Marked changes occur in the hypothalamic-pituitary-adrenal (HPA) axis during pregnancy, resulting in a state of increased HPA function.^77,113 (See Figure 2-7 for an illustration of the HPA axis.) These changes are mediated primarily by placental hormones, including placental ACTH, GH, and CRH. Maternal hypothalamic-pituitary function is discussed further in Chapter 2 in conjunction with the hypothalamic-pituitary-ovarian axis. Changes in the hypothalamus and pituitary during pregnancy are summarized in Box 19-1 on page 628.

Anterior pituitary function.

The anterior pituitary is composed of six cell types, each of which produces different hormones. These types of cells and their major hormones include lactotroph (prolactin), corticotroph (pro-opiomelanocortin [POMC] and its derivatives including ACTH, β-endorphin, and β-lipotropin), somatotroph (GH), gonadotroph (follicle-stimulating hormone [FSH] and luteinizing hormone [LH]), and cells producing thyroid-stimulating hormone (TSH) (thyrotropin). The anterior pituitary gland increases in size and weight (from an average of 660 mg in the nonpregnant woman to 760 mg or greater during pregnancy) due to an estrogen-induced increase in the lactotroph cells.^{32,35,86,93,97,151} The anterior pituitary also develops a more convex, dome-shaped surface, which may cause it to bulge upward in some women, compressing the optic chiasma.³² For these women, this can result in a transient hemianopia. Changes in pituitary function during pregnancy are summarized in Box 19-1 on page 628.

In the nonpregnant woman, the prolactin-producing lactotroph cells make up approximately 20% of the anterior pituitary; this increases to around 60% during pregnancy.¹⁵¹ Prolactin isoforms increase during pregnancy, with the nonglycosylated forms exceeding the N-linked glycosylated form that is most common in nonpregnant women.^32,151 The nonglycosylated form may be more bioactive and function to prepare the breast for lactation (see Chapter 5). Prolactin increases 10-fold during pregnancy to peak at delivery at 140 ng/mL (6068 pmol/L).^32,35,74,97 Most of the increase in maternal prolactin is from the maternal anterior pituitary, although prolactin is also produced by the maternal decidua. Decidual prolactin is found primarily in amniotic fluid; little enters the maternal circulation. Prolactin levels in the amniotic fluid peak in the second trimester at 6000 ng/mL (260,886 pmol/L).^32,35,151

Corticotroph cells do not change in size during pregnancy.¹⁵¹ However, ACTH secretion and plasma ACTH levels increase progressively, peaking during the intrapartum period (Figure 19-1), from approximately 10 pg/mL (2.2 pmol/L) in nonpregnant women to 50 pg/mL (11 pmol/L) at term.^32,35,97,151 ACTH secretion is stimulated by CRH and, in turn, stimulates release of cortisol by the adrenal gland. Changes in ACTH parallel the increase in free and total cortisol (see Figure 19-1).^35,86 During pregnancy, the adrenal gland is more responsive to ACTH with a blunted HPA axis response to exogenous glucocorticoids.⁷⁷ There is a two- to fourfold increase in ACTH from the first to third trimesters, in spite of the increased bound and free plasma cortisol.⁹⁷ The increase in ACTH in the face of increased cortisol suggests a change in the set point for cortisol release that alters the ACTH-cortisol feedback loop.^44,97 ACTH maintains its diurnal variation during pregnancy, although this cycling may be blunted.^{35,43,77,86,97} Placental ACTH increases in the second and third trimesters and it is unclear how much of increased maternal serum ACTH comes from the maternal anterior pituitary versus the placenta.⁹³ The effects of ACTH on the adrenal gland and changes in cortisol during pregnancy are described further under Adrenal Function.

The increased ACTH secretion during pregnancy is thought to be due primarily to increased placental (and some decidual and fetal membrane) CRH, rather than maternal hypothalamic CRH (Figure 19-2, B).^{32,35,77,86,151,159} Other factors that may contribute to this increase are the decreased pituitary gland sensitivity to cortisol feedback, enhanced pituitary responsiveness to corticotropin-releasing factors such as vasopressin, and CRH.^77,159 Maternal serum CRH increases markedly beginning by 8 to 10 weeks and rises from prepregnant values of 10 to 100 pg/mL (47.6 to 476 pmol/L) to 300 to 1000 pg/mL (1429 to 4762 pmol/L) by the third trimester.^86,151,159 CRH-binding protein (CRH-BP) decreases the bioactivity of CRH throughout most of gestation. CRH-BP levels are similar to nonpregnant levels until the third trimester and then fall by two thirds during the last 6 weeks in preparation for birth. CRH has multiple roles in establishing and maintaining pregnancy and is produced by placental and uterine tissues in addition to the hypothalamus.¹⁵⁹ CRH plays an important role in the onset of parturition; increased CRH prior to term plays a role in preterm labor onset (see Chapter 4).¹⁵⁹

Somatotroph and gonadotroph cells of the anterior pituitary decrease during pregnancy.⁶ Hypothalamic gonadotropin-releasing hormone (GnRH) is suppressed in pregnancy by the elevated CRH, β-endorphins, and cortisol, with a blunted response of the pituitary to GnRH and low LH and FSH levels by 6 to 7 weeks.¹⁵⁹ By midpregnancy, LH and FSH levels are undetectable.^32,35,97,151 Gonadotropin function is described in Chapter 2. β-endorphins during pregnancy and the intrapartum period are described in  Chapter 15.

