Pregnancy: Impact of Maternal Nutrition on Intrauterine Fetal Growth

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Introduction

This chapter of the Yearbook on Nutrition and Growth reviews major studies published between July 2019 and June 2020 addressing the issue of the association of maternal nutrition during pregnancy on intrauterine fetal growth. For the current edition, we carefully selected human studies, mainly of prospective design, along with several animal studies dealing with the effect of maternal dietary patterns at different stages of pregnancy or the use of nutrient supplementations during and prior to pregnancy on fetal growth and metabolic programming. Hopefully, this chapter will assist researchers, clinicians, and other healthcare providers, who are involved in prenatal and postnatal care, to update their knowledge on the effect of various interventions and their effect on fetal growth and development.

Human Studies

Preconception nutrition intervention improved birth length and reduced stunting and wasting in newborns in South Asia: The Women First Randomized Controlled Trial

Comments: This is a secondary analysis of the Women First Preconception Maternal Nutrition Trial, a randomized controlled prospective trial in India and Pakistan. It was designed to assess whether nutritional supplements, such as lipid and protein, can reduce the risk for small for gestational age (SGA) and increase birth anthropometry parameters, such as weight and height of newborns. The results highlighted the importance of nutritional interventions during the preconception period (>3 months prior to conception). spring’s life. Another setback is the inability to separate the exact influences of the different components of the nutritional supplementations (i.e., protein vs. lipid). In conclusion, this trial emphasized the importance of nutritional intervention prior to conceiving in order to minimize fetal growth restriction in poor and rural populations. The 26% reduction in the relative risk of SGA was stronger in women who consumed nutritional supplements prior to conception as compared to those who started the intervention in the 1st trimester. No significant difference was found in the risk of preterm delivery.

As fetal growth restriction is multifactorial, this trial succeeds to isolate maternal nutrition as an important factor, which can be improved in simple measures. Another strength of the current study over previous nutritional prospective trials is the duration of intervention starting more than 3 months prior to conceiving. The major weakness is the short postpartum follow up time (48 h) and therefore the lack of data regarding the potential benefits of maternal intake of supplements later in the off-spring’s life. Another setback is the inability to separate the exact influences of the different components of the nutritional supplementations (i.e., protein vs. lipid). In conclusion, this trial emphasized the importance of nutritional intervention prior to conceiving in order to minimize fetal growth restriction in poor and rural populations.

 

Associations between first trimester maternal nutritional score, early markers of placental function, and pregnancy outcome

Comments: This is a prospective cohort study investigating the association between a healthy diet and first trimester placental markers and volume. Adherence to a healthy diet was measured by a first trimester questionnaire scoring 1–10 when 10 is the optimal diet (based on FIGO recommendations [1]). A total of 112 women underwent testing for serum pregnancy-associated plasma protein- A (PAPP-A) and free β-human chorionic gonadotropin (β-HCG) as well as ultrasound scans done by a single expert measuring umbilical artery pulsatility index (PI) and placental volume. Pregnancy outcomes including estimated fetal weight and the rate of preterm delivery were recorded. The researchers reported that women with a healthier diet were found to have a significantly higher concentration of PAPP-A, lower β-HCG levels, lower placental volumes, and umbilical artery PI. A positive association between placental weight and fetal weight was demonstrated as well as an association between nutritional score and gestational age at birth. These results demonstrate the effect of a healthy maternal diet on early sonographic and biomarkers of placental function in relation to fetal growth. Women with low scores had larger but less efficient placentas.


The major weakness of the study is the small number of participants (n = 112). Other important weaknesses are the fact that it relies on subjective recollections of maternal
diets (by a questionnaire only) and that placental function later in pregnancy was not assessed. With that being said, this study is novel for showing a clear association between maternal food habits and early pregnancy placental biomarkers and ultrasound features. Future studies should encompass more women and measure more placental factors for a longer duration.

