacy of maternal nutritional supplements or dietary interventions were included. There were 91 meta-analyses included, covering 23 types of supplements and three types of dietary interventions. We found evidence that supports supplementary vitamin D and/or calcium, omega-3, multiple micronutrients, lipid-based nutrients, and balanced protein energy in reducing the risks of adverse maternal and fetal health outcomes. However, these findings are limited by poor quality of evidence. Nutrient combinations show promise and support a paradigm shift to maternal dietary balance, rather than single micronutrient deficiencies, to improve maternal and fetal health. The review is registered at PROSPERO (CRD42020160887).

The importance of nutrition in pregnancy and lactation: lifelong consequences

“…A meta-analysis restricted to LMIC reported a significant effect of omega-3 supplementation on preeclampsia (RR 0.40, 95% CI: 0.21-0.77, I 2 0%, six studies, N=1343), but there was no difference in severe preeclampsia, eclampsia, or gestational hypertension. 133 There are also some intriguing possibilities that deserve further studies, including periconceptional vitamins, [135][136][137] dietary nitrates, 138 reduced sodium intake 139 and antioxidants other than vitamins C and E, but thus far none have been of proven benefit. 140 Omega-3 supplementation reduced the risk of early preterm delivery at < 34 weeks (RR 0.42, 95% CI 0.27-0.66, p=0.0002, 6 studies, n=4193) and any preterm birth (RR 0.83, 95% CI 0.70-0,98, p=0.03, 9 studies, n=5980) according to a systematic review.…”

“… 129 Therapy with vitamins C and E as administered in several large studies has not proven effective to prevent preeclampsia. 130 , 131 Several other micronutrients, including folic add, 132 , 133 vitamins A and D, 133 zinc, 134 iodine, 135 omega-3 FAs, 136 and arginine, 137 are supported by some, but not all, supplementation studies. A meta-analysis restricted to LMICs reported a significant effect of omega-3 supplementation on preeclampsia (risk ratio [RR], 0.40; 95% confidence interval [CI], 0.21–0.77; I 2 , 0%; 6 studies, n=1343), but there was no difference in severe preeclampsia, eclampsia, or gestational hypertension.…”

“…A meta-analysis restricted to LMICs reported a significant effect of omega-3 supplementation on preeclampsia (risk ratio [RR], 0.40; 95% confidence interval [CI], 0.21–0.77; I 2 , 0%; 6 studies, n=1343), but there was no difference in severe preeclampsia, eclampsia, or gestational hypertension. 136 Moreover, some intriguing possibilities deserve further studies, including periconceptional vitamins, 138 – 140 dietary nitrates, 141 reduced sodium intake, 142 and antioxidants other than vitamins C and E, but thus far, none has been of proven benefit. 143 …”

Dietary factors that affect the risk of pre-eclampsia

“…Fixed-effects meta-analysis of the RCTs indicated that vitamin D supplementation was a prevention factor for pre-eclampsia; however, random-effects meta-analysis of trials found no significant association between vitamin D and pre-eclampsia 80. The most recent summary (2021) described itself as an ‘umbrella analysis’ and found a reduced risk of developing pre-eclampsia among pregnant women who received vitamin D supplementation (RR 0.62, 95% CI 0.43 to 0.91, I 2 =0%, 12 studies, n=1353) 85…”

Association of mid‐trimester maternal angiogenic biomarkers with small‐for‐gestational‐age infants in an urban Zambian cohort: a nested case‐control study

“…The International Fetal and Newborn Growth Consortium (INTERGROWTH‐21 st ) study demonstrated similar fetal growth in eight geographically defined urban populations, when controlled for nutrition, antenatal care, and environmental growth constraints, suggesting that at least some SGA is modifiable 16,21 . Inflammation from malnutrition, infection, or helminth infestation has been implicated in the pathogenesis of several adverse obstetric outcomes, 22,23 but might not generate the placental angiogenic profile traditionally associated with SGA. An investigation of circulating sEng levels in pregnant women from Malawi and Cameroun reported higher levels of sEng in primigravid women—the demographic that trended towards higher incidence of SGA in this sample—and showed higher sEng concentrations with both infection and fetal growth restriction 24 .…”