Pituitary GH (GH-N) decreases after the first trimester as placental GH (GH-V) increases.^35,93,97 GH-V is a GH variant that stimulates bone growth and regulates maternal insulin-like growth factor-I (IGF-I), which in turn alters maternal metabolism, stimulating gluconeogenesis and lipolysis.⁹³ GH-V is secreted continuously, as opposed to the pulsatile secretion characteristic of GH-N.⁵ GH-N is the main maternal GH until 15 to 20 weeks; then it decreases and becomes undetectable by term. GH-V increases progressively from 15 to 20 weeks until term.⁹⁷ GH-V stimulates IGF-I, with negative feedback suppression of maternal GH-N.^5,32

Hypothalamic-pituitary-thyroid axis

Marked changes are also seen in the HPT axis during pregnancy. These changes occur primarily in the first half of gestation so that the woman achieves a new steady state in HPT function by midgestation that is maintained until delivery.^62,71 The net result of changes in thyroid function during pregnancy is to increase the availability of thyroid hormones by 40% to 100%.¹⁴² Morreale de Escobar et al. summarized the major changes in thyroid function during pregnancy: (1) Increased estrogen leads to a two- to threefold increase in thyroid-binding globulin production by the liver. This decreases levels of free thyroid hormone and stimulates the hypothalamic-pituitary-thyroid (HPT) axis; (2) increased human chorionic gonadotropin (hCG), which has a structure similar to thyroid-stimulating hormone (TSH), stimulates increased T₃ and T₄. This leads to negative feedback to the pituitary gland and a decrease in TSH (especially during weeks 8 to 14 when hCG is peaking); (3) peripheral metabolism of thyroid hormones increases in the second and third trimesters due to increased production of type II and III monodeiodinases (see Box 19-3 below) by the placenta.⁹⁵

BOX 19-3   Thyroid Function

The thyroid gland consists of multiple colloid-filled follicles that serve as a storage site for thyroid hormone (see Figure 19-3). The major component of the colloid is thyroglobulin. Thyroid cellular functions include iodine transport and thyroxine (T₄) and triiodothyronine (T₃) formation and release into the blood. T₄ acts as a prohormone for T₃ and by itself has little intrinsic metabolic activity.¹³¹ Iodide is actively transported into the thyroid cell, where it is stored and oxidized. Oxidized iodide is bound to tyrosine to form monoiodotyrosines (MIT) and diiodotyrosines (DIT). T₃ is composed of 1 MIT and 1 DIT; T₄ is formed from 2 DIT. These substances are held within the thyroglobulin and used to form T₄ and T₃. T₄ and T₃ are stored in the thyroid, bound to thyroglobulin. Under the influence of thyroid-stimulating hormone (TSH), T₄ and a small amount of T₃ are cleaved from thyroglobulin and secreted. In peripheral tissue, T₄ is deiodinated to T₃ (80% of T₃ in tissues is derived from this process).¹³¹ The iodine released by this process is reconcentrated by the thyroid or excreted by the kidneys. T₄ can also be metabolized to reverse T₃ (rT₃), which is an inactive compound. T₃ and rT₃ are in a reciprocal relationship. Nearly all of the thyroid hormones circulate in plasma bound to proteins, including thyroxine-binding globulin (TBG) (the major carrier), transthyretin (TTR), or albumin. Changing levels of TBG, such as occurs during pregnancy, alter serum thyroxine levels without changing thyroid status. The small amount of free T₃ in the blood forms the most physiologically active fraction.

Three types of the monodeiodinase (MDI) enzymes catabolize thyroid hormones: (1) MDI-I (found in the liver, kidney, thyroid, and pituitary); (2) MDI-II (found in the brain, pituitary, brown adipose tissue, keratinocytes, and placenta; and (3) MDI-III (found in the placenta, brain, and epidermis). MDI-I and MDI-II act on the outer ring of the iodothyronine molecule; MDI-III acts primarily on the inner ring. MDI action on the inner rings catabolizes T₄ to the inactive rT₄ or T₃ to the inactive T₂. MDI action on the outer ring converts T₄ to T₃.

Thyroid hormones bind to nuclear thyroid hormone protein receptors in cells, which have a 10-fold greater affinity for T₃ than for T₄, that regulate gene transcription resulting in the production of proteins that affect a variety of metabolic and other processes.^29,99,131 Thyroid hormones are involved in the regulation of protein and lipid metabolism, glucose absorption and utilization, increasing the rate of cellular oxidation, heat production, fluid balance, calcium and vitamin D homeostasis, and liver functions.¹³¹ Thyroid hormones are also critical for maturation of the retina, cochlea, and brain, including neural differentiation and migration (see Chapter 15).¹³¹

From references 29, 47, 99, 131.

Adaptations during pregnancy related to thyroid physiology mimic hyperthyroidism. The pregnant woman can be described as being in a state of euthyroid hyperthyroxinemia, however, since thyroid function per se does not change during pregnancy.⁹⁵ Thyroid hormone changes are important in supporting the altered carbohydrate, protein, and lipid metabolism of pregnancy and changes in basal metabolic rate (see Chapter 16).⁷⁹ The factors primarily responsible for changes in HPT axis function during pregnancy are the elevated hCG and thyroid-binding globulin (TBG) levels and the increased urinary iodide excretion that lowers maternal plasma iodine.^40,43 Box 19-3 on page 630, Box 19-4 below and Figure 19-3 review thyroid hormone production and regulation. Figure 19-4 illustrates regulation of maternal thyroid hormone function during pregnancy.

BOX 19-4   Regulation of Thyroid Hormone Secretion

Thyroid-stimulating hormone (TSH) acts through receptors on the thyroid cell membrane to activate adenyl cyclase. This stimulates formation of cyclic adenosine monophosphate (cAMP), which activates cellular systems to increase iodide uptake and thyroid hormone production and synthesis. TSH secretion is stimulated by thyrotropin-releasing hormone (TRH). TRH is secreted primarily by paraventricular nuclei of the hypothalamus and is released into the hypothalamic-pituitary portal system. TRH binds to receptors on the plasma membrane of thyrotropic cells within the anterior pituitary to activate synthesis and secretion of TSH. Secretion of thyroid hormones decreases the responsiveness of the pituitary to TRH. Secretion of TSH is also influenced by circulating levels of free thyroid hormone and intrapituitary triiodothyronine (T₃) levels via negative feedback to the pituitary gland; that is, increased free thyroid hormone levels decrease secretion of TSH by the pituitary and vice versa. Circulating thyroxine (T₄) regulates TSH primarily through intrapituitary deiodination of T₄ to T₃. The pituitary-thyroid axis is controlled in turn by the hypothalamus and TRH. TSH is inhibited by excess circulating thyroid hormone.

From references 29, 47, 99, 131.

