Maternal Adaptations To Pregnancy: II - pediagenosis
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Monday, October 22, 2018

Maternal Adaptations To Pregnancy: II

Maternal Adaptations To Pregnancy: II
Thyroid gland
Maternal thyroid hormone is critical for normal embryonic and fetal development. Among the hepatic proteins stimulated by the elevated circulating levels of estrogen in pregnancy is thyroid-binding globulin (TBG). The increased TBG results in a decrease in circulating free T3 and T4 that will stimulate thyroid-stimulating hormone (TSH) production by the pituitary gland, thereby increasing the production of thyroxine by the thyroid gland. The alfa subunit of human chorionic gonadotropin (hCG) also appears to stimulate the thyroid gland, thereby assuring a timely increase in thyroxine production with pregnancy onset.

Interpretation of thyroid tests in pregnancy can be confusing because of the increased TBG. Total T3 and T4 will be elevated as will T3 resin uptake (T3RU), the indirect measure of total thyroxine binding capacity. Because of these changes, thyroid testing in pregnancy should rely on measurements of serum TSH and/or free T3 and T4.

Gastrointestinal tract
Pregnancy is a potentially diabetogenic state. It is a state of relative hyperinsulinism with peripheral insulin resistance. The high maternal levels of estrogen, progesterone and human placental lactogen (hPL) cause hypertrophy, hyperplasia and hypersecretion of insulin by the beta islet cells of the pancreas. Still, many pregnant women show prolonged hyperglycemia after meals. In addition, most pregnant women exhibit: (i) exaggerated insulin release in response to glucose infusion; (ii) reduced peripheral uptake of glucose; and (iii) suppressed glucagon secretion. Taken together, these traits characterize insulin resistance. The mechanism(s) for insulin resistance in pregnancy are not well understood. The growth hormone-like activity of hPL may be responsible. In addition, hPL may also promote lipolysis and liberation of free fatty acids that facilitate tissue resistance to insulin. These metabolic changes ensure a continuous supply of glucose for transfer to the fetus. Women at increased lifetime risk for developing type 2 diabetes mellitus (DM) will often develop a condition known as gestational diabetes mellitus (GDM). The presence of GDM confers a sevenfold risk of future type 2 DM. The same mechanisms that ensure a continuous supply of fetal glucose produce an “accelerated starvation” profile during fasting. Fasted pregnant women are relatively hypoglycemic and have higher circulating free fatty acids, triglycerides and cholesterol. Prolonged fasting or persistent vomiting in pregnant women can rapidly lead to ketonemia.
High maternal levels of circulating estrogens increase the synthesis of hepatic proteins. These include procoagulants, bile acids and multiple hormone binding proteins. The procoagulants most markedly elevated are factors I (fibrinogen), VII, VIII, IX and X. The higher circulating concentrations of clotting cascade proteins protect the mother from excessive blood loss at the time of delivery; however, they also predispose pregnant and postpartum women to venous thrombosis and embolism. Estrogens also stimulate the cytochrome P450 oxidative pathway in the liver. This increases the production of steroid precursors and can dramatically alter drug metabolism. The latter effect necessitates careful monitoring of the maternal plasma drug levels of many commonly used therapeutics. Most notable are the anticonvulsants and antibiotics.

The calcium requirements of the developing fetal and neonatal skeleton produce a profound maternal calcium stress during pregnancy and lactation. Maternal plasma parathyroid hormone (PTH) concentrations rise despite a minimal decrease in circulating free calcium. Intestinal absorption of calcium is enhanced by an increase in circulating 1,25-dihydroxyvitamin D3, the active metabolite of vitamin D. 1,25-(OH)2-D3 increases for two reasons: (i) PTH increases the hepatic synthesis of 25-(OH)-D3, and (ii) the activity of 1α-hydroxylase increases in pregnancy. In nonpregnant women and men, conversion of 25-(OH)-D3 to the 1,25 active form is limited by the activity of 1α-hydroxylase, the final converting enzyme in D3 metabolism. 1α-hydroxylase is typically present only in the kidney but, in pregnancy, it is produced by both the decidua and placenta. This ensures an adequate amount of active D3 to optimize dietary calcium absorption during pregnancy. If dietary calcium intake is adequate, minimal mobilization of maternal bone calcium occurs. If it is not, fetal and neonatal skeletal mineralization will proceed at the expense of maternal bone density.
Progesterone relaxes smooth muscle and thereby affects all parts of the gastrointestinal tract during pregnancy. Gastric emptying is delayed, as is movement of digested material along the remainder of the tract. Gallbladder emptying is slower and bile tends to sludge in the bile duct and common duct. Minor disorders of the gastrointestinal tract are very common in pregnancy. These include nausea, vomiting, constipation and heartburn.

