Which of the following nutrients are required in higher amounts during pregnancy due to their role in the synthesis of red blood cells?

Folate

Folate is a term used to describe both folate that occurs naturally in food sources and folic acid, the form of the vitamin found in fortified foods and dietary supplements. Folate is essential for nucleic acid synthesis, red blood cell synthesis and maintenance, and fetal and placental growth. Maternal folic acid deficiency can cause neural tube defects (NTDs) in the fetus and other congenital anomalies. As noted earlier, the CDC recommends 0.4 mg/day of folic acid from diet or supplements for all women capable of becoming pregnant to reduce the risk for NTDs.19Box 12.2 shows folate-rich foods and the amount of folate per serving. Women with a previous pregnancy affected by an NTD should take 4 mg of folic acid beginning 1 month before conception and throughout the first trimester. The United States began mandatory fortification of cereal and grain products with folic acid in 1998. Fortification substantially improved the folate status of US women of childbearing age and reduced the incidence of pregnancies affected by NTDs by 25%.28 However, there is concern that folic acid supplementation may no longer further reduce risk of NTDs because fortification may provide the amount of folic acid required to prevent most folate-sensitive NTDs.29,30

Folate deficiency has also been associated with a number of adverse birth outcomes, including spontaneous preterm birth.31,32 Folic acid supplementation in pregnancy has been shown to lengthen gestation in some, but not all, studies.33–35 There has been no decline in the prevalence of preterm birth since nationwide folic acid fortification was instituted. It is possible that the relative concentrations of folate species, which mediate the varied biologic effects of folate, may prove more critical than total folate concentration in preventing preterm birth. A recent study reported a biologic interaction between two major folate metabolites, serum 5-methyl-tetrahydrofolate and 5-formyl-tetrahydrofolate, on the occurrence of preterm birth.36 Subsequently, investigators found that these folate species were related to maternal inflammation in the lower genital tract, a potential mediator of preterm birth.37,38

Abstract

Maternal nutrition and physiology are intimately associated with reproductive success in diverse organisms. Despite decades of study, the molecular mechanisms linking maternal diet to the production and quality of oocytes remain poorly defined. Nuclear receptors (NRs) link nutritional signals to cellular responses and are essential for oocyte development. The fruit fly, Drosophila melanogaster, is an excellent genetically tractable model to study the relationship between NR signaling and oocyte production. In this review, we explore how NRs in Drosophila regulate the earliest stages of oocyte development. Long-recognized as an essential mediator of developmental transitions, we focus on the intrinsic roles of the Ecdysone Receptor and its ligand, ecdysone, in oogenesis. We also review recent studies suggesting broader roles for NRs as regulators of maternal physiology and their impact specifically on oocyte production. We propose that NRs form the molecular basis of a broad physiological surveillance network linking maternal diet with oocyte production. Given the functional conservation between Drosophila and humans, continued experimental investigation into the molecular mechanisms by which NRs promote oogenesis will likely aid our understanding of human fertility.

Inadequate Maternal Nutrition

Numerous animal studies have demonstrated that undernutrition of the mother caused by protein or caloric restriction can affect fetal growth adversely. However, profound alterations in nutrition are required to have a significant effect in human pregnancies.

The important effects of maternal nutrition on fetal growth and birth weight were demonstrated by studies in Russia and Holland among women who had inadequate nutrition during World War II. The population in Leningrad underwent a prolonged siege, during which both preconception nutritional status and gestational nutrition were poor, and birth weights were reduced by 400 to 600 g.47 In Holland, a 6-month famine created conditions that permitted evaluation of the effect of malnutrition during each of the trimesters of pregnancy in a group of women previously well nourished.48 Birth weights declined by approximately 10% and placental weights by 15% only when undernutrition occurred in the third trimester (daily caloric intake <1500 kcal). The difference in severity of FGR in these two populations suggests the importance of prepregnancy nutritional status, an idea that has been substantiated elsewhere.18,49

It is still unclear whether it is generalized calorie intake reduction, specific substrate limitation (e.g., protein, key minerals), or both that is important in producing FGR. Glucose uptake by the fetus is critical because there is the suggestion that little gluconeogenesis occurs in a normal fetus. In a fetus with FGR, the maternal-fetal glucose concentration difference is increased as a function of the severity of the growth restriction,50 facilitating glucose transfer across the small placenta. In addition, if a fetus is receiving decreased oxygen delivery as a result of decreased uteroplacental perfusion and has adapted by slowing metabolism and growth, it may not be advisable to increase substrate delivery.

