Pregnancy: Impact of Maternal Nutrition on Intrauterine Fetal Growth

Editor(s): Yariv Yogev, Liran Hiersch.



Introduction
This chapter of the Yearbook on Nutrition and Growth reviews major studies published
between July 2019 and June 2019 addressing the issue of the influence 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 on fetal growth and metabolic programming. Hopefully, this chapter will assist clinicians, researchers, and other healthcare providers, who are involved in prenatal and postnatal care, to update their knowledge on the effect of various intervention options and their effect on fetal growth and development.

Human Studies

Dietary patterns before and during pregnancy and birth outcomes: a systematic review

Background:
 Maternal diet before and during pregnancy could influence fetal growth and birth outcomes. 
Objective: Two systematic reviews aimed to assess the relationships between dietary patterns before and during pregnancy and (1) gestational age at birth and (2) gestational age- and sexspecific birth weight.
Methods: Literature was searched from January, 1980 to January, 2017 in 9 databases including PubMed, Embase, and Cochrane. Two analysts independently screened articles using predetermined inclusion and exclusion criteria. Data were extracted from included articles and risk of bias was assessed. Data were synthesized qualitatively, a conclusion statement was drafted for each question, and evidence supporting each conclusion was graded.
Results: Of the 9,103 studies identified, 11 (representing 7 cohorts and 1 randomized controlled trial [RCT]) were included for gestational age and 21 (representing 19 cohorts and 2 RCTs) were included for birth weight. Limited but consistent evidence suggests that certain dietary patterns during pregnancy are associated with a lower risk of preterm birth and spontaneous preterm birth. These protective dietary patterns are higher in vegetables; fruits; whole grains; nuts, legumes, and seeds; and seafood (preterm birth, only), and lower in red and processed meats, and fried foods. Most of the research was conducted in healthy Caucasian women with access to health care. No conclusion can be drawn on the association between dietary patterns during pregnancy and birth weight
outcomes. Although research is available, the ability to draw a conclusion is restricted by inconsistency in study findings, inadequate adjustment of birth weight for gestational age and sex, and variation in study design, dietary assessment methodology, and adjustment for key confounding factors. Insufficient evidence exists regarding dietary patterns before pregnancy for both outcomes.
Conclusions: Maternal dietary patterns may be associated with a lower preterm and spontaneous preterm birth risk. The association is unclear for birth weight outcomes.
Comments:
This is one of the largest and extensive systematic reviews published to diet addressing
the question “what is the relationship between dietary patterns before and during pregnancy and gestational age- and sex-specific birth weight?” Methodologically, combining several studies to answer this question is not an easy task. Therefore, the
definition of the exposure must be clear. In the current systematic review, studies
without an adequate description of the dietary pattern or a valid comparator were excluded. Yet, one must realize when interrupting the results that even after applying
these exclusion criteria, the studies that were included in final analysis were highly
inconsistent across the body of evidence with 10/21 reporting no association between
dietary patterns before or during pregnancy and birth weight outcomes and the remaining were inconsistent regarding the direction of the effect that was associated with various dietary patterns. The main take-home message should be that in order to assess the association of maternal diet on fetal growth, strict definitions should be applied in order be able to reach practical conclusions and implement them to official recommendations and guidelines.

Development of a novel Periconceptual Nutrition Score (PENS) to examine the
relationship between maternal dietary quality and fetal growth