Thyroid hormones are transported in the blood bound to binding proteins, such as TBG, albumin, and transthyretin (TTR; formerly called thyroxine-binding prealbumin). In the nonpregnant individual, about two thirds of the T₄ is bound to TBG, increasing to 75% or greater during pregnancy.^34,43 Under the influence of estrogen, hepatic synthesis and sialylation of TBG increase twofold to threefold beginning within a few weeks after fertilization and plateau from midgestation to delivery.^{34,71,99,100,144} Increased sialylation increases the half-life of TBG. The ability of TBG to bind thyroxine doubles during this period; TTR, also influenced by estrogen, decreases.⁴³ These changes increase serum TBG levels, decrease the percent of T₄ bound to TTR and increase total T₄ and T₃.¹⁰⁰ The increased TBG is accompanied by 10% to 15% decrease in free T₄ and free T₃ if iodine is sufficient; if iodine is inadequate, T₄ levels increase.⁹⁹

A transient increase in free T₄ is reported in the first trimester, related to the increase in hCG, with a decrease in the second and third trimesters.^71,72 Variations in findings are most often due to differences in the iodine status of the populations studied and measurement techniques.⁷³ Free T₃ changes parallel those of free T₄.⁷² Concentrations of free T₃ and free T₄, although low, remain within normal physiologic limits.^72,99 The basis for these changes is thought to be primarily related to the interaction of estrogen, TSH, and thyroid-binding proteins.⁷² 

Resin T₃ uptake (RT₃U) decreases during pregnancy. RT₃U measures TBG-binding capacity by quantifying the number of unbound sites, and approximates the amount of free T₄. Although T₄-binding sites and binding capacity increase in pregnancy, the number of binding sites exceeds the available T₄. The increased number of unbound sites is reflected by decreased RT₃U.

In contrast to changes in free T₃ and free T₄, total T₃ and T₄ increase, peaking at 10 to 15 weeks’ gestation and then plateauing at levels 40% to 100% higher than nonpregnant values.^142,144 This increase is primarily due to increases in TBG and hCG, and possibly to an increase in the production of MDI-III (see Box 19-3 on page 630) by the placenta.⁷¹ This enzyme converts T₄ to reverse T₃ (rT₃), an inactive compound, and T₃ to T₂, another inactive compound.⁹⁸ Levels of T₃ are elevated because of the increased availability of T₄ for deiodination to T₃ in peripheral tissue rather than due to increased T₃ production per se.

The increased T₃ and T₄ are also related to increased TSH bioactivity stimulated by hCG, which peaks at about the same time.⁵⁸ hCG has a mild TSH-like activity that increases secretion of T₄.^34,100 hCG is a partial inhibitor of the pituitary gland and has β subunits similar to TSH (as well as luteinizing and follicle-stimulating hormone). Thus hCG has thyrotropic activity and can activate TSH receptors.^34,100 Serum hCG is positively correlated with free T₄ and inversely correlated with TSH levels in early pregnancy.^40,73 Elevated T₃ and T₄ suppress endogenous TSH secretion by the anterior pituitary.⁹⁸ TSH decreases transiently from 8 to 14 weeks’ gestation at the time of the hCG peak, progressively returning to prepregnancy levels by term.^34,100,151 Occasionally some otherwise healthy pregnant women will experience a transient hyperthyroxinemia (generally without clinical signs) associated with higher than usual hCG levels in the first trimester and a greater fall in TSH.^43,72,99 The increase in total T₃ and T₄ is less than the increase in TBG, resulting in a decreased T₄/TBG ratio, leading to a state of relative hypothyroxinemia during pregnancy.

Pregnancy is characterized by significant changes in iodide metabolism with increased renal iodide clearance and increased iodine needed to make thyroid hormones.^38,71 The increased total T₄ and T₃ stimulate increased serum protein-bound iodine (PBI).³⁸ Because circulating levels of free thyroid hormone are not significantly altered, increased PBI does not reflect maternal hyperthyroidism. Thyroid iodine uptake increases because of a decrease in the total body iodine pool. This pool is altered because of increased renal iodide loss secondary to the increased renal blood flow and glomerular filtration rate (see Chapter 11) and placental transfer of iodine to the fetus.^43,71,99,144

The thyroid compensates for the increased loss of iodine by hyperplasia and increased plasma iodine clearance, reducing plasma iodine levels.^88,99 Iodine is stored in the colloid of the thyroid gland follicles (see Figure 19-3). With TSH stimulation, thyroglobulin is catabolized to form T₄ and T₃.⁹⁹ Serum thyroglobulin increases in the first trimester but is most marked in later pregnancy. This increase is associated with an increase in thyroid volume, especially in areas of low iodine intake.^43,72,99 The degree of hyperplasia is related to the degree of imbalance between iodine needs versus iodine intake and stores (see Iodine Needs during Pregnancy).⁷² Mild thyroid hyperplasia (10% to 15% increase), due primarily to increased vascularity, is seen in areas such as North America, where diets are generally thought to be iodine sufficient.^38,99,100 Therefore moderate to marked thyroid enlargement in these women cannot be considered normal and requires further evaluation. Women who live in iodine-poor areas have an increase in thyroid volume of 15% to 30% during pregnancy.^36,99 Goiter is generally not a risk if iodine levels are greater than 0.08 mcg/dL (0.006 μmol/L); in North America, levels average 0.3 mcg/dL (0.023 μmol/L). Goiter is a significant risk in areas with low iodine intake.

Intrapartum period

The HPA and HPT axes undergo further alterations during the intrapartum period. CRH appears to be a trigger in the initiation of labor, and activation of the HPA axis may serve as a “biologic clock” timing the length of gestation.⁹⁹ Maternal plasma CRH, ACTH, β-endorphin, and cortisol levels increase up to sevenfold with labor onset and during labor (see Chapter 4).^{20,35,77,86,93,172} ACTH reaches its highest level, increasing from 50 pg/mL (11 pmol/L) at term to 300 pg/mL (66 pmol/L) in labor (see Figure 19-1).^32,77,151 Further increases in ACTH and cortisol are seen in women with poor progress in labor.³¹ Low β-endorphin levels at term have been associated with an increased need for pain medication during labor, although a causal relationship is unclear.²⁰

Levels of total and free T₃ increase during labor. This change probably reflects the energy demands of labor on the maternal system. T₃ and T₄ have similar functions, but T₃ is three to five times more active. T₃ and T₄ increase intracellular enzymes (increased cellular metabolism), the number and activity of mitochondria (to provide energy for cellular enzyme systems), and Na-K adenosine triphosphatase (ATPase) (because of the increased energy use for myometrial contractions).⁴⁷

