Pregnancy: The Impact of Maternal Nutrition on Intrauterine Fetal Growth (N&G 2024)

Pregnancy: The Impact of Maternal Nutrition on Intrauterine Fetal Growth

Introduction

This chapter of the 2024 edition of the yearbook on Nutrition and Growth reviews important
manuscripts published between July 2022 and June 2023 addressing the association of maternal nutrition during pregnancy and intrauterine fetal growth. In the current edition, ten studies with high impact were chosen. The studies demonstrate the influence of macro- and micronutrition on maternal diet and of different diet composition on fetal growth.

We also included several animal studies, which should be noticed due to major findings
through basic science or strict methodology in areas without enough evidence among
human studies. We hope that this chapter will help us improve the medical care we can
provide to our patients and will also give researchers new ideas for future studies.

Human Studies

Periconceptional maternal protein intake from animal and plant sources and
the impact on early and late prenatal growth and birthweight: the Rotterdam
Periconceptional Cohort

Comments: Most studies demonstrated a positive association between maternal protein intake and birth weight, but only a few of them distinguished between animal-based and plant-based proteins. Therefore, this study was conducted to determine the associations of periconceptional maternal protein (animal and plant) intake and embryonic growth. In this cohort study which includes 501 pregnancies, data were taken from the Rotterdam Periconceptional Cohort. Only women who completed periconceptional Food Frequency Questionnaire with living nonanomalous singleton pregnancies were included. The study found that periconceptional protein intake, and in particular animal source protein, was positively associated with embryonic growth. Beside one cohort study that found a nonlinear association between maternal protein intake and birth weight, other past studies showed that maternal protein intake was associated with a reduced risk of fetal growth restriction and a higher birth weight, which strengthens this study findings. An analysis including an “animal/plant protein intake” ratio showed that consuming more animal proteins relative to plant proteins was associated with increased prenatal growth and birth weight. To our knowledge, this is the first study that investigated the effect of protein sources on embryonic growth. This finding might be explained by the fact that animal proteins usually provide all essential amino acids, while plant proteins are deficient in one or more (such as lysine and threonine). It is important to consider the complex effect of maternal nutrition on prenatal growth. Therefore, residual unobserved/unknown factors might act as confounders. Future research on amino acid composition, nutrient metabolism, digestibility, and the interaction with microbiota are warranted to further investigate the association between protein sources and prenatal growth and birth weight.

Maternal association of maternal HDL2-c concentration in the first trimester and
the risk of large for gestational age birth

Comments: Maternal high-density lipoprotein cholesterol (HDL-c) levels throughout gestation were negatively associated with birth weight. However, whether HDL2-c concentration correlates with large for gestational age (LGA) incidence has not yet been determined. In addition, early pregnancy is a critical period for fetal development, and it is important to pay attention to maternal lipid levels during this time. In this prospective study performed in China, 549 women were evaluated and had their blood collected during 6–14 weeks of pregnancy. The study found that LGA mothers had significantly lower serum HDL-c concentrations than appropriate for gestational age (AGA) mothers and that maternal HDL-c concentration was negatively associated with the risk of LGA. Based on the difference in density, HDL can be divided into HDL2 and HDL3. Which of the two plays a critical role in fetal growth and birth weight is unclear. In the study, HDL2-c concentrations of LGA mothers were significantly lower than those of AGA mothers, but HDL3-c concentrations were similar between the groups. A logistic regression model showed that after adjusting for maternal age, prepregnancy body mass index, and parity, HDL2-c concentration was negatively correlated with the risk of LGA. As for the study limitations, it important to mention that small for
gestational age infants were excluded for the evaluation of HDL2-c. Furthermore, there was no information on women’s lifestyle, such as diet or physical activity. To conclude, we should consider evaluating maternal first trimester HDL2-c levels.

