Pregnancy: Impact of Maternal Nutrition on Intrauterine Fetal Growth

Introduction

This chapter reviews manuscripts of major impact published between July 2020 and June 2021 addressing the issue of the association of maternal nutrition during pregnancy and intrauterine fetal growth. In this current edition, we selected seven human studies, most of which were randomized controlled trials (RCTs), as well as two animal clinical trials. At the center of attention were both lifestyle and nutritional interventions potentially affecting the development of fetal growth restriction and prevention of fetal overgrowth. This chapter will hopefully spark enthusiasm in health care providers and researchers to design future studies addressing this important topic.

Human Studies

Association between maternal caffeine consumption and metabolism and neonatal anthropometry: a secondary analysis of the NICHD Fetal Growth Studies – Singletons

Comments: This is a secondary analysis of a longitudinal cohort study, the National Institute of Child Health and Human Development Fetal Growth Studies – Singletons. The study aimed to evaluate the correlation between caffeine intake in the first trimester and neonatal anthropometry. Results demonstrated that even small increases in plasma caffeine concentrations were associated with lower birth weight and decreased lean tissue.

While caffeine metabolism slows throughout pregnancy, its metabolites accumulate in fetal tissues causing uteroplacental vasoconstriction and fetal growth restriction, assumedly exposing the newborn to obesity and cardiovascular morbidity later in life. This study has multiple strengths. First, it is one of the few studies in which measuring of actual caffeine intake was made. The authors not only addressed self-reported consumption, but also measured caffeine and paraxanthine (its major metabolite) plasma levels which assisted in decreasing the risk of reporting bias.

Another novelty is the aim to show a correlation with the maternal genotype (CYP1A2*1F, known to regulate caffeine metabolism). This method was not extensively used previously. While results failed to show a difference between fast or slow caffeine metabolism genotype, the attempt alone is still noteworthy. As previous reports suggested a negative impact on fetal growth after 200 mg of maternal daily caffeine consumption (a threshold effect), the current study demonstrated that a negative effect was shown even at lower doses (50 mg) as well as a linear effect at a small increment in consumption. Nevertheless, plasma levels were only measured once in the first trimester, explaining the low correlation between reported intake and plasma levels. The conclusion depicting an effect on fetal growth at minuscule amounts of caffeine has to be challenged. As technology advances, we hope future studies may further examine the dose-response relationship more accurately by using continuous caffeine plasma level monitoring. In addition, an association with other placenta-mediated pregnancy complications (besides fetal growth restriction) and placental pathology should also be examined.

Effectiveness of wheat soya blend supplementation during pregnancy and lactation on pregnancy outcomes and nutritional status of their infants at 6 months of age in Thatta and Sujawal districts of Sindh, Pakistan: a cluster randomized-controlled trial

Comments: A wheat soya blend supplementation government program is the center of focus in this RCT assessing its influence in malnourished pregnant women. When comparing women in the intervention group to their counterparts in the control group, remarkable results were demonstrated. At the age of 6 months, infants born to mothers receiving supplementation throughout pregnancy and breastfeeding had a statistically significant lower rate of stunting, wasting, underweight, and anemic infants. These results were not different to previous studies addressing this issue, but were with different nutritional blends. Therefore, the importance of the study lies not in the specific nutritional supplement that was used, but rather in the fact that an existing government program was developed. Surprisingly, the study failed to demonstrate a significant difference in the rate of small for gestational age at birth. One potential reason for this result is the fact that only a quarter of the deliveries had a documented newborn weight at birth, which resulted in a small sample size. It is important to acknowledge that although the aim was to explore the effect of wheat soya blend supplementation from prior to conception and throughout pregnancy and the lactation period, as many as 80% of the participants were recruited only after the first trimester. Thus, the fact that the effect of the supplementation was noticed only at the age of 6 months and not already at birth may be related to the late administration of supplementation during pregnancy.