Oxygen is also probably a primary determinant of fetal growth. Infants with FGR have a decrease in the partial pressure of oxygen (Po2) and decreased oxygen saturation values in the umbilical vein and artery.51 The median birth weight of infants of women living more than 10,000 feet above sea level is approximately 250 g less than the median birth weight of infants of women living at sea level.52 Pregnancies complicated by maternal cyanotic heart disease usually result in IUGR, but it is unclear whether abnormal maternal hemodynamics or the reduction in oxygen saturation (by approximately 40% in the umbilical vein) accounts for the poor fetal growth.53

FGR resulting from inadequate substrate availability is rare in developed countries. However, it is not unusual to see fetal growth velocity decrease in women with poorly controlled, severe inflammatory bowel disease who fail to gain or are losing weight. When treated with peripheral hyperalimentation, the fetal weight may be observed to improve.

Maternal Nutrition

Maternal nutrition, preconception and throughout pregnancy, has an important impact on pregnancy outcomes and fetal growth.3,5 Mothers who themselves may have been born small, as reflected by short maternal stature or maternal underweight, are anemic, smoke, drink alcohol, or consume caffeine during pregnancy have a higher risk of having a LBW, SGA, or preterm infant.3,16 Maternal diets deficient in calories, protein, Vitamin A, sodium, zinc, or iron have been associated with reduced nephron numbers in offspring of experimental animals (Table 20.2).8 Maternal vitamin A deficiency was associated with smaller newborn kidney size in Indian neonates.39 Optimization of maternal nutrition is therefore important for fetal kidney development.

In humans, exposure to famine at the time of conception or at various stages of gestation has also been associated with higher risk of hypertension, proteinuria, and renal dysfunction in offspring in later life.8 In these studies, blood pressures were higher and rose earlier in Nigerian compared with Caucasian and Chinese populations.8,40,41,42 Fasting during Ramadan has not been found to affect offspring birth weight, which may suggest that intermittent fasting may not affect fetal growth.43

Maternal Nutrition and Weight Gain

The two factors that most influence neonatal outcome are gestational age at delivery and the adequacy of fetal growth. Maternal nutritional status during gestation is closely linked to both these outcomes. The increased physiologic stress of a multifetal pregnancy demands a higher maternal resting energy expenditure, which can lead to a 40% increase in caloric requirements in a twin gestation.

Both total maternal weight gain and the timing of that weight gain are critical to optimizing twin birthweights and perinatal outcomes. Luke and colleagues93 have shown that weight gain before 28 weeks accounts for 80% of the effects of maternal weight gain on infant birthweights. Underscoring this point, these researchers demonstrated that even when weight gain is appropriate after 24 weeks, suboptimal gain before 24 weeks is still associated with earlier delivery and poorer intrauterine growth. Body mass index (BMI) or specific weight gain patterns associated with ideal twin pregnancy outcomes is defined as a birthweight of 2850 to 2950 g at 36 weeks or later; this is summarized inTable 39.7.94 Although the BMI categories used are slightly different from current BMI definitions, the differences in recommended weight gain by BMI category can easily be appreciated.

Results from the recent NICHD Fetal Growth Study of Twins—a prospective cohort enrolled in 2012 and 2013 at eight institutions throughout the United States—confirm this earlier data. Among 143 DC diamniotic twin gestations, second-trimester (both 14- to 20- and 21- to 27-week time periods) maternal weight gain was significantly associated with increases in twin birthweight. For each kilogram gained between 14 and 20 weeks, there was a mean 132.8 g increase in the birthweight of each twin.95 This paper also reported on the association between maternal weight gain and estimated fetal growth throughout gestation. Maternal weight gain in the second trimester (14 to 20 and 21 to 27 weeks) was significantly associated with increasedEFW at 21 weeks (increase of 10.5 g/kg of maternal weight gain) and 28 weeks (increase of 21.3 g/kg of maternal weight gain). Maternal weight gain between 14 and 20 weeks was also associated with larger AC and biparietal diameter at 21 weeks. Maternal weight gain between 21 and 27 weeks was associated with longer femur and humerus lengths at 28 weeks.