Dietary protein intake during pregnancy and birth weight among Chinese
pregnant women with low intake of protein

Comments: Animal studies have shown that both insufficient and excessive dietary protein intake during pregnancy produced low-birth-weight offspring. However, human observational studies on the effect of dietary protein intake during pregnancy on birth weight are inconsistent. A few studies alone have evaluated the associations of dietary protein intake from different sources and fetal growth. The current study aimed to explore the associations of different dietary protein sources with birth weight. In this population-based cross-sectional study, which was performed in China, 7,310 women were evaluated. Maternal dietary intake was collected by semiquantitative food frequency questionnaire at 0–12 months after delivery. Higher intake of dietary protein, in particular animal protein, but also from dairy products, was found to be associated with higher birth weight and lower risks of low birth weight, small for gestational age, and intrauterine growth restriction. The different effects of animal and plant protein on fetal growth may be due to differences in amino acid composition. Animal protein
can provide all nine indispensable amino acids, while plant protein can be deficient in one or more indispensable proteins such as lysine or threonine. Another explanation for the effects of different sources of protein may be due to the fact that pregnant women with higher intake of animal protein may have a much better baseline protein status. Some limitations to mention are, first, the dietary information was retrospective. Second, since blood samples were not taken, the effects of amino acids status could not be evaluated. Future studies on body amino acids or protein status are still warranted.

Does trans fatty acid affect low birth weight? A randomised controlled trial

Comments: This is a randomized controlled trial that was conducted to examine the effect of low trans-fatty acid (TFA) dietary patterns on the development of low birth weight (LBW),
below 2,500 g. In the study, which was performed in Iran, 800 healthy women with singleton pregnancy, before 8 weeks and with normal body mass index, were randomized to two groups: a diet with TFA content <1% of total daily energy intake and a routine pregnancy dietary recommendation. All women received supplementation with folic acid, multivitamins, and iron. A 24-h diet log was performed at the end of each trimester. The risk of LBW in the intervention group was decreased by about 50%, with incidence of 12% in the intervention group versus 19% in the control group. Conflicting results were described in some cohorts and case-control studies, which did not demonstrate the same association between maternal TFA intake and birth weight, but with lower sample size. Several other cohorts did observe an association between higher levels of TFAs and reduced birth weight. Some limitations to mention are that there was no objective evaluation of maternal serum TFA level. Secondly and
more important, the study population had a narrow intake range for industrial TFAs, which might limit the results only to specific populations that do not consume industrialized TFAs. To conclude, this novel randomized controlled trial demonstrated that by limiting the level of TFAs, we might be able to lower the rate of LBW babies.

Effect of iodine nutrition status on thyroid function and pregnancy outcomes

Comments: Iodine is essential for synthesizing triiodothyronine (T3) and thyroxine (T4). Pregnant women are recommended to consume approximately 250 μg per day of iodine by the World Health Organization with a median urinary iodine concentration (UIC) < 150
μg/L defined as iodine deficiency during pregnancy. Whether iodine nutrition status itself could lead to adverse pregnancy outcomes was still controversial. The study aims to explore whether iodine nutrition status is correlated with thyroid function and to analyze its effect on pregnancy outcome. In this prospective study performed in China, 212 euthyroid women were evaluated between 18 and 32 weeks pregnancy. UIC/urinary creatinine (UCr) was used to evaluate the iodine nutrition status. The study found an association between UIC/UCr and the incidence of low-birth-weight infants. A low UIC/UCr was found to be a risk factor for low birth weight and was also found to be associated with higher free thyroxine and lower thyroid stimulating hormone. Lower UIC/UCr might be associated with an increased risk of autonomous production of thyroid hormone through goiters, leading to lower thyroid stimulating hormone levels. Both excessive and deficiency of iodine intake may negatively influence thyroid function, though the conjunction between the two remains contentious. Maternal iodine deficiency is known to have a long-term effect on fetal growth, especially on the nervous system. However, its short-term effect during pregnancy remains controversial. An important limitation to be mentioned is that there was no quantitative analysis of autoimmune antibodies, which could affect thyroid function and pregnancy outcomes. To conclude, it is recommended to take care of iodine supplementation during pregnancy. Also, in future studies, attention should be paid to the effects of iodine nutrition status.