Effects of a modestly lower carbohydrate diet in gestational diabetes: a randomized controlled trial

Comments: This is an Australian cohort study which aimed to test whether intervening with a modestly low carbohydrate diet in women with gestational diabetes (GDM) would affect ketonemia, pregnancy, and fetal outcomes such as macrosomia and fetal body mass. In pre-GDM and GDM, reducing carbohydrate intake is recommended on the assumption that this will improve glycemic control and decrease pregnancy complications. Numerous studies have challenged this theory, showing conflicting results. The current study aimed to show a beneficial effect while maintaining patient safety, an issue that has rarely been handled. The results demonstrated that this specific diet was not associated with a higher risk of maternal ketonemia, which was not surprising due to a caloric intake (targeting 135 g/day or less) not reaching starvation status. There were no statistically significant differences between the groups regarding fetal weight, macrosomia, newborn fat mass, or mode of delivery, nor did a modestly low carbohydrate diet provide an additional benefit for glucose management. This could be due to the study’s main weakness, its size: following randomization and applying exclusion criteria, only 45 women were included in the study group. Moreover, there was a lack of adherence to the study protocol as only 20% of participants consumed up to 135 g/day of carbohydrates. Another constraint was that results could have also been influenced by insulin levels and the intake of other nutrients that were not measured. A significant difference in iodine and iron levels in the study and control groups can also be a confounder for the results. Given that GDM rates have increased over the last few decades, it is crucial to find the optimal diet in order to avoid macrosomia as well as other diabetes-related complications.

Effects of guided counseling during pregnancy on birth weight of newborns in West Gojjam Zone, Ethiopia: a cluster-randomized controlled trial

Comments: Low birth weight (LBW) is of utter importance in Africa as it is very common and considered a major risk factor for neonatal morbidity and mortality. As it is multifactorial, the high rates reported in some areas of Africa are partly related to maternal malnutrition. The current study was a randomized controlled community trial in rural west Ethiopia assessing the impact of personal guided nutritional counseling on fetal growth. The results showed that monthly nutritional counseling was very effective in increasing fetal weight. Mean birth weight was increased by 0.26 kg and LBW was reduced by more than half (6 vs. 14% in the control group). In contrast to other trials exploring various nutritional supplements and blends, the current one focuses mainly on personal counseling. In interventions based solely on nutritional packages it is difficult to measure the quantity of consumption as participants may share it with family members, avoid or sell their given packages. However, by focusing on nutrition education, the burden is justifiably on the caregiver. It is enlightening to acknowledge that maternal counseling by itself has such an important impact and can help decrease the levels of LBW in that setting. Nevertheless, some of the limitations of the current study should be considered mainly the high lost-to follow- up rate that may promote selection bias and the fact that results may not be generalized worldwide to all communities.

The effects of a combined intervention (docosahexaenoic acid supplementation and home-based dietary counseling) on metabolic control in obese and overweight pregnant women: the MIGHT study

Comments: Comments on this study are incorporated in the comments on the following manuscript by Massari et al.

Multiple micronutrients and docosahexaenoic acid supplementation during pregnancy: a randomized controlled study

Comments: These are two RCTs focusing on the added benefit of DHA in pregnancy and its effect on fetal growth. The MIGHT study focuses on overweight women in Chile and explores the possible role of DHA on the reduction in the rate of GDM and fetal macrosomia. The other study explores the combined effect of DHA and other micronutrients in a low-risk population from an industrialized country on the rate of adverse pregnancy outcomes. The MIGHT study is a large RCT assessing the effect of combined omega-3 PUFA supplementation and dietary counseling on metabolic control, macrosomia, and insulin resistance in newborns of overweight women in Chile, where fish consumption is lower than the average world intake. Despite succeeding to enlist a very large and heterogeneous study population, the results were less significant than expected. No difference was shown in the incidence of GDM or the incidence of macrosomia. This could be explained by implementing the intervention at the first trimester and not prior to pregnancy, possibly inflicting a real change in fetal growth. However, one of the strengths of this study is the combined measurement of both fetal weight as well as cord blood parameters for insulin resistance. Surprisingly, with regards to cord blood analysis, there was even a higher rate of neonatal insulin resistance when comparing group 1 to the control group (12 vs. 5%), although these differences did not reach statistical significance. The second study is a multicenter RCT conducted in Milan, Italy, evaluating the use of a supplement containing 200 mg of DHA and other micronutrients administrated during the 2nd and 3rd trimesters.

The primary outcome was blood DHA levels; however, fetal anthropometry and pregnancy complications were also explored. In contrast to the MIGHT trial, the control group in the current study was comprised of pregnant women receiving no supplements. As predicted, women receiving supplementation were found to have higher levels of RBC DHA and a higher omega-3/non-omega-3 ratio. This result mainly demonstrates adherence to the study protocol. However, fetal weight, height, abdominal, and head circumference remained unaffected. Nevertheless, differences were noted with regards to a higher subscapular skinfold and a lower bone density in the study group compared to the controls. The main strength of this study is the novelty of the design since the intervention was combined micronutrients and DHA in pregnant women. The effect of omega-3 PUFA supplements in pregnancy on neurodevelopmental and metabolic outcomes has been researched widely in the past, yet no conclusive hard evidence has been published. There is still a major gap between what is known regarding the immunomodulatory and metabolic traits of omega-3 PUFA.

