Do nutritional interventions before or during pregnancy affect placental phenotype? Findings from a systematic review of human clinical trials.

Background: Maternal nutritional interventions aim to address nutrient deficiencies in pregnancy, a leading cause of maternal and neonatal morbidity and mortality worldwide. How these interventions influence the placenta, which plays a vital role in fetal growth and nutrient supply, is not well understood. This leaves a major gap in understanding how such interventions could influence pregnancy outcomes and fetal health. We hypothesised that nutritional interventions influence placental phenotype, and that these placental changes relate to how successful an intervention is in improving pregnancy outcomes. Methods: We searched PubMed, ClinicalTrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform using pre-defined search terms for records published from January 2001 to September 2021 that reported on clinical trials in humans, which administered a maternal nutritional intervention during the periconceptional or pregnancy period and reported on placental phenotype (shape and form, function or placental disorders). These records were then screened by two reviewers for eligibility. Results: Fifty-three eligible articles reported on (multiple) micronutrient- (n = 33 studies), lipid- (n = 11), protein- (n = 2), and diet-/lifestyle-based (n = 8) interventions. Of the micronutrient-based interventions, 16 (48%) were associated with altered placental function, namely altered nutrient transport/metabolism (n = 9). Nine (82%) of the lipid-based interventions were associated with altered placental phenotype, including elevated placental fatty acid levels (n = 5), altered nutrient transport/metabolism gene expression (n = 4), and decreased inflammatory biomarkers (n = 2). Of the protein-based interventions, two (66%) were associated with altered placental phenotype, including increased placental efficiency (n = 1) and decreased preeclampsia risk (n = 1). Three (38%) of diet and lifestyle-based interventions were associated with placental changes, namely placental gene expression (n = 1) and disease (n = 2). In studies with data on maternal (n = 30) or offspring (n = 20) outcomes, interventions that influenced placental phenotype were more likely to have also been associated with improved maternal outcomes (n/N = 11/15, 73%) and offspring birth outcomes (n/N = 6/11, 54%) compared to interventions that did not associate with placental changes (n/N = 2/15 (13%) and n/N = 1/9 (11%) respectively). Conclusions: Periconceptional and prenatal nutritional interventions to improve maternal/pregnancy health associate with altered placental development and function. These placental adaptations likely benefit the pregnancy and improve offspring outcomes. Understanding the placenta's role in the success of interventions to combat nutrient deficiencies is critical for improving interventions and reducing maternal and neonatal morbidity and mortality globally.