These data suggest a snowball effect of early weight gain in improvingmaternal nutrient stores for use later in pregnancy, when fetal demands increase. In addition, optimal maternal nutrition and weight gain early in pregnancy may enhance placental growth, thus providing an enhanced mechanism for ongoing nutrient supply to the babies.

Luke et al. have recommended a diet in which 20% of calories are from protein, 40% from low-glycemic-index carbohydrates, and 40% from fat, similar to that endorsed for gestational diabetes. For patients with a normal prepregnancy BMI, a daily intake of 3500 calories composed of 175 g of protein, 350 g of carbohydrate, and 156 g of fat is recommended.96

5 Consequences of Altered Maternal Nutrition in Pregnancy

Maternal nutrition is a modifiable risk factor of public health importance that can be integrated into efforts to prevent adverse birth outcomes, particularly among economically developing/low-income populations (Abu-Saad & Fraser, 2010). Different dietary interventional studies concluded that there is additional high quality randomized controlled trials are required to identify maternal diet intakes that optimize neonatal and infant outcomes (Gresham, Byles, Bisquera, & Hure, 2014). Studies reported that dietary interventions showed some small, but significant differences in pregnancy outcomes including a reduction in the incidence of preterm birth (Gresham et al., 2014). Further high-quality randomized controlled trials are required to identify maternal diet intakes that optimize pregnancy outcomes.

Altered micronutrient levels in the one carbon cycle may induce oxidative stress either by affecting the folate pool or by impairing remethylation of homocysteine (Mohammad et al., 2011). Influences of maternal nutrition on epigenetic programming are most important during prenatal and early postnatal development, when epigenetic mechanisms undergo establishment and maturation. Disruption of normal gene-specific methylation patterns by perturbations in maternal nutrition may affect the pregnancy outcome having long-term implications in the offspring. Thus, studies in pregnancy complications and in first episode psychotic patients suggest that altered metabolism of micronutrients like folic acid, vitamin B12, and DHA through the one carbon cycle may epigenetically regulate neurotrophic factors.

Our study, for the first time, indicates a close association of constituents of one carbon cycle, DHA, and neurotrophins in preterm pregnancy (Dhobale, Wadhwani, Mehendale, Pisal, & Joshi, 2011; Dhobale et al., 2012). The lower levels of cord BDNF and NGF in preterm pregnancies may provide clues to predict cognitive deficits in children. Children born preterm are suggested to be at risk for developing neurodevelopmental disorders in later life. Identification of these genes can be of use in elucidating the molecular basis of the pathology and may further also lead to identification of suitable disease early biomarkers.

These altered levels of neurotrophins (BDNF and NGF) may be a consequence of altered gene expression and promoter methylation due to changes in the one carbon cycle. It is likely that these changes in the one carbon cycle influence epigenetic programming of the placenta. This may have implications for micronutrient mediated fetal programming of diseases in adult life.

Maternal Diet and Primary Prevention

Maternal diet during pregnancy and lactation has been thought to be one of the factors that influences an infant’s immune response to early exposure. In the past, maternal dietary restrictions for pregnant and lactating mothers had been proposed as a strategy to reduce the risk of food-related allergy in infants and children, particularly when there was a strong family history of atopy (AAP, 2000). Because prenatal life is a critical period for the development of the immune system, the role of intrauterine exposure from the maternal diet during pregnancy has been proposed to influence fetal immune responses that might predispose the fetus to allergy in childhood (Devereaux et al., 2002). However, recent studies fail to support any value of maternal dietary restriction during pregnancy or lactation (Boyce et al., 2010; Greer et al., 2008) as a strategy to prevent atopic disease in their off-spring. A 2006 Cochrane meta-analysis showed that avoiding antigens during pregnancy not only is unlikely to substantially reduce the unborn child’s risk for atopic disease, but also may adversely affect the nutrition of the mother or fetus (Kramer and Kakuma, 2006). The American Academy of Allergy, Asthma, & Immunology (AAAAI) noted that maternal avoidance during pregnancy of essential foods, such as milk and egg is not recommended (Fleischer et al., 2013). Likewise, the Australasian 2016 Guidelines note that exclusion of any particular foods (including foods considered to be highly allergenic) from the maternal diet during pregnancy or breastfeeding is not recommended, as this has not been shown to prevent allergies (ASCIA, 2016). Based on the evidence, it is reasonable to conclude that restrictions of the maternal diet during pregnancy and lactation, as a strategy for risk reduction of allergy in the infant, are not advised (WAO, 2011; Boyce et al., 2010; Fleischer et al., 2013; Muraro et al., 2004).