Postpartum period

The alterations in the HPA (see Figure 19-2, C) and HPT axes during pregnancy are reversed during the postpartum period. CRH levels drop rapidly with removal of the placenta and placental CRH.¹⁵¹ Maternal ACTH and cortisol levels decrease rapidly in the immediate postpartum period and reach nonpregnant values by 1 to 4 days postpartum.^35,77,86 The HPA axis is depressed with a reduction in hypothalamic CRH for 3 to 6 weeks, returning to normal levels by 12 weeks.⁸⁶ This depression of the HPA axis may play a role in postpartum mood disorders or in exacerbation of autoimmune disorders in the postpartum period.^1,62 Although ACTH secretion may be suppressed, total serum cortisol is within normal limits, probably secondary to a mild hypertrophy of the adrenal cortex.⁸⁶ Hyperplasia of the lactotrophs of the anterior pituitary gland peaks in the first 3 days postpartum. This tissue decreases in size by 1 month in nonlactating and more slowly in lactating women, but never returns to nulliparous size.^32,93,97 Prolactin falls at delivery and returns to nonpregnant values by 3 months; in breastfeeding women, prolactin increases after delivery.^32,35,151 β-endorphins decrease by 24 hours after birth and are higher in colostrum than in maternal plasma.¹⁷³ Serum growth hormone levels may remain elevated for several months.³² Postpartum changes in prolactin, FSH, and LH are described in Chapter 5.

After delivery with removal of the placenta and reduction in estrogen, hepatic synthesis of TBG decreases, as does the renal excretion of iodine. As a result, the metabolic alterations in thyroid processes gradually reverse over 4 to 6 weeks, although they may persist for up to 6 to 12 weeks.^43,144 Thyroid-releasing hormone (TRH) is a (minor) stimulus of prolactin release and has been used to induce relactation.⁷⁰ Free T₄ may be low and TSH elevated in the first 3 to 4 days, which may confound assessment of thyroid function.⁶⁵ Transient disorders in thyroid function are seen in some postpartum women (see Postpartum Thyroid Disorders).

Thyroid hormones are secreted in breast milk. Levels are low initially and then rise. Breast milk T₄ and T₃ have been reported to delay the development of hypothyroidism in some infants with this disorder.¹³¹

Iodine needs during pregnancy

Adequate iodine stores and nutrition are essential for normal function of the maternal and fetal thyroid.^23,36,39 Iodine needs increase during pregnancy due to increased renal loss and increased placental—and thus fetal—uptake.^30,36,131 Dietary iodine is converted to iodide; 20% of this is absorbed by the thyroid gland, the rest is cleared by the kidney. During pregnancy renal iodide clearance doubles due to the increased renal blood flow and glomerular filtration rate (see Chapter 11).⁹⁹ The World Health Organization recommends an iodine intake of 250 μg/day during pregnancy and lactation; others recommend 200 or up to 300 μg/day.^{30,76,88,131,174,175} Iodine needs can be met by iodine in prenatal vitamins and use of iodinated salt.⁴³ Mean urinary iodine excretion, used to assess iodine deficiency, is insufficient if less than 150 μg/L during pregnancy or less than 100 μg/L during lactation.³⁰

Iodine deficiency is lowest in North America, higher in Europe, with Southeast Asia accounting for nearly one fourth of the worldwide population with insufficient iodine uptake.⁸⁸ Iodine stores are low in developing countries and have been falling in many developed countries, for example, 50% to 65% of women in western and central Europe were found to be iodine deficient (versus 11% of women in the United States).^36,175 Recent reports suggest a decline in iodine sufficiency in childbearing women in the United States.¹⁵ Women who enter pregnancy in an iodine-deficient state fall even further behind so that iodine deficiency in the first trimester tends to become more severe in later pregnancy.^71,73 Iodine deficiency is the most frequent cause worldwide of preventable mental retardation and often the damage is done by the time of birth.^88,175 Iodine deficiency is also associated with an increased risk of spontaneous abortion and stillbirths.^88,175 Even in iodine-sufficient areas, there has been increasing concern that iodine deficiency may increase the risk of later neurodevelopmental impairment of offspring in women with marked subclinical thyroid dysfunction.⁷² Various professional groups have differing recommendations regarding whether all pregnant women should be routinely screened to identify subclinical hypothyroidism.^{1,2,9,14,30,62,167}

Thyroid function tests during pregnancy

Changes in TBG and thyroid hormones during pregnancy alter parameters for many tests used to assess thyroid status. These alterations, which vary with trimester, must be considered when evaluating thyroid function in pregnant and postpartum women. Free T₃ and T₄ assays, rather than total values, are generally preferred because of the increased thyroxine-binding globulin (TBG).³⁰ Glinoer and Spencer indicate that serum TSH assay “is the most sensitive index to reliably detect thyroid function abnormalities” during pregnancy.⁴⁰ Reference ranges for thyroid function tests during pregnancy have been described in several studies, with variations by trimester of testing, number of fetuses, and testing method.³⁰ Table 19-1 summarizes the changes in thyroid function during pregnancy that lead to alterations in these tests. As noted in the previous section, recommendations for routine thyroid screening during pregnancy vary among different professional groups worldwide.^{1,2,9,14,30,62,167}

Maternal stress responses and fetal endocrine programming

Even though both ACTH and cortisol are elevated during pregnancy, physiologic responses (e.g., blood pressure, heart rate, and cortisol reactivity) to stress, although maintained, appear to be blunted in the pregnant woman.^13,21,25 However, data are limited and wide individual differences have been reported. This blunting may be due to glucocorticoid negative feedback, possibly nitric oxide, urocortins, β-endorphins, and other endogenous opioids.¹³

Fetal programming refers to the effects of the fetal environment on susceptibility to later disorders. For example, the nutritional/hormonal status during fetal/early postbirth life can alter organ development including the hypothalamus and other endocrine structures. Increases in cortisol with stress in the mother can lead to increases in fetal cortisol. This is important because before birth, fetal systems such as the fetal HPA axis are programmed for postnatal function, with adverse consequences for later function if programming is altered.^13,159 Normally most of the cortisol reaching the placenta is broken down into inert metabolites by placental enzymes, such as 11-β-hydroxysteroid dehydrogenase, in the syncytiotrophoblast. These enzymes convert active glucocorticoids, such as cortisol and corticosterone, to inactive metabolites.⁷⁷ As a result, fetal circulating cortisol levels are maintained lower than maternal levels.