 

Effect of antenatal dietary interventions in maternal obesity on pregnancy weight-gain and birthweight: Healthy Mums and Babies (HUMBA) randomized trial

Comments: Previous trials have shown that dietary intervention and probiotic supplementation may alter maternal weight gain and fetal weight. This randomized controlled trial focused on obese pregnant women (body mass index >30) in New Zealand. The study cohort, 230 women, were allocated to either dietary interventions (dietary handbook and health education sessions) or dietary advice only (pamphlets). The study cohort was also randomized for daily probiotic or placebo capsules. Recruitment was done at the end of the first trimester. The results showed that neither dietary intervention nor probiotic supplementation had a significant effect on maternal weight gain or fetal growth. There was also no change in the rate gestational diabetes. When excluding noncompliant women, probiotic supplementation
had a negative effect on fetal gestational weight (3,701 g in the probiotic group vs. 3,540 g in the placebo group), although it did not reach statistical significance.


The design is the major strength of this study along with the focus on obese women. Nevertheless, it seems that the intervention period was not long enough in order to have a significant effect on maternal and fetal weight. Future studies should focus on the preconception period and start interventions earlier. The use of probiotics should be dealt with caution due to the potential negative effect found in this trial.

 

Maternal preconception lipid profile and gestational lipid changes in relation to birthweight outcomes

Comments: This is a secondary analysis of the Effects of Aspirin in Gestation and Reproduction Trial (EAGeR) that aimed to assess the association of maternal lipids and fetal weight. Overall, 585 women were assessed for LDL cholesterol, HDL cholesterol (HDLc), triglyceride (TG) levels at preconception and at 28 weeks of gestation, and their influence on fetal weight. The study focused on the lipid concentration change between the preconception period
and the third trimester of pregnancy (28 weeks) and the effect on the odds for large (LGA) or small for gestational age (SGA) newborns. After stratifying groups for BMI, the study showed that the main effects on birth weight in pregnant women can be achieved through lowering HDL levels and slowing down the expected increase in TG levels throughout gestation: A 10 mg/dL increase in HDLc was linked to a 37% decreased risk for LGA (not dependent on maternal BMI) and a 38% reduction in the risk for SGA (only in BMI >25). An increase of 10 mg/dL in TG levels during the same period was associated with a modest increase in the risk for LGA (5%). Differences were more profound in overweight and obese women.


The main weakness of the study is its limited generalizability. Only women with at least one prior pregnancy loss were included in the study population. The main strength of the study, apart from its size, is that it focused on the change in lipid levels throughout pregnancy and not only on a single measurement. By doing that, the study opened the path for diet and lifestyle modification during pregnancy aiming to affect cholesterol homeostasis and potentially fetal growth.

 

A maternal “mixed, high sugar” dietary pattern is associated with fetal growth

Comments: As maternal obesity and gestational diabetes rates rise dramatically in South African women, the importance of maternal diet is crucial. Maternal nutrition in South Africa has shifted from a traditional diet consisting of whole grains and vegetables to western diets consisting of processed foods and added sugars. This study was designed to assess the effect of this notorious diet pattern on fetal anthropometry. This was a prospective study in which 495 women were included. They had ultrasound surveillance on 6 different occasions during pregnancy, and fetal size was recorded. The results demonstrated an increase in each of the sonographic fetal growth parameters that were examined (in women consuming the “mixed, high sugar” diets). This change was statistically significant even after adjusting for maternal BMI and gestational weight gain implying that the effect is mainly due to nutrition.

However, this association was demonstrated only in male newborns. Although a similar positive correlation in their female counterparts, the effect was not found to be
significant. This study is unique as it focuses on the negative effects of an “empty calorie” diet on fetal weight and biometry in the traditional African community. Its major strength is that the results were significant independent of preconception maternal BMI and gestational weight gain. However, the study did not take into account physical activity which could serve as an important predictor of fetal weight. Future studies could go beyond lowering processed foods and added sugars in these women and perhaps also showing a modification in fetal size and macrosomia-related complications.

