Pregnancy: The Impact of Maternal Nutrition on Intrauterine Fetal Growth

Introduction

This chapter of the 2023 edition of the Yearbook on Nutrition and Growth reviews important manuscripts published between July 2021 and June 2022 addressing the association of maternal nutrition during pregnancy and intrauterine fetal growth. In the current edition, 8 studies with high impact were chosen, most of which were human clinical trials. In the center of attention were studies that not only showed the associations of maternal malnutrition and abnormal fetal growth but also addressed changes reflected by the placenta. Despite the importance of human studies in this field, animal studies are not to be overlooked as they pave the way for future human studies in fields with scant medical evidence. Hopefully, this chapter will spark enthusiasm in health care providers and researchers to design future studies addressing this important topic.

Human Studies

Maternal plasma lipids during pregnancy, insulin-like growth factor-1, and excess fetal growth

Comments: This 2-stage clinical study was aimed to explore the association between maternal plasma lipids and excess fetal growth. In the first part of the study, the authors observed higher rates of triglycerides (TG), fatty acids (FA), and insulin-like growth factor-1 (IGF-1) in pregnant women with large for gestational age (LGA) fetuses. In the second and more interesting part of the study, cell cultures were used to show that the addition of several FA to human trophoblast cell lines results in higher IGF-1 mRNA formation. The strengths of the current study lie in the relatively large number of participants. In addition, the fact that both in vivo and in vitro experiments were conducted is also an important addition to the existing literature in this field. As previous studies showed associations between FA and TG levels and LGA, this article stands out in its originality and by showing a direct relationship between FA and IGF-1. From the 4 FA that were studied (linoleic acid, oleic acid, palmitic acid, and stearic acid), only 3 were shown to affect IGF-1 levels. In contrast, in both pregnant women and the placenta models, oleic acid was not associated with fetal growth. Unfortunately, the authors could not find an explanation for this finding. Nevertheless, this observation is promising and can aid in reducing the rate of LGA fetuses and perhaps decrease the rate of small for gestational age babies. By highlighting the major FA responsible for excess fetal growth, this study should be the cornerstone for future studies of clinical nature.

Maternal blood fatty acid analysis reveals similar n-3 fatty acid composition in nonpregnant and pregnant women and their neonates in an Israeli pilot study

Comments: This novel observational study set out to compare FA composition between pregnant and nonpregnant women and between mothers and their offspring. Pregnant women had higher levels of saturated FA, monounsaturated FA, and n-6 FA than their nonpregnant counterparts. n-3 FA levels were similar between the groups, and when comparing mothers and their newborn, the latter had a small advantage. Acquiring essential and especially n-3 FA solely from one’s diet was suggested to be not sufficient in previous trials. An increased n-3/n-6 FA ratio was shown to be important to fetal growth and was mostly related to neurocognitive development. As pharmaceutical companies and health care organizations suggest the use of n-3 FA supplements during pregnancy, this study succeeds in filling the scientific gap that was lacking. It seems that pregnancy by itself does not pose a risk for a lower n-3 FA levels and even more so, higher levels of n-3 FA are evident in newborn blood, perhaps a sign of efficient placental transfer. The limitations of this study make generalizability difficult. A single blood sample was collected from only a small number of women from a single tertiary center and only at the third trimester and not beforehand. We believe that this study can serve as a pioneer in understanding the role of FA composition in fetal growth. However, larger clinical trials are further needed before final conclusions can be drawn.

Short-term fetal nutritional stress and long-term health: child height

Comments: This study was aimed to explore the impact of in utero exposure to nutritional deprivation during Ramadan (a month of daytime fasting) on height at ages 0–18 for a sample of children from Tehran, Iran. As hypothesized, exposure to Ramadan was associated with shorter stature. The large sample size and the model chosen for measuring the exposure to nutritional deprivation are impressive. We believe it is not only the nutritional deprivation but also the constant metabolic stress that affected fetal growth. Although height at childhood may serve as an indicator of fetal growth, there are other outcomes, such as fetal weight and other anthropometric measures that are also important in the assessment of fetal metabolic status or the potential in utero deprivation. In addition, although statistically significant, the clinical significance of the approximately 1 cm difference between the groups is questionable. Research done in the field of nutritional deprivation is rare due to ethical reasons. We hope for more studies based on ritual fasting that could advance our understanding on the potential association between the exposure of maternal fasting periods during pregnancy and the long-term growth potential of the offspring.