Exposure to ultra-processed foods during pregnancy and ultrasound fetal growth
parameters

Comments: This study aimed to evaluate the influence of ultra-processed food (UPF) consumption on embryonic growth. It was a cohort study, including 417 women in Brazil. Participants completed structured interviews and UPF was defined within the NOVA classification system. Frequency of food group’s consumption in the previous month was categorized as no/monthly/weekly/daily. Ultrasound biometry evaluation was performed at 27.5 (interquartile range: 26.9, 28.6) weeks. The study demonstrated that increased frequency of UPF consumption was negatively associated with fetal head circumference (HC) and femur length (FL). Daily maternal consumption of UPF was particularly unfavorable with significant negative differences of HC compared with the lowest frequency of UPF consumption. Those findings are supported with past studies that identified impairment of embryonic growth following exposure to higher UPF consumption. On the other hand, in the current study, a detailed dietary assessment was performed with fetal evaluation during the third trimester. Unlike another study which reported that each 1% increase in energy intake from UPF in the second trimester was associated with a 0.62% higher neonatal total body adiposity, this study could not ascertain a significant relationship between the frequency of UPF consumption and abdominal circumference (AC). There are several limitations to mention. Pregnant women who missed ultrasound examinations were from poorer households and more frequently smoked. Also, it is important to mention that the outcomes were depicted according to a single ultrasound scan, as multiple measurements in late pregnancy were not available. To conclude, negative associations between maternal UPF consumption and skeletal components of HC and FL were observed but were not apparent for AC. These findings reinforce the relevance of maternal diet in a life course approach for promoting healthier infant growth trajectories, with potential repercussions on body composition.

Maternal seafood consumption and fetal growth: a birth cohort study in urban
China

Comments: This study was aimed to examine the association between seafood consumption and fetal growth. In this cohort study, 10,179 women with singleton child were recruited
in China and completed a Food Frequency Questionnaire 1–3 days after delivery. The study demonstrated that higher consumption of seafood had a beneficial effect on low birth weight, mainly driven by freshwater fish and shellfish. Among women who consumed more than 75 g of seafood/week, significant reduced rates of low birth weight were found compared to women with no or very low intakes. Gestation weight gain partially mediated the association between seafood consumption and birth weight. Those findings are supported by several previous epidemiological studies that showed that increased seafood intake was associated with increased fetal growth measures. The n-3 long-chain polyunsaturated fatty acids that widely exist in seafood promote the shift of the prostacyclin/thromboxane A balance to a more antiaggregatory and vasodilator state, which may increase the placental flow and, therefore, fetal growth. Contamination of fish has frequently been suggested as an explanation for the negative associations of fish intake with fetal growth. The differences in the associations between seafood consumption with fetal growth were probably explained by the different effects between beneficial nutrients, mainly docosahexaenoic acid, and pollutants present in each meal. One limitation is a low rate of gestational diabetes mellitus of 1.01%, which might be explained by the low living standards of the sample. The study population are less likely to have high-calorie, high-fat, and low-fiber diets, which are characteristic in areas with higher rates of gestational diabetes mellitus. Another limitation is that the nutritional assessment might be subject to recall bias. The study findings suggest to recommendation for intervention programs to improve birth outcomes through the improvement of seafood consumption.

The effect of pre-pregnancy obesity on gut and meconium microbiome and
relationship with fetal growth

Comments: The intestinal microbiota serves important physiological functions, including the absorption of dietary fats and fat-soluble vitamins, digestion of complex carbohydrates and plant-based polysaccharides, and bile acid metabolism. All these processes affect the development of obesity, and in addition, short-chain fatty acids resulting from the digestion of dietary fiber in the gut are responsible of regulating appetite. This study investigated the effects of pre-pregnancy body weight on maternal stool and newborn meconium microbiota and fetal growth. In the study, which was performed in Turkey, 20 women with normal weight before pregnancy (body mass index 18.5–24.9) and 20 obese women (body mass index >30), without any pregnancy complications, all with adequate gestational weight gain (11.5–16 and 5–9 kg) were enrolled. All women delivered vaginally and at term. Maternal stool samples were collected in the first trimester and meconium samples were collected after birth. Among the obese women, a relative abundance of Firmicutes was found with lower amount of Proteobacteria compared to normal weight women. Among the meconium samples of the newborns of pre-pregnancy obese mothers, lower abundances of Firmicutes, Bacteroides, and Prevotella and higher relative abundances of Proteobacteria were found compared to those of newborns from mothers with normal body weight. The birth weight, weight/height ratio of newborns, and maternal gut microbiota alpha diversity indices were associated. Dysbiosis occurring during pregnancy at an advanced age may be associated with an increased risk for hypertension, gestational diabetes, and pregnancy loss. The fact that type of food consumption was not considered is a limitation of the study results. The results demonstrate that pre-pregnancy body weight may influence the microbiome composition of the maternal gut in the first trimester and meconium of the newborn, though there is still a need for studies on microbiota in which variables are equalized.