Background:
 Maternal nutrition may influence intrauterine fetal development. To date, the relationship between contemporary European dietary guidelines and fetal growth has not been examined.
Aims: To develop a novel Periconceptual Nutrition Score (PENS) to assess maternal dietary quality in early pregnancy and examine its relationship with fetal growth.
Study Design: Women were recruited conveniently at their first clinic visit and completed a supervised 4-day retrospective diet history. The PENS was developed using European Food Safety Authority recommended dietary intakes for pregnancy. The relationship between PENS and fetal growth was examined.
Subjects: Women with a singleton pregnancy.
Outcome Measures: Birthweight, small for gestational age (SGA), neonatal head circumference.
Results and Conclusions: Of the 202 women, the mean age was 32.2 ± 5.0 years and 44.6% were nulliparas. The mean PENS was 9.4 ± 3.1. On multivariable regression, there was a positive relationship between the PENS and birthweight (beta = 45.3, 95% CI 14.8–75.9, p = 0.002) and neonatal head circumference (beta = 0.12, 95% CI 0.01–0.23, p = 0.03). Compared with the lowest PENS quartile, the mean birthweight was increased in the highest quartile (Mean difference 328 g, p = 0.02). The incidence of SGA was 16.4% (n = 10/61) in the lowest PENS quartile compared to 6.5% (n = 9/139) in the top 3 quartiles (p = 0.03). Thus, higher maternal dietary quality was associated
with increased intrauterine fetal growth. The PENS is potentially useful in identifying those women before or during pregnancy who may benefit from dietary interventions that may optimise fetal growth. It may also be useful in tracking maternal dietary quality during pregnancy.
Comments:
As opposed to many modified food frequency questionnaires (FFQ) currently used to
evaluate the quality of maternal dietary intakes in the second half of pregnancy, the current study focuses on the periconceptual period. The scoring system used for this
study has some clear advantages, mainly the fact that it is very easy to use. Women were classified as either those meeting or not meeting recommended daily intake
guidelines for dietary macronutrients and micronutrients. The same approach can be
used in future studies exploring associations of maternal diet and adverse pregnancy
and long-term outcome. Yet, it is important to acknowledge some of the limitations of this method. The scoring system described in the study consisted of a total of 23 nutrients. If a woman met the recommendation for an individual nutrient, she received 1 point per recommendation meaning that all nutrients were given equal weight in the scoring system. This may be misleading as inadequate intake of vitamin A and fat or carbohydrates, for example, affected the score in a similar manner. In addition, although it may imply that higher PENS was associated with lower rate of SGA, no multivariable analysis was done so other confounders were not adjusted for. Therefore, further research is needed to validate the proposed scoring system.

A multicountry randomized controlled trial of comprehensive maternal nutrition supplementation initiated before conception: the women first trial

Background: 
Reported benefits of maternal nutrition supplements commenced during pregnancy in low-resource populations have typically been quite limited.
Objectives: This study tested the effects on newborn size, especially length, of commencing nutrition supplements for women in low-resource populations ≥ 3 mo before conception (Arm 1), compared with the same supplement commenced late in the first trimester of pregnancy (Arm 2) or not at all (control Arm 3).
Methods: Women first was a 3-arm individualized randomized controlled trial (RCT). The intervention was a lipid-based micronutrient supplement; a protein-energy supplement was also provided if maternal body mass index (kg/m 2 ) was < 20 or gestational weight gain was less than recommendations. Study sites were in rural locations of the Democratic Republic of the Congo (DRC), Guatemala, India, and Pakistan. The primary outcome was length-for-age z score (LAZ), with all anthropometry
obtained < 48 h post delivery. Because gestational ages were unavailable in DRC, outcomes were determined for all 4 sites from WHO newborn standards (non-gestational-age-adjusted, NGAA) as well as INTERGROWTH-21st fetal standards (3 sites, gestational age-adjusted, GAA).
Results: A total of 7,387 nonpregnant women were randomly assigned, yielding 2,451 births with NGAA primary outcomes and 1,465 with GAA outcomes. Mean LAZ and other outcomes did not differ between Arm 1 and Arm 2 using either NGAA or GAA. Mean LAZ (NGAA) for Arm 1 was greater than for Arm 3 (effect size: +0.19; 95% CI 0.08–0.30, p = 0.0008). For GAA outcomes, rates of stunting and small-for-gestational-age were lower in Arm 1 than in Arm 3 (RR 0.69; 95% CI 0.49–0.98, p = 0.0361 and RR 0.78; 95% CI 0.70–0.88, p < 0.001, respectively). Rates of preterm birth did not differ among arms.
Conclusions: In low-resource populations, benefits on fetal growth-related birth outcomes were derived from nutrition supplements commenced before conception or late in the first trimester.
Comments:
Fetal stunning as expressed by low birth weight and growth that does meet the individual’s potential is one of the main problems in obstetrics. Although preventing fetal
growth restriction is universally important, it has a special role in low resource countries,
as a good “starting point” is of most importance. From the high rate of stillbirth (2–3%) in the study cohort, one can understand that the study population is considered at very high risk. In the current study, a relatively simple intervention was shown have a beneficial impact on fetal growth-related birth outcomes. The 87–88% compliance rate represents mainly a dedicated work of the investigators and research teams, stressing the importance of monitoring compliance to treatment and interventions also in common practice by the caregivers. Yet, although the results are promising, it may not be applicable to other cohorts from middle- or high-resource populations.