Maternal and placental zinc and copper status in intra-uterine growth restriction

Comments: Zinc is necessary for protein synthesis and carbohydrate metabolism and therefore speculated to play an important role in fetal growth. However, studies addressing the association of zinc levels and intrauterine growth are scarce. In the current study, the researchers explored the relation of zinc concentrations in maternal plasma samples as well as in the placentas of normal-weight fetuses and compared the results to those with intrauterine growth restriction (IUGR). Zinc levels in the placenta were lower for those with IUGR. However, no difference was found in maternal plasma zinc levels between the groups. Although limited by small sample size, the current study was a pioneer for the fact that both the placenta and maternal serum levels were sampled for zinc and copper levels, which was not done in previous studies addressing this issue. It seems that it is not the amount of zinc digested that may have an association with IUGR but the amount that eventually reaches the placenta. In addition, the decrease in placenta zinc and zinc/copper ratio levels in the IUGR group may be an indicator for the importance of zinc in fetal development and growth. Finally, placental zinc level correlation with birthweight suggests for the important role of zinc in neonatal development.

Association of the maternal serum albumin level with fetal growth and fetal growth restriction in term-born singletons: a prospective cohort study

Comments: It is well established that serum albumin serves as an indicator for nutritional status in adults and children. In this cohort study from China, the researchers investigated the association of maternal serum albumin levels with fetal growth restriction. A reverse U-shaped relationship between maternal albumin level and birth size was found. The association between a low-protein diet as represented by low albumin levels and fetal growth restriction is not surprising and was addressed in previous studies. However, the current study excelled in its design and size and most intriguing, by the correlation not shown before between high albumin levels and fetal growth restriction. Confounders such as liver disease and inflammatory status were dealt with and even after adjustment, the results remained statistically significant. The exact mechanism for the association of growth restriction with high levels of albumin is yet to be determined and should be assessed in future studies. In addition, the findings of the current study raise the possibility of maternal albumin as a target for maintaining maximum fetal growth potential and preventing fetal growth restriction

Weight gain rate in the second and third trimesters and fetal growth in women with gestational diabetes mellitus: a retrospective cohort study

Comments: The prevalence of gestational diabetes (GDM) is rising over the past few decades mainly due to the increase in maternal obesity and advanced maternal age at delivery. One of the most important complications of GDM is fetal overgrowth. In the current study, the researchers aimed to define the optimal gestational weight gain goals for pregnant women with GDM while minimizing the rates of LGA newborns and macrosomia. As expected, the rate of LGA and macrosomia was associated with weight gain rate in the second part of pregnancy. However, there was no association between weight gain and small for gestational age newborns. Thus, raising the bar for a stricter diet, especially for overweight or obese women with GDM, should be considered for the prevention of fetal overgrowth. When trying to control weight gain in women with GDM, one must keep in mind that the diagnosis of GDM is usually made at the late second or the third trimester. Therefore, there is a narrow time frame remaining for the lifestyle and dietary modifications. Instead, it may be more clinically effective to allocate pregnant women at risk of GDM for potential intervention with strict diet early in gestation if proven effective in future well-designed prospective observations.

Animal Studies

Maternal high-fat diet during pregnancy with concurrent phthalate exposure leads to abnormal placentation

Comments: The major determinant of fetal growth in mammals is nutrient delivery via the placenta, which occurs primarily by transporter-mediated mechanisms and diffusion. Transport of nutrients in the placenta is dependent on many factors, including placental size, morphology, transporter capacity/availability, and placental blood flow, among others. In this study, the researchers demonstrated the combined effect of a high-fat diet and phthalate exposure on placentation and fetal growth. Phthalate exposure along with a high-fat diet had a detrimental effect on placental vasculature and regulation as expressed by low PAPP-A levels and PPARγ function. This fascinating research is the first to be done with environmentally relevant levels of phthalate exposure. Although previous studies showed a tremendous negative effect on fetal
growth, most of them were flawed due to exposure levels much higher than the average human exposure. 
This study also indicates that the combined exposure to high-fat diet and phthalate suppresses the expression of key PPARγ target genes, which mediates placental functions. It would be interesting to explore the association of high-fat diet with concurrent phthalate exposure and the risk of clinical expression of placental complications such as hypertensive disorders of pregnancy and placental abruption. Nevertheless, the results of the current study provide novel insight into potential etiological factors underlying pathological placentation, which are among the leading causes of maternal and fetal morbidity and mortality.

Maternal exposure to oxidized soybean oil impairs placental development by modulating nutrient transporters in a rat model

Comments: While most of nutritional studies focused on beneficial supplements affecting fetal growth, the current study was conducted to understand the notorious effects of oxidized lipids on the placenta. The results of the current study imply that dietary oxidized soybean oil (OSO) treatment dramatically decreased the weights of the placenta and the embryo and adversely affected the growth and development of the placenta. Moreover, this study also found that OSO treatment significantly increased the coefficients of the liver and kidney in gestational rats. On day 20 of gestation of female rats, OSO was associated with decreased placental and embryonic weights as the oxidative degree increased in a linear manner. This effect was also shown in biochemical and pro-apoptotic markers. The formation of free radicals and their inflammatory effect is well known. However, the effect on placental development was less clear prior to the current study. As soybeans are commonly consumed worldwide, the results of the current study warrant special attention regarding the handling and consumption of soybeans during gestation, especially if others will support findings of this study.