Nutritional requirements of pregnancy
The nutritional requirements of pregnancy are complex and include water, oxygen, macronutrients (glucose, essential amino acids and fatty acids) and micronutrients (vitamins and minerals). Water is necessary for volume support of the fetus and placenta and for the increase in maternal blood volume (Chapter 20), oxygen for efficient energy production as ATP, macronutrients for energy production and body growth, and micronutrients for regulating the expression of developmental genes and subsequent tissue functions.
Total maternal water retention at term is approximately 6.5 L with approximately 3.5 L in the fetus, placenta and amniotic fluid and another 3.0 L in the expanded uterus, breasts and blood volume (Table 21.1). Glucose is the predominant source of reduced nicotinamide adenine dinucleotide phosphate (NADPH), which is an essential cofactor for antioxidative enzymes and diverse metabolic pathways in all cell types. Fetal glucose is primarily derived from the uptake and transport of maternal glucose by the placenta. Amino acids serve as building blocks for proteins and as essential precursors of hormones, neurotransmitters, nitric oxide (NO), creatine, glutathione, carnitine and polyamines. Essential amino acids cannot be synthesized by either mother or fetus and must be derived from high quality protein foods or supplements. Long chain fatty acids readily cross the placenta from mother to fetus where they serve as major metabolic fuels.
The three most important dietary minerals in pregnancy are calcium, iodine and iron. Besides being a major component of the fetal skeleton, cytoskeleton and teeth, calcium is also required for calcium activated enzymes involved in digestion, cell cell adhesion, blood clotting, intracellular proteolysis and NO synthesis. Iodine is required for thyroid hormone synthesis; thyroid hormones, in turn, are required for normal fetal neuronal development. Iodine requirements in pregnancy increase by 30%, -from 150 to 225 μg/day. Severe maternal iodine deficiency is associated with cretinism and milder forms of deficiency with impaired cognitive development of the infant. Iron, the most abundant trace element in the body, is a component of hemoglobin, myoglobin and cytochromes. Thus, physiologic levels of iron are necessary for (i) oxygen binding, transport, storage and sensing; (ii) metabolism of glucose, proteins and lipids; (iii) mitochondrial electron transport and ATP production; (iv) DNA synthesis; (v) immunity; and (vi) antioxidant activity. Iron requirements in pregnancy almost double from 15 to 27 mg/day.
Clinical observations and animal studies have demonstrated that vitamins A, B6, B12, D and folate have a major impact on pregnancy outcomes. Pyridoxal phosphate, the active form of vitamin B6, folic acid and vitamin B12 are of significance to fetal development because of their role in one-carbon-unit metabolism. Folate is essential to normal embryonic and fetal development and growth. Folate defi- ciency in early pregnancy can disrupt neural tube formation; supple- mentation has been shown in clinical studies to reduce the incidence of neural tube defects.
The absolute quantities of macro and micronutrients required during pregnancy in a given woman will vary depending on her prepregnancy nutritional status. Anemic women will require more iron. It is estimated that only half of women in developed countries have adequate dietary intake of micronutrients; hence, prenatal supplements are typically recommended. In the underdeveloped and developing world, supplementation is even more critical but often absent. Women with a low body mass index (BMI) will require more calories during pregnancy to support normal fetal growth than women with a normal BMI. The interaction between prepregnancy nutritional status and caloric intake during pregnancy was first recognized when the off spring born during a 6-month famine in the Netherlands near the end of World War II were followed into adulthood. The offspring of previously well-nourished women who experience caloric deprivation during pregnancy are at increased risk of being born small for gestational age (SGA) and developing hypertension, coronary heart disease and type 2 DM in adulthood. If the woman is undernourished entering pregnancy, the growth restriction and subsequent abnormalities are more severe and earlier in onset. It is hypothesized that maternal undernutrition leads to development of a “thrifty phenotype” in the fetus that reallocates energy and nutrition to favor development of organs critical to immediate survival. Obesity and metabolic and cardiovascular abnormalities subsequently develop when these individuals are raised in an environment with a great abundance of high energy foods. Overweight or obese women are at risk of delivering both SGA and excessively large infants who also have an increased risk of obesity in childhood and adulthood.
The biologic basis for these fetal origins of adult disease appears to be epigenetic programming, the stable and inheritable alterations of genes through covalent modifications of their DNA and core his- tones without changes in the DNA sequence. Recent studies indicate that abnormal fetal growth is associated with hypomethylation or hypermethylation of genes involved with the synthesis and regulation of the insulin-like growth factor (IGF) system. Changes in leptin secretion and sensitivity that affect eating may also be involved.

Immune system
The immunology of pregnancy is fairly complicated and may vary fairly significantly over the course of gestation. The processes of implantation and parturition are inflammatory in nature, yet maternal immune reactivity over the majority of pregnancy requires a significant level of immune tolerance. The fetus represents a hemi-allograft in a typically immunocompetent host, however, graft rejection usually does not occur. Although the fetus is recognized by the maternal immune system, the incited alloresponse is not cytotoxic in healthy pregnancies. Rather, there is an increase in maternal regulatory T helper cell (T reg) number and activity that promotes tolerance to the recognized fetus-specific antigen. Further, normally cytotoxic CD8+ T cells at the maternal-fetal interface tend to be deficient in the expression of cytolytic molecules such as perforin and granzyme B.
Several additional factors are known to be involved in maternal immune tolerance to the developing fetus; many remain to be discovered. For example, the fetally-derived placenta does not express classic transplantation antigens that would typically provoke rejection. This includes major histocompatibility complex (MHC) class II and most MHC class I products. Tolerogenic changes in maternal immunity do not come without costs. For example, pregnant women experience a higher attack rate and more severe or prolonged disease upon exposure to certain viral pathogens (e.g. varicella/chickenpox).
Maternalantibody-mediatedimmunityisactivelytransferredtothefetus beginning at approximately 16 weeks’ gestational age when receptors for the Fc region of immunoglobulin G (IgG) appear in the placenta.

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