Maternal Adaptations To Pregnancy: II
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.