Wide individual differences have been reported in both maternal stress reactivity and in the activity and sensitivity of these placental enzymes.^21,25 There is increasing evidence in both human and animal studies of the effects of prenatal stress on offspring, including prematurity, low birth weight, delivery complications, and impaired prenatal and postnatal growth and development.^{18,21,41,109,159,161,166} For example, the risk of early pregnancy loss with maternal stress may be mediated by alterations in glucocorticoids, progesterone/prolactin, and the immune system, leading to alterations in the early pregnancy cytokine environmental balance (see Chapter 13) needed for implantation and early pregnancy maintenance.¹³ Early stress may also induce epigenetic changes in gene expression that increase the risk of later metabolic, vascular, and neurodevelopmental disorders in offspring.^18,89,159 Prolonged exposure to maternal stress mediators may permanently reset the HPA axis and increase the risk of adult-onset disorders such as type 2 diabetes, hypertension, obesity, coronary artery disease, end-stage renal disease, and depression.^{13,150,159,162}

The specific mechanisms by which maternal stress affects the fetus are unclear, but probably involve changes in the fetal HPA axis from maternal increases in sympathetic nervous system and HPA activity and perhaps changes in the limbic system with stress.²⁴ Glucocorticoids are thought to have a major role in fetal tissue programming because excess levels can inhibit growth; alter expression of receptors, enzymes, ion channels, and transporters; and alter growth factors, structural proteins, binding proteins, and signaling pathways.¹¹³ Possible mechanisms include (1) stress-induced increase in maternal cortisol results in increased fetal cortisol and changes in the feedback regulation of the fetal HPA axis; (2) hormones from the maternal HPA axis stimulate the placenta to increase CRH, which alters brain glucocorticoid receptor development and function in the fetus; and (3) increased cortisol and catecholamines seen with stress may alter uteroplacental blood flow, leading to poorer fetal growth, prematurity, and other complications.^{21,56,113,159,166} Figure 19-7 illustrates a proposed model of factors contributing to indirect and direct effects of stress on the fetus. Fetal programming is discussed further in Chapters 12 and 16.

The hypothalamus and anterior pituitary glands develop simultaneously but independently of each other. As a result, growth of the various cell types within the anterior pituitary is not dependent on the presence of the hypothalamus. For example, anencephalic infants do not have a hypothalamus but have thyroid-stimulating hormone (TSH) cells within their rudimentary anterior pituitary gland.

The hypothalamus develops from 6 to 12 weeks from the ventral portion of the diencephalon. Hypothalamic nuclei and supraoptic track fibers develop by 12 to 14 weeks, with maturation of the hypothalamic neurons by 30 to 35 weeks.²⁸ The anterior pituitary arises from the anterior wall of the Rathke pouch, an upward offshoot of the primitive oral cavity.⁴⁵ The posterior pituitary and stalk develop from the infundibulum, a thickening on the floor of the diencephalon.¹³⁵ The anterior pituitary can be seen by 4 weeks and is independent of the oral cavity by 12 weeks. During the fifth week, the primitive anterior pituitary becomes connected with the infundibulum.

Cellular differentiation within the anterior pituitary gland begins at 7 to 8 weeks, under the influence of Pit-1 (a transcription regulator) that activates expression of genes encoding growth hormone (GH) and prolactin and differentiation of the different anterior pituitary cell types.⁴⁵ Thyrotropic cells appear at 12 to 13 weeks. An increase in TSH-secreting cell volume occurs by 23 weeks. Corticotroph cells can be identified by 6 weeks and express adrenocorticotropic hormone (ACTH) by 7 weeks; somatotroph can be seen by 8 weeks. TSH and gonadotropin β subunits are seen by 12 weeks. Lactotroph cells do not produce prolactin until after 24 weeks.³²

The adrenal cortex arises in the fourth to fifth week from the intermediate mesoderm in the notch between the primitive urogenital ridge and the dorsal mesentery.¹⁹ These cells proliferate and form cords migrating medially and laterally to the cranial end of the mesonephros (primitive transitional renal structures).^90,96 Neural crest cells form a medial mass on the primitive cortex. These cells are surrounded by the cortex cells and differentiate into the adrenal medulla. Later, another wave of cells surrounds the initial cortical cells to form the definitive cortex.^19,135 By 8 weeks, the cortex is organized into the fetal zone, with the definitive zone appearing a week later.^19,90,96 The fetal zone increases in size from 10 to 15 weeks and dominates from 16 to 20 weeks, being similar in size to the fetal kidneys.¹⁹ By 28 to 30 weeks, a transitional zone that is initially similar to the fetal zone appears between the fetal and definitive zones. During the second and third trimesters, the adrenal glands continue to enlarge, with hypertrophy of the fetal zone and hyperplasia of the definitive zone.^19,90 Adrenal growth and zonation are stimulated by fetal ACTH, IGF-II, fibroblast growth factor, and epidermal growth factor.¹⁹

By midgestation, the fetal zone occupies 85% of the adrenal volume and is highly vascularized.^127,128 The adrenals double in size between 20 and 30 weeks and double again between 30 and 40 weeks as steroidogenic activity increases.¹⁹ At term, the adrenal glands weigh 3 to 4 g and, relative to adult proportions, are 20 to 30 times larger.^19,90,96,127 After birth, the adrenal undergoes extensive remodeling, with a decrease in size and disappearance of the fetal zone.