 

Mediterranean-style diet in pregnant women with metabolic risk factors (ESTEEM): A pragmatic multicenter randomized trial

Comments: The Mediterranean diet has been shown to reduce metabolic and cardiovascular complications in the general population. This study is the first to test the possible effect of Mediterranean diet on maternal and fetal metabolic health. The study cohort comprised women with metabolic risk factors including obesity, chronic hypertension, or hypertriglyceridemia. The intervention was the introduction of Mediterranean diet to patients as well as personalized session to make sure there is proper adherence to the diet. Primary outcomes were a composite of fetal outcomes (including the rate of SGA fetuses) and maternal outcomes (e.g., weight gain, diabetes, and preeclampsia). The results were disappointing as no statistically significant reduction was shown for the overall fetal and maternal outcomes. It is also difficult to explain the finding of a non-significant 25% increase in the risk for LGA fetuses in pregnant women who were in the Mediterranean diet group (p value 0.23).


This study is important due to its novelty. Nevertheless, one cannot ignore the difficulty of understanding the exact adherence to the diet as it was self-reported. Understanding the exact dietary intervention and its right time in pregnant women with metabolic complications is crucial in order to have a real influence on fetal growth.
Further research is definitely warranted in this field.

 

Efficacy of two different doses of oral vitamin D supplementation on inflammatory biomarkers and maternal and neonatal outcomes

Comments: Vitamin D deficiency is very common in Iran. Recent studies have demonstrated the association between vitamin D and pregnancy outcomes such as birth weight and preterm labor, probably due to its anti-inflammatory nature. In this randomized control trial in Iranian pregnant women, a 1,000 IU/day supplementation of vitamin D was compared to a 2,000 IU/day dosage. Primary outcome was 25(OH)D levels in maternal plasma as well as cord blood. Secondary outcomes were newborn anthropometric values, inflammatory biomarkers, and pregnancy outcomes.


Results showed a significant increment in plasma 25(OH)D levels in the group prescribed the high dosage supplementation. No difference was shown in inflammatory markers except for lower IL-6 levels in cord blood in the higher dosage group. Pregnancy outcomes were not shown to be different apart from anthropometric values: newborns of mothers receiving a 2,000 IU/day dosage of vitamin D weighed more (3,103 vs. 3,369 g; p value 0.018) and had greater head circumference and length. Although showing improved birth outcomes, this study did not prove a difference in the rate of SGA newborns. Therefore, the mean 260 g difference in fetal weight observed between the groups is perhaps statistically significant, but devoid of clinical significance. Another setback is the fact that although showing lower levels of IL-6 in women with 2,000 IU/day supplement, there was no difference in the rate of preeclampsia, SGA newborns, and preterm deliveries – all with a proinflammatory pathogenesis. Nevertheless, this study is important due to its prospective control design and its focus
on high dosage of vitamin D supplements which have been seldom studied before.

 

Paleolithic diet during pregnancy – A potential beneficial effect on metabolic indices and birth weight

Comments: This retrospective control study aimed to study the effect of the Paleolithic diet on pregnancy. The main components of this diet are meat, fish, vegetables, fruits, roots, eggs, and nuts. Although relatively low sample size as the cohort included 37 pregnant women with a strict Paleolithic diet compared to 39 low-risk pregnant females, the results showed a statistically significant reduction in glucose challenge test scores and increased hemoglobin levels in the study group. Fetuses were slimmer than their control group counterparts but not at the expense of increased rate of growth restriction. An explanation for these results stems from this diet’s effect on insulin resistance when avoiding grain, wheat, and refined sugar. This study is innovative and the first to assess the possible association of Paleolithic diet in pregnancy. Nevertheless, its small size and retrospective nature are not sufficient to recommend adherence to the diet during conception. Hopefully, it will inspire others to perform larger cohort studies in this field.