Role of maternal preconception nutrition on offspring growth and risk of stunting across the first 1,000 days in Vietnam: a prospective cohort study

Abstract: 
Growing evidence supports the role of preconception maternal nutritional status (PMNS) on birth outcomes; however, evidence of relationships with child growth are limited. We examined associations between PMNS (height, weight and body mass index-BMI) and offspring growth during the first 1,000 days. We used prospective cohort data from a randomized-controlled trial of preconception micronutrient supplementation in Vietnam, PRECONCEPT (n = 1,409). Poisson regression models were used to examine associations between PMNS and risk of offspring stunting (<–2 HAZ) at 2 years. We used path analytic models to examine associations with PMNS on fetal growth (ultrasound measurements) and offspring HAZ at birth and 2 years. All models were adjusted for child age, sex, gestational weight gain, education, socioeconomic status and treatment group. A third of women had a preconception height < 150 cm or weight < 43 kg. Women with preconception height < 150 cm or a weight < 43 kg were at increased risk of having a stunted child at 2 years (incident risk ratio [IRR] 1.85, 95% CI 1.51–2.28; IRR 1.35, 95% CI 1.10–1.65, respectively). While the traditional low BMI cut-off (< 18.5 kg/m 2 ) was not significant, lower BMI cut-offs (< 17.5 or < 18.0 kg/m 2 ) were significantly associated with 1.3 times increased risk of child stunting. In path models, PMNS were positively associated with fetal growth (ultrasound measurements) and offspring HAZ at birth and 2 years. For each 1 SD increase in maternal height and weight, offspring HAZ at 2 years increased by 0.30 SD and 0.23 SD, respectively. In conclusion, PMNS influences both offspring linear growth and risk of stunting across the first 1,000 days. These findings underscore the importance of expanding the scope of current policies and strategies to include the preconception period in order to reduce child stunting.
Comments:
In the current study, the association of maternal preconception maternal nutritional
status (PMNS) and fetal growth was explored using a prospective randomized trial (secondary analysis). Maternal PMNS was positively associated with fetal growth. The study is important mainly due to its prospective design, which allowed the researchers to
adjust to many potential confounders, including the infant’s sex, maternal gestational weight gain, and more. The study was conducted in Vietnam and almost one-third of
patients had low pregestational weight (< 43 kg) or their height was < 150 cm. It will be
interesting to see if similar interventions (or even a modified one) can also be used in a
western society with a more diverse population. The results of the current study join those of the previous study presented in this chapter (Hambidge et al.) in stressing the
importance of the preconception period as a major determinant of future pregnancy
outcome, and especially, fetal growth. Future research should focus on additional detailed prospective information on inflammation and environmental exposures (i.e., mycotoxins; household air pollution) and biomarkers of nutritional status to examine the direct and indirect effects and interactions with maternal nutritional status.