Adrenal function

As noted above, the fetal adrenal gland initially consists of two zones: the fetal zone (analogous to the adult zona reticularis) and the definitive zone (becomes the postnatal adrenal neocortex producing aldosterone—see Chapter 11). Later the transitional zone, which gives rise to the glucocorticoid-producing zona fasciculata, develops between the fetal and definitive zones. The fetal zone contains large lipid-containing steroidogenic cells, which are the major source of dehydroepiandrosterone (DHEA) and its sulfate (DHEA-S), which are precursors for production of estrone and estradiol-17β in the placenta. DHEA-S is also the precursor for 16-hydroxydehydroepiandrosterone, which is needed for estriol production by the placenta (see Chapter 3). Cholesterol is the precursor for these steroid hormones and the fetus uses both endogenous cholesterol synthesized from low-density lipoproteins and cholesterol transferred across the placenta.^57,127

The placenta does not produce these precursors, so is dependent upon the fetal adrenal (primary source) or mother. In fetuses with decreased adrenal function, such as anencephalic fetuses, estriol production by the placenta remains low. Enzymes to synthesize DHEA-S are present by 6 to 8 weeks.^90,123 High levels of 17α-hydroxylase (17-OH or CYP17) and probably 21-hydroxylase (21-OH or CYP21) are seen early in gestation (Figure 19-8). 17-OH and 21-OH are cytochrome P-450 enzymes not expressed by the placenta.¹⁶⁴ Deficiency of 21-OH is the most common cause of congenital adrenal hyperplasia (see p. 651); a lack of 21-OH can result in virilization of the female external genitalia. Because the genital tract differentiates at 7 to 10 weeks (see Chapter 1), this enzyme must be present early in gestation.¹⁹ Levels of 3β-hydroxysteroid dehydrogenase (involved in cortisol production) are low in the fetus.¹⁹ The large size of the adrenal glands allows the fetus to secrete larger amounts of adrenal androgens daily, predominantly DHEA-S, than do adults. The fetus supplies 90% of the DHEA-S to the placenta after 16-hydroxylation by the fetal liver (see Figure 19-7).^127,128

Cortisol is produced as early as 8 to 12 weeks but in small amounts and primarily from progesterone.^19,90,123 Production of cortisol from cholesterol, the usual precursor in later life, requires 3β hydroxysteroid dehydrogenase (3β HSD) which is not available in early gestation.¹⁶² 3β HSD is not expressed before 23 weeks’ gestation, with limited adrenal capacity for synthesis until after 30 weeks.^97,123 Cortisol secretion is present by 20 to 24 weeks’ gestation.²⁹ Fetal cortisol levels gradually increase to term. Cortisol is essential for fetal maturation of the lungs, gut, liver, and central nervous system.¹⁰³ Cortisol is also found in amniotic fluid. During labor, fetal cortisol levels double.⁹⁶ Most fetal tissues and especially the placenta contain enzymes such as 11β hydroxysteroid dehydrogenase type 2 (11β HSD2) that convert cortisol to inactive cortisone. This serves as a protective mechanism against elevated cortisol in the fetus.

Maternal cortisol enters the placenta. However, since about 85% is deactivated by 11β HSD2, little reaches the fetus.^96,162 Maternal cortisol that does reach the fetus has a negative feedback effect on the fetal HPA axis, suppressing fetal cortisol production. Placental CRH stimulates pituitary ACTH production that in turn stimulates the fetal adrenal to produce cortisol, DHEA, and DHEA-S.¹⁶² In the third trimester, placental 11β HSD2 activity increases with increased conversion of both fetal and maternal cortisol to cortisone. This reduction in active cortisol reaching the fetal hypothalamus and pituitary further reduces negative feedback to the HPA axis that would normally reduce CRH, ACTH, and cortisol levels. This increases adrenal DHEA-S synthesis. DHEA-S production increases estrogen production, which in turn stimulates increased 11β HSD2.^{29,103,127,162} CRH plays a major role in regulating fetal adrenal steroidogenesis in late gestation and in labor onset (see Chapter 4).¹²⁷ Placental CRH stimulates the fetal HPA axis and is itself stimulated by fetal cortisol (whereas hypothalamic CRH is inhibited by high cortisol levels). Seven to ten weeks prior to birth fetal adrenal cortisol production increases with a decrease in the conversion of cortisol to inactive cortisone, mediated by an increase in 11β HSD activity (stimulated by estrogens).²⁹ Factors influencing fetal adrenal function are summarized in Table 19-4.

Table 19-4

Factors Affecting Fetal Adrenal Function

FACTOR	EFFECT
Maternal cortisol passively transferred to the fetus suppresses the fetal HPA axis	Increased production during maternal stress Increased transfer during early gestation Increased transfer in the presence of decreased placental 11β-HSD2 activity

Placental 11β-HSD2

Converts maternal cortisol to cortisone

Modulates exposure of fetus to maternal cortisol

Thyroid function

TRH synthesis begins in the hypothalamus by 6 to 8 weeks and is found in fetal serum by 9 weeks.^{90,100,129,138} TRH is also synthesized by the placenta, fetal pancreas, and gut. Fetal serum TRH levels are high during the first and second trimesters due to these extrahypothalamic sources; hypothalamic TRH production matures by 35 to 40 weeks along with maturation of the hypothalamic-pituitary portal system.^29,103 TSH can be detected in fetal serum by 10 to 12 weeks.¹³¹ Levels are low until 18 weeks, then increase to 28 weeks, and then plateau and decrease to term.^43,90,131

By 10 to 12 weeks, the thyroid gland begins to accumulate and concentrate iodine and has begun to synthesize and secrete iodothyronines. T₄ can be detected in fetal serum by 12 weeks, increasing to 2 μg/dL by 20 weeks and 10 μg/dL by term.^{30,63,90,100,119,129,131,156} Fetal thyroid function remains at basal levels until midgestation, even though the capacity to secrete these hormones as well as TSH and TRH develops earlier.^28,43,90 As a result, significant amounts of fetal thyroid hormone are not produced before 18 to 20 weeks’ gestation.^95,99 TSH, T₄, and free T₄ increase from 15 to 42 weeks.¹⁶⁸ At term, T₄ levels in cord blood are 10% to 20% lower than maternal values; most fetal T₄ is bound to TTR and albumin.¹³¹ Free T₄ concentrations in fetal fluids reflect the interaction between T₄-binding proteins and maternal T₄, which maintains sufficient free T₄ for fetal needs but prevents toxic levels.⁹⁵ Thyroxine-binding globulin (TBG) can be detected by 12 weeks and reaches term values by midgestation.¹³¹ Concentrations of iodine increase after 13 to 15 weeks with peak concentrations at 20 to 24 weeks.⁷² Changes in fetal thyroid hormones are summarized in Figure 19-9.