Animal Studies

Association between high-fat diet during pregnancy and heart weight of the
offspring: a multivariate and mediation analysis

Comments: Cardiac remodeling caused by maternal obesity has been found to be associated with many factors such as diet, placenta, sex, and fetal weight. However, the level of effect of these factors remains unclear. Therefore, this animal study was performed to evaluate, by mouse models, the maternal obesity and high-fat diet supplementation effect on myocardial remodeling. Twenty mice were randomly divided into 4 groups of feeding – before/during pregnancy of high-fat/normal diet. Pregnant mice were subjected to a cesarean section on day 18.5 of gestation with delivery of 97 pups. Combined with multifactorial analysis and based on gradual screening, it was found that fetal weight and a pregnancy high-fat diet were two important factors affecting heart weight/body weight (HW/BW). It was demonstrated that a pregnancy high-fat diet has a greater effect on the myocardial remodeling of offspring. A sex difference was also noted with the male offspring of the pregnancy high-fat diet mothers who had higher HW/BW. The authors of the study also performed a qRT-PCR to examine the
myocardial-related indicators and they found that the genes Nppa, Nppb, and Mef2c were highly expressed among the pregnancy high-fat diet mice. Nppa and Nppb genes were found to play a role in the development of cardiac hypertrophy and are used as significant markers of cardiac hypertrophy. MEF2C is involved in cardiac morphogenesis and myogenesis and regulates the expression of cardiac proteins. The results of this study demonstrate the important influencing factors of the effect of the maternal nutrition model on fetal heart weight and HW/BW. This study also demonstrates that a high-fat diet during pregnancy, rather than before pregnancy, is more closely associated with cardiac remodeling in offspring.

Effect of a maternal high-fat diet with vegetable substitution on fetal brain
transcriptome

Comments: Both maternal high-fat diet (HFD) and low vegetable intake are associated with low birth weight. However, whether intrauterine growth restriction–associated abnormal
neuronal development, caused by a maternal HFD, can be ameliorated by vegetable
supplementation is still unknown. In this animal study, 2-month-old female mice were
fed a diet containing either normal fat, HFD, or 45% fat substituted with 5% energy from vegetables (HF+VS) prior to and during pregnancy. Fetuses and placentas were harvested in mid and late gestation. RNA was isolated from fetal whole brains and sequenced using Illumina HiSeq. HF+VS diet prevented maternal HFD-induced decreases in placental weight at day 19. Feeding of a maternal HFD was associated with 79 differentially expressed genes, while maternal vegetable substitution was associated with 131 differentially expressed genes. The vegetable substitution diet decreased Apold1, Spata2l, and Celsr1 expression compared to HFD. In previous studies, it was found that expression of APOLD1 is increased in postmortem brains of human schizophrenia patients. As for Spata2l, there is no information about its function in the brain. Celsr1 belongs to the adhesion receptor cadherin family of proteins, and it is expressed in the nervous system with expression upregulated in the adipose tissue of obese mice. The study’s limitation is that it did not address for a specific maternal nutrient deficiency, and also it has not yet determined whether the mentioned differentially expressed genes in the fetal brain cause postnatal cognitive and behavioral alterations. In conclusion, this study suggests that vegetable supplementation might have a protective effect against abnormal placental and fetal growth due to maternal HFD.

Overall Commentary

Maternal nutrition affects fetal growth in various mechanisms. Both macro- and micronutrients during pregnancy affect fetal outcome. A balanced maternal diet, including the source of protein and the type of fat consumed, should be evaluated to improve the offspring’s outcome. But we should remember that nutrition’s impact is attenuated by genetic, demographic, and behavioral factors. Therefore, we need to try to achieve a personalized approach while giving medical care.