 

ANIMAL STUDIES

Maternal supplementation with citrulline or arginine during gestation impacts fetal amino acid availability in a model of intrauterine growth restriction (IUGR)

Comments: This was a study testing the effect of amino acid supplementation on IUGR offspring. Arginine is an essential amino acid and is the only endogenous source for nitric oxide which has been proven to be a crucial component in fetal growth. Citrulline is a nonessential amino acid that is converted in the kidney to arginine. In this study, pregnant rats were treated with normal-protein diet versus low-protein diet to mimic fetal restriction. Rats that received low-protein diets were further allocated to 3 subgroups: arginine oral supplementation, citrulline oral supplementation, and those with no supplementation.

The results showed not only an increase in arginine and citrulline plasma concentration with supplementation, but also an upregulation of gene expression of amino acid transporters. Fetal weight was up to 11% higher in low-protein diet-fed dams but was still significantly lower when compared to normal-protein diet. The major strength of the current study is the ability to demonstrate both a molecular and genetic effect as well as an actual difference in fetal weight. Hopefully, this study will promote the conduction of similar human studies.

 

Maternal curcumin supplementation ameliorates placental function and fetal growth in mice with intrauterine growth retardation

Comments: The current study investigated the effect of curcumin on the risk of fetal growth restriction in rats. Curcumin is known as a strong antioxidant. This study examined the effect of maternal curcumin supplementation on fetal weight, placental apoptosis, area of blood sinusoids in the placenta, and its antioxidant trait. Growth-restricted pregnancies were mimicked by providing low protein diet to female rats. Curcumin was given together with olive oil in two different dosages: 100 mg/kg and 400 mg/kg, and the results were compared to those without curcumin supplementation (either with normal or low-protein diets). The results supported curcumin supplementation in rats with IUGR. Curcumin increased fetal weight, blood sinusoid area, and antioxidant activity in a dose-effect manner when compared to growth restricted fetal rats without maternal curcumin supplementation. Moreover, placental apoptosis level was significantly reduced in the high dose of curcumin group, even when compared to the normal protein diet group.


This study, although promising, may have serious difficulties when compared to human fetal growth restriction. The curcumin doses given to rats in this study, even in the lower concentration, would be too much to ingest when given to an average weight human mother. However, the fact that curcumin was found to affect fetal growth restriction also at a genetic and molecular level is encouraging and may be an interesting field for further research in the future.

 

Reduced dietary calcium and vitamin D results in preterm birth and altered placental morphogenesis in mice during pregnancy

Comments: Calcium (Ca) and vitamin D (VD) are important components of maternal diet. Whereas VD can also be obtained through UV-B conversion of 7-dehydrocholesterol, Ca can only be obtained through the diet. Both VD and Ca have been studied in pregnancy, and reduced levels have been associated with preterm labor and placental dysfunction which adversely affect fetal growth. This study examined different aspects of animal models regarding the association of Ca and VD deprivation and adverse outcome. More than half of mice with Ca- and VD-deprived diets delivered preterm. Mice consuming the +Ca+VD diet did not deliver preterm, as well as the +Ca–VD and –Ca+VD diets. When assessing the deprivation effect on fetal and placental weight and efficiency, results were baffling: –Ca–VD fetuses were 8% larger than the control group, while placental weight did not differ between the groups. Placental microstructure was found to be significantly different: Junctional zone area and maternal blood space was increased by 25–27% in dams deprived of Ca and VD, and their trophoblast barrier thickness was slightly reduced. These changes suggest that diets which lack normal amounts of Ca and VD have a positive effect on placental efficiency, perhaps acting in a compensating manner. It is unclear if this study’s conclusions are relevant to humans: VD deficiency is rare and Ca deficiency is also not one of the major electrolyte deficiencies in pregnancy.