Serum T₃ levels remain low until 30 weeks and then increase slightly, but never approach maternal values.^28,100,156 At term, fetal T₃ and free T₃ levels are 30% to 50% of maternal values.¹³¹ T₃ levels remain low because the fetus is unable to convert T₄ to T₃ peripherally due to incomplete enzyme systems. The increase in T₃ after 30 weeks is associated with maturation of these enzymes.²⁸ Type II and type III monodeiodinases (MDI; see Box 19-3 on page 630) are present by midgestation; MDI-I (which converts T₄ to the highly active T₃) matures later and levels are low during gestation.^29,156 As a result, a greater proportion of T₄ is converted to the inactive rT₃ in the fetus than in the adult.^28,98 Iodothyronines are inactivated by sulfation as well, which also helps to regulate the amount of active thyroid hormone; these analogues are also metabolized to the inactive rT₃S.¹⁶⁸ Increased production of sulfated analogues of thyroid hormones are seen in the fetus.²⁹ In the hypothyroid fetus, MDI-II increases and MDI-I is suppressed so T₄ is shunted to the central nervous system (CNS), where it is converted to T₃ by MDI-II.²⁹ The control by these monodeiodinases of the levels of active thyroid hormones at different stages of development is an important protective mechanism because too much T₃ could damage cells. Organs such as the brain, which are dependent on T₃ for normal development, have higher levels of enzymes needed to convert T₄ to T₃.^88,98,99

Serum rT₃ levels rise early in the third trimester and then progressively decrease to term as MDI activity increases.^90,131,156 As noted earlier, the elevated serum rT₃ levels in the fetus are a result of increased MDI-III activity (see also Box 19-3 on page 630).²⁸ MDI-III is the predominant deiodinase in the fetus and placenta with levels 10 to 15 times greater than in adults.^28,29 This increases conversion of T₄ to the biologically inactive rT₃ (rather than to biologically active T₃) and T₃ to the inactive T₂; this may be a way the fetus counteracts high T₄ levels and maintains metabolic homeostasis.^28,29 Thyroid maturation in the late fetal and early neonatal period is related to progressive increases in hypothalamic TRH secretion, TRH responsiveness by the pituitary (by 26 to 28 weeks, the fetus responds to TRH in a manner similar to that of adults), sensitivity of the thyroid to TSH, and maturation of feedback mechanisms.^28,29 Fetal thyroid function is summarized in Table 19-5.

Role of maternal thyroid hormones

Thyroid hormones are critical for brain development, neuronogenesis, neuron migration, axon and dendrite formation, and organization. Thyroid hormone receptors develop early in the fetal brain, appearing by at least 9 weeks’ postmenstrual age, increasing 10-fold by 18 weeks; 25% to 30% of the receptors are occupied by T₃ during this time.⁹⁵ Levels of T₃ in the cerebral cortex reach adult values by midgestation.¹⁰⁸ Thyroid hormones are much higher in the brain than fetal serum at each stage of development due to activity of MDI-II and brain MDI-III.⁹⁵

Maternal thyroid hormones are transferred to the fetus in the first trimester, beginning soon after conception and increase rapidly over the next weeks to biologically relevant values that correlate with maternal values.^88,94,95,100 Even during the second and third trimesters when the fetal thyroid is producing hormone, much of the T₄ needed for development and neuroprotection is of maternal origin.^88,94 This has implications for the infant born prematurely, especially very low–birth weight (VLBW) infants, who lose this protection by their early birth.⁹⁵ Maternal hypothyroidism is particularly damaging to the fetal brain in the first half of pregnancy when fetal T₄ production is low.^94,129 T₃ generation from T₄ by MDI-II increases in the cerebral cortex until midgestation, reaching values similar to those in the adult brain. Cerebral T₃ levels are dependent on local production in the brain, via MDI-II that converts T₄ to T_3, and are thus not affected by circulating T₃ levels, but by circulating T₄. Therefore if the mother is hypothyroxinemic with low T₄ levels, the fetal brain will have a deficiency of T₃ for normal development, even if circulating T₃ is normal or increased.⁹⁴ Maternal iodine deficiency results in altered thyroid function and inadequate thyroid hormone for development; maternal iodine excess can also block thyroid hormone synthesis and secretion.¹²⁹

Hypothalamic-pituitary-adrenal axis

Remodeling of the adrenal glands after birth occurs via apoptosis of the fetal zone, remodeling of the fetal zone cells, and development of the other zones.^19,90,164 Apoptosis of the fetal zone is mediated by activin and transforming growth factor-β (TGF-β). The size of the adrenals decreases 25% in the first 4 days after birth.¹⁶⁴ Adequate pituitary function is seen in both term and preterm infants.⁸⁶ 

At birth, the infant’s free cortisol levels are about one third or less than maternal levels, possibly related to higher levels of cortisol-binding globulin (CBG) in the mother. A cortisol surge begins in late gestation, increasing during labor and transition to extrauterine life.²⁹ This surge is blunted in VLBW infants.²⁹ Cortisol levels double during labor, increase further in the first 1 to 2 hours after birth, and then gradually fall during the first week.⁹⁶ There is an inverse relationship between cortisol levels and gestational age. ACTH and cortisol levels are higher in infants delivered vaginally than in those delivered by cesarean birth.^91,134 ACTH and BE levels are elevated in cord blood and decrease significantly by 24 hours and reach adult levels by 4 to 5 days in healthy infants.^75,83,126 After birth the high placental corticotropin releasing hormone (CRH) levels fall. This may lead to a refractory period over the first few days where newborn CRH production by the hypothalamus is transiently suppressed, accompanied by a refractory pituitary gland response. These changes result in a decreased ability to increase ACTH to stimulate the adrenal gland. This transition is tolerated well in healthy infants, but in immature or ill infants may lead to a relative adrenal insufficiency and cardiovascular compromise (see Adrenal Cortex Insufficiency).^27,105,123

BEs are endogenous opioid-like substances that are derived, along with ACTH and other substances, from a large precursor molecule (pro-opiomelanocortin). BEs increase markedly with birth in both term and preterm infants. The BE increase at birth is greater with perinatal hypoxic-ischemic events or other stress such as forceps delivery and is reported to be inversely related to PO₂.^16,126,149 Other endogenous opioids, such as the enkephalins, are also increased at birth and further increased with hypoxia, acidosis and ischemia.