Maternal fruit and vegetable or vitamin C consumption during pregnancy is associated with fetal growth and infant growth up to 6 months: results from the Korean Mothers and Children’s Environmental Health (MOCEH) cohort study

Background:
 Based on data obtained from pregnant women who participated in the Mothers and Children’s Environmental Health (MOCEH) study in South Korea, we aimed to determine whether maternal intake of fruits and vegetables or vitamin C is associated with fetal and infant growth.
Methods: A total of 1,138 Korean pregnant women at 12–28 weeks gestation with their infants were recruited as study participants for the MOCEH. Intake of fruits and vegetables or vitamin C during pregnancy was assessed by a 1-day 24-h recall method. Fetal biometry was determined by ultrasonography at late pregnancy. Infant weight and length were measured at birth and 6 months.
Results: A multiple regression analysis after adjusting for covariates showed that maternal intake of fruits and vegetables was positively associated with the biparietal diameter of the fetus and infant’s weight from birth to 6 months. Also, maternal vitamin C intake was positively associated with the abdominal circumference of the fetus and infant birth length. In addition, there was a significant inverse relationship between consumption of fruits and vegetables (below the median compared to above the median of ≥ 519 g/day) and the risk of low growth (< 25th percentile) of biparietal diameter (OR 2.220; 95% CI 1.153–4.274) and birth weight (OR 1.434; 95% CI 1.001–2.056). A significant inverse relationship also existed between vitamin C consumption (below vs above the estimated average requirement [EAR] of ≥ 85 mg/day) and the risk of low growth (< 25th percentile) of birth weight (OR 1.470; 95% CI 1.011–2.139), weight from birth to 6 months (OR 1.520; 95% CI 1.066–2.165), and length at birth (OR 1.579; 95% CI 1.104–2.258).
Conclusions: An increased intake of fruits and vegetables or vitamin C at mid-pregnancy is associated with increased fetal growth and infant growth up to 6 months of age.
Comments:
Fruit and vegetables are considered as an excellent source of vitamin C. During
pregnancy, vitamin C consumption has been shown to be positively associated with
neonatal birth weight. The current study reaffirms the results of a few previous prospective cohort studies addressing this issue. The main advantages of the current
report lie in the large cohort with > 700 babies followed up to 6 months of age. Yet, it is important to emphasize that some of the outcome measures, for example, biparietal
diameter < 25th percentile, are not commonly used to assess outcomes related to abnormal intrauterine growth. Therefore, caution should be used in understanding
the terminology of outcomes to better understand the impact of fruit and vegetables consumption on fetal growth. The researchers also investigated maternal oxidative stress (MDA level), following the hypothesis that it might partly explain the underlying reason for their results. Antioxidant defense systems are crucial for the protection of tissues, cells, and organs from damage related to oxidative stress. Therefore, an imbalance between increased oxidative stress and decreased antioxidant defense can adversely affect pregnancy outcomes, including suboptimal fetal growth.

The impact of restricted gestational weight gain by dietary intervention on fetal growth in women with gestational diabetes mellitus