Influence of Maternal Nutrition on Reproductive Processes

Maternal nutrition impacts ovulation, fertilization, and fetal development. The process of increasing maternal nutritional intake through administration of a high energy feedstuff in the month prior to breeding is known as flushing. In ewes suffering from diminished body condition this process has the potential to increase ovulation and fertilization rates. Maternal nutrition is also critically important during pregnancy. Ewes receiving less than the National Research Council (NRC) recommendations are at risk for compromised pregnancies as maternal nutrition during pregnancy impacts fetal growth. Insufficient nutrient availability can cause restricted fetal growth resulting in lambs that are small for gestational age. Lamb production, the main source of income for sheep flocks worldwide, is dependent on the birth of viable lambs with appropriate birth weight, which is a key determinate of neonatal survival.

The placenta plays a key role in responding to maternal nutritional constraints to facilitate fetal growth. As pregnancy depends upon cross-talk between the maternal and the fetal compartments via the placenta an insufficient supply of nutrients from the mother, leads to compensatory adaptations to enhance size, architecture and function of the placenta allow demands for fetal-placental growth to be met. Placental gene expression influencing nutrient transport is altered in an effort to promote fetal growth as a means to enhance lamb viability.

Maternal metabolic stress resulting in diminished birth weight also translates into poor post-natal performance of lambs. Growth restricted and/or small birth weight lambs demonstrate slower growth rates, decreased feed intake, and either reduced adult carcass merit or reproductive performance when compared to their counterparts from well-fed dams.

Poor maintenance of a ewe’s body condition during pregnancy can also lead to post-partum difficulties including decreased lactation and a slower return to cyclicity. While sheep are adaptable to a wide range of forage quality and availability, it is necessary to consider nutritional needs in order to facilitate reproductive success and offspring viability.

Epigenetics and Other Interactions.

Maternal diet is one of the ways in which the supply of nutrients vital to DNA methylation may be affected. Famine provides an extreme example of disruption to the supply of nutrients essential in the methylation pathway. Individuals exposed to famine in utero have been shown to have lower birth weights,37 and furthermore, exposure to famine during any stage of gestation was associated with glucose intolerance later in life.63 Individuals born during the Dutch famine born 60 years ago were later found to have less DNA methylation of the imprinted IGF2 gene compared with their famine-unexposed same-sex siblings.64 This observation supports the hypothesis that exposure to adverse environmental factors in utero could permanently alter epigenetic marks, which might have a bearing in adult disease risk.

Intrauterine growth restriction (IUGR)

Poor maternal nutrition during gestation can lead to IUGR, a main cause of low birth weight associated with high neonatal morbidity and mortality. Deficiency of macronutrients, protein and carbohydrates, during pregnancy results in low birth weight, and subsequently insulin resistance, glucose intolerance, hypertension and adiposity in adulthood [110].

Epidemiologic studies examining the effects of maternal nutrition on the offspring's fertility are rare, but a link between impaired fetal growth, possibly caused by maternal malnutrition, and reproductive function, has been established [111]. Further studies are needed to better understand the mechanisms. A study conducted in an IUGR rat model induced by gestational protein deficiency found differential gene expression of Wnt2 (Wnt family member 2) and Dlk1 (Delta like non-canonical notch ligand 1) and a site-specific hypomethylation in Wnt2 promoter region in IUGR placentae. This supports a key role of maternal nutrition on determining the epigenome of the neonate [112]. Another study shows that maternal peri-conceptional folic acid supplementation is associated with hypermethylation of H19 gene in SGA infants [113].