Both term and preterm infants in the neonatal intensive care unit (NICU) have higher BE levels than healthy term infants. Preterm infants (especially preterm males) have higher BE levels than both healthy term and ill term infants.⁷⁵ Elevated BE levels are seen in stressed preterm infants with apnea, but not in nonstressed infants.⁸³ Release of BE is a component of neonatal respiratory control and is triggered by hypoxia.⁸³ BE levels are also higher in infants with respiratory distress.⁷⁵

The administration of antenatal corticosteroids (see Chapter 10) leads to a transient suppression of the pituitary and adrenal glands. Long-term effects on hypothalamic-pituitary-adrenal (HPA) function have not been well studied.⁸⁷ Even with this suppression, healthy, preterm infants respond to stress with increased cortisol.¹⁰³ The ill infant, however, is less able to respond to stress and is more vulnerable to stress-related morbidity (see sections on Neonatal Stress and Adrenal Cortex Insufficiency).

Growth hormone (GH) decreases rapidly after birth as free fatty acids, which block GH release, increase with nonshivering thermogenesis.⁴² GH levels are higher in preterm infants than in term infants. Somatostatin levels in preterm infants are higher during the second week but decrease by the third to fourth weeks. Levels are even higher in infants with respiratory distress syndrome.⁵⁵

Prolactin increases in the late fetal and early neonatal periods. Levels are higher in preterm infants than in term infants due to increased sensitivity to thyroid-stimulating hormone (TSH) and estrogens, pituitary insensitivity to dopaminergic inhibition, and reduced renal excretion by the immature kidney (with its lower glomerular filtration rate).¹⁴⁹ Prolactin may have a role in lung maturation and fluid homeostasis with transition. Dopamine levels are twice those of adults and function as a prolactin release–inhibiting factor.⁹⁰

Hypothalamic-pituitary-thyroid axis

The newborn is in a state of physiologic hyperthyroidism because of marked changes in thyroid function at birth (Table 19-6 and Figure 19-9).^121,131 Thyroid-releasing hormone (TRH) and TSH levels increase rapidly after birth, followed by increases in T₄, free T₄, T₃, and free T₃.¹²⁴ Exposure of the newborn to the cooler extrauterine environment is believed to stimulate skin thermal receptors, TRH release by the hypothalamus, and TSH release by the pituitary gland.²⁹ The TSH surge is also stimulated by cutting of the umbilical cord and the catecholamine surge at birth.^29,121 The increase in TSH (and T₄) with cord cutting is limited in extremely low–birth weigh (ELBW) infants.²⁹ TSH increases from 9 to 10 μU/mL (IU/L) at birth to peak at 60 to 70 mU/L within the first hour after birth.²⁹ TSH rapidly decreases to 50% of peak values by 2 hours and to 20% by 24 hours, followed by a progressive decrease over the next 2 to 3 days to levels similar to or lower than cord blood values (see Figure 19-9).^28,29,74,90 During the first week, periodic oscillations in serum TSH have been reported, possibly reflecting establishment of a new equilibrium in the negative feedback exerted by thyroid hormone on the anterior pituitary.¹³⁵ Although TSH generally falls to adult ranges within 3 to 10 days, TSH may remain somewhat elevated for several months.^129,131

The TSH surge leads to a rapid threefold to sixfold increase in T₄, and twofold increase in free T₄.^29,168 T₃ and rT₃ levels are correlated with gestational age and birth weight.¹²⁹ T₄ levels peak at 24 to 48 hours after birth (see Figure 19-9), and then slowly decrease over the next few weeks.^{29,100,129,131,156} Newborn T₄ levels are usually 10% to 20% less than maternal values.¹³¹

Cord blood T₃ values average 45 to 50 ng/dL (0.69 to 0.77 pmol/L) (30% to 50% of maternal values). The newborn quickly changes from a state of T₃ deficiency to T₃ excess. T₃ levels increase rapidly with birth with a sixfold increase in T₃ secretion and eightfold increase in free T₃.¹⁵⁶ T₃ peaks at 24 to 48 hours at 260 to 300 ng/mL (4 to 4.62 pmol/L) (values exceeding those in adults) in most infants and then gradually fall.^{28,29,129,131} The increase in T₃ is due to the TSH surge and increased MDI-I activity (see Box 19-3 on page 630), with increased conversion of T₄ to T₃ and removal of the placenta (with its high levels of MDI-III that convert T₃ to inactive forms).^29,156 The increase in T₃ is also related to cutting the umbilical cord, which increases liver blood flow and conversion of T₃ to T₄.²⁹ Serum T₃ and T₄ levels gradually fall to values seen in infancy with the first few weeks after birth.¹²⁹

Levels of rT₃ remain high for 3 to 5 days and then gradually decrease to adult values by 1 to 2 months.¹³¹ Thyroxine-binding globulin (TBG) tends to be high because of transplacental passage of estrogens that stimulate its production. TBG-binding capacity in the infant is higher than in the pregnant woman and about 1.5 times that of the adult.¹³¹ Radioactive iodine uptake by the thyroid is higher in the newborn because of increased avidity of the neonatal thyroid for iodine. Iodine concentrations in the thyroid gland at birth are correlated with gestational age with increased 24-hour ¹²³I uptake for the first month and a greater concentration of ¹²³I in infants than adults.¹³¹

The TSH surge is also seen in preterm and SGA infants, although it may be blunted.^29,168 Thyroid hormones in preterm infants follow patterns similar to those in term infants but may take longer to reach stable values.^{43,129,131,175} Thyroid hormone levels are inversely related to gestational age.^29,99,129 Free T₄ and T₃ levels are lower and rT₃ levels higher in preterm infants than in term infants for the first weeks due to persistence of fetal levels of MDI enzymes (see p. 630) and higher sulfated iodothyronine analogues.^{29,100,125,156,168} TSH levels and response are generally similar to those in term infants, but TSH may be in the normal adult range.¹⁰⁰ In ELBW infants, TSH response to low T₄ levels is limited.²⁹ Serum T₄ and T₃ levels may decrease to below birth levels in VLBW preterm infants during the first week to levels two to three times lower than in term infants.^124,129,156 In addition, some ill and VLBW preterm infants develop a characteristic syndrome of transient hyperthyroxinemia with normal or low TSH and low free T₄ levels without other evidence of hypothyroidism (see Transient