Abstract Aims/Hypothesis: 
We aimed to investigate the impact of maternal gestational weight gain (GWG) during dietary treatment on fetal growth in pregnancies complicated by gestational diabetes (GDM).
Methods: This was a retrospective cohort study of 382 women consecutively diagnosed with GDM before 34 weeks’ gestation with live singleton births in our centre (Center for Pregnant Women with Diabetes, Rigshospitalet, Copenhagen, Denmark) between 2011 and 2017. The women were stratified into 3 groups according to restricted (53%), appropriate (16%) and excessive (31%) weekly GWG during dietary treatment (using the Institute of Medicine guidelines) to estimate compliance with an energy-restricted “diabetes diet” (6,000 kJ/day [1,434 kcal/day], with approximately 50% of energy intake coming from carbohydrates with a low glycaemic index, and a carbohydrate intake of 175 g/day). Insulin therapy was initiated if necessary, according to local clinical guidelines.
Results: Glucose tolerance, HbA1c, weekly GWG before dietary treatment (difference between weight at GDM diagnosis and prepregnancy weight, divided by the number of weeks) and SD score for fetal abdominal circumference were comparable across the 3 groups at diagnosis of GDM at 276 ± 51 weeks (gestation time is given as weeksdays). The women were followed for 100 ± 51 weeks, during which 54% received supplementary insulin therapy and the average (mean) GWG during dietary treatment was 0, 3 and 5 kg in the 3 groups, respectively. Excessive weekly GWG during
dietary treatment, reflecting poor dietary adherence was associated with increasing HbA1c (p =0.014) from diagnosis of GDM to late pregnancy and infants with a birthweight-SD score of 0.59 ± 1.6. In contrast, restricted weekly GWG during dietary treatment, reflecting strict dietary adherence, was associated with decreasing HbA1c (p = 0.001) from diagnosis of GDM to late pregnancy and infants with a birthweight-SD score of 0.15 ± 1.1, without increased prevalence of infants born small for gestational age. Excessive GWG during dietary treatment and late-pregnancy HbA1c were
identified as potentially modifiable clinical predictors of infant birthweight-SD score (p = 0.02 for both variables) after correction for confounders.
Conclusions/Interpretation: Restricted GWG during dietary treatment was associated with healthier fetal growth in women with GDM. GWG during dietary treatment and late-pregnancy HbA1c were identified as potentially modifiable clinical predictors of infant birthweight-SD score.
Comments:
The rate of gestational diabetes mellitus is increasing worldwide. Although gestational
diabetes mellitus is related to several maternal, fetal, and neonatal complications, one of the early signs of uncontrolled gestational diabetes mellitus is accelerated fetal growth in response to maternal hyperglycemia. The effect was noticed in both twins and singleton pregnancies. The main challenge with gestational diabetes mellitus is that the diagnosis is usually made late in the second trimester, and there is only little time to react in order to modify the risk for complications. In the current study, it was shown that restricted gestational weight gain during dietary treatment was associated with improved fetal growth in women with gestational diabetes mellitus. As opposed to prior studies addressing this issue, in the current one, data on weekly maternal gestational weight gain were available from before and after the diagnosis of gestational diabetes, so it was possible to assess the effect of an energy restricted diet in the cohort. Some limitations of the study should be mentioned. There is a risk for bias as self-reported pre-pregnancy weight was used to calculate body mass index (BMI) and also gestational weight gain prior to intervention. In addition, the intervention was uniform for all women, but the compliance and adherence to treatment were not reported. Finally, no subgroup analysis was done according to maternal pre-pregnancy BMI; thus, it remains unclear if this intervention is uniformly effective or if there are subgroups in which it may be of better use.

Animal Studies

Effects of high-fat diets on fetal growth in rodents: a systematic review

Background:
 Maternal nutrition during pregnancy has life-long consequences for offspring. However, the effects of maternal overnutrition and/ or obesity on fetal growth remain poorly understood, for example, it is not clear why birthweight is increased in some obese pregnancies but not in others. Maternal obesity is frequently studied using rodents on high-fat diets, but effects on fetal growth are inconsistent. The purpose of this review is to identify factors that contribute to reduced or increased fetal growth in rodent models of maternal overnutrition.
Methods: We searched Web of Science and screened 2,173 abstracts and 328 full texts for studies that fed mice or rats diets providing ∼ 45% or ∼ 60% calories from fat for 3 weeks or more prior to pregnancy. We identified 36 papers matching the search criteria that reported birthweight or fetal weight.
Results: Studies that fed 45% fat diets to mice or 60% fat diets to rats generally did not show effects on fetal growth. Feeding a 45% fat diet to rats generally reduced birth and fetal weight. Feeding mice a 60% fat diet for 4–9 weeks prior to pregnancy tended to increase in fetal growth, whereas feeding this diet for a longer period tended to reduce fetal growth.
Conclusions: The high-fat diets used most often with rodents do not closely match Western diets and frequently reduce fetal growth, which is not a typical feature of obese human pregnancies. Adoption of standard protocols that more accurately mimic effects on fetal growth observed in obese human pregnancies will improve translational impact in this field.
Comments:
The current study is an important systematic review dealing with the potential effects
of high-fat diets on the growth of rodent fetuses. The results of the 36 selected studies
have shown that not only that high-fat diet is not associated with accelerated fetal growth in rats, but also it generally reduced birth and fetal weight. The effect of highfat diet was also related to the time period in which the pregnant (or prepregnant) rats were fed with longer period of exposure leading to reduced fetal growth. The results of the current study suggest that although animal studies are an important and even crucial aspect in understanding biological processes, applying the conclusions of animal studies on human subjects is inappropriate. It seems that the high-fat diets used most often with rodent studies are not similar match to Western diets. Thus, using protocols that more accurately mimic effects on fetal growth observed in obese human pregnancies will improve the conclusions that can be drown from animal studies and will assist in the planning of human studies in this field.