Pre conceptional lipid-based nutrient supplementation in 2 low-resource countries results in distinctly different IGF-1/mTOR placental responses

Comments: This study stems from the Women First Preconception Maternal Nutrition Trial (WF). Women from Guatemala and Pakistan were given preconceptional maternal smallquantity lipid-based nutrient supplementation (SQLNS), which was given throughout pregnancy and the results were compared to women given no supplementation. The objective of the study was to analyze the effect of SQLNS on fetal growth and placental function as expressed by mTOR, IGF-1, AMPK, PAPP-A, and zinc taken from placental samples or maternal serum. Although the prevalence of infant stunting was similarly high in both countries, there were significant differences between them. Pakistani women were much leaner (BMI 19 vs. 26) with smaller placentas. The most interesting conclusion to be deducted was that lipid-based nutritional supplements have a tremendous effect, but only when given selectively. In Pakistani participants, SQLNS supplementation resulted in decreased placental AMPK activity, indicating improved cellular energy levels and activation of placental nutrient sensing through the mTOR pathway.

One of the limitations of the study is an additional protein-energy supplement provided to the Pakistani participants. As mTOR is particularly responsive to amino acid availability, it may have contributed to placental mTOR activation and affected fetal growth. The maternal serum IGF-1 concentration and placental IGF-1 mRNA expression were also correlated with fetal growth in Pakistani women. Conversely, Guatemalan participants receiving SQLNS did not have any effect in measured biomarkers and therefore no correlation with fetal anthropometry. This is of great relevance as results could be generalized to populations with not only malnourishment but also caloric deficiencies. However, genetic variations between the populations may have also contributed, although they were not measured in the current study. Despite the relatively small sample size (48 patients in total), this study is of great importance, attributable to both its focus on molecular signaling pathways as well as the fact that the results highlight the need for tailored medicine for optimal interventions and reducing fetal growth restriction.

Animal Studies

Effect of maternal nutrient restriction on skeletal muscle mass and associated molecular pathways in SGA and non-SGA sheep fetuses

Comments: This animal clinical trial aimed to examine the effect of restricted nutrition in sheep on fetal muscle mass and molecular markers involved in protein degradation. Ewes were divided into two groups: one with normal nutritional requirements and the other had restricted nutrition (NR group; 50% of normal requirements). At 135 days of gestation, fetal plasma and organs were collected and compared. Interestingly, results found that nutrition-restricted sheep had a spectral phenotype of fetal growth. Some were SGA, as could be assumed, but a comparable number of fetuses were non- SGA and similar to the control group in almost all parameters. We cannot ignore the fact that no information was provided on the weight and other characteristics of the ewes in this study, which could perhaps give a reason for the changed phenotype. When comparing SGA-NR to the control group, this study showed a remarkable reduction in muscle mass and myofiber cross-sectional area with a smaller amount of myonuclei. This is of great relevance as many human studies focus mainly on fetal weight results without distinguishing between fat and muscle hypertrophy in biopsies due to obvious ethical reasons. Nevertheless, when assessing molecular pathways associated with protein degradation and cortisol receptors, no major differences were found, perhaps due to a small sample size. The importance of this study lies not in its results addressing the muscle mass, but rather in the spectral phenotype after the same nutrient restriction.

Effects of maternal nutrient restriction during the periconceptional period on placental development in the mouse

Comments: The authors of this study examined the effect of periconceptional caloric restriction from 3 weeks prior to pregnancy up until mid-gestation on several placental parameters in mice. These parameters included placental histology, nutrient transporter expression, and DNA methylation levels. Compared to the controls, calorie-restricted placentas had an approximate 20% increase in maternal blood sinuses yet no difference in overall placental weight. This result highlights the importance of the pre-conception period as caloric restriction showed such an irreversible effect on placental pathology. In addition, there was also a 3-fold decrease in mRNA encoding a key placental nutrient transporter. No difference was found regarding DNA methylation. The vast number of growth-related parameters are a major strength of the study. However, it is difficult to conclude that the periconceptional period is a crucial time when it was not efficiently isolated from other periods in pregnancy (as food was restricted up to mid-gestation). Controversy persists regarding whether placentas can adapt to nutritional changes during pregnancy. Although the periconceptional period is a detrimental time in which caloric restriction may permanently alter placental development and function, there is still no apparent difference in placental and fetal weight.