Evidence for liver energy metabolism programming in offspring subjected to intrauterine undernutrition during midgestation

Background:
 Maternal undernutrition programs fetal energy homeostasis and increases the risk of metabolic disorders later in life. This study aimed to identify the signs of hepatic metabolic programming in utero and during the juvenile phase after intrauterine undernutrition during midgestation.
Methods: Fifty-three pregnant goats were assigned to the control (100% of the maintenance requirement) or restricted (60% of the maintenance requirement from day 45 to 100 of midgestation and realimentation thereafter) group to compare hepatic energy metabolism in the fetuses (day 100 of gestation) and kids (postnatal day 90).
Results: Undernutrition increased the glucagon concentration and hepatic hexokinase activity, decreased the body weight, liver weight and hepatic expression of G6PC, G6PD, and PGC1α mRNAs, and tended to decrease the hepatic glycogen content and ACOX1 mRNA level in the dams. Maternal undernutrition decreased the growth hormone (GH) and triglyceride concentrations, tended to decrease the body weight and hepatic hexokinase activity, increased the hepatic PCK1, PCK2 and PRKAA2 mRNAs levels and glucose-6-phosphatase activity, and tended to increase the hepatic PRKAB1 and CPT1α mRNAs levels in the male fetuses. In the restricted female fetuses, the hepatic hexokinase activity and G6PC mRNA level tended to be increased, but PKB1 mRNA expression was decreased and the ACACA, CPT1α, NR1H3 and STK11 mRNA levels tended to be decreased. Maternal undernutrition changed the hepatic metabolic profile and affected the metabolic pathway involved in amino acid, glycerophospholipid, bile acid, purine, and saccharide metabolism in the fetuses, but not the kids. Additionally, maternal undernutrition increased the concentrations of GH and cortisol, elevated the hepatic glucose-6-phosphate dehydrogenase activity, and tended to decrease
the hepatic glycogen content in the male kids. No alterations in these variables were observed in the female kids.
Conclusions: Maternal undernutrition affects the metabolic status in a sex- and stage-specific manner by changing the metabolic profile, expression of genes involved in glucose homeostasis and enzyme activities in the liver of the fetuses. The changes in the hormone levels in the male fetuses and kids, but not the female offspring, represent a potential sign of metabolic programming.
Comments:
It is well known that the intrauterine environment may have long-term effects via epigenetic changes and fetal programming. The current study focused on different aspects of maternal undernutrition in offspring of pregnant goats including the effects
at the level of circulating blood, hepatic metabolites, genes, and enzymes. Interestingly,
maternal undernutrition changed the hepatic metabolic profile and affected the metabolic pathway involved in amino acid, glycerophospholipid, bile acid, purine, and saccharide metabolism in the fetuses but not in the kids. This implies that the effect may be reversible with proper nutrition after birth. Of note, during the juvenile stage, the kids were not exposed to an overnutrition environment. It is important to notice that the restricted arm in this study included 40% energy restriction and that the exposure began at mid-gestation. It would be interesting to explore different levels of malnutrition and the effect when it starts in various stages of pregnancy and during the preconception period. In addition, as differences were noted between males and females, investigating the sexual dimorphism of fetal programming in liver metabolism following a nutritional challenge is warranted, as also suggested by the authors.

Overall Commentary
Primary prevention remains one of the most effective strategies in medicine. The advantages of education for healthier lifestyle and other modifications is that not only it can positively affect pregnancy outcome and decrease long-term morbidity of the offspring, but it may also serve as a window of opportunity for future maternal well-being. Nevertheless, a balanced diet is merely a single component in the determinants of fetal/offspring growth and development, which is attenuated by genetic, demographic, behavioral, and other factors. Thus, maternal nutrition, like any other intervention, should be personalized in order to achieve its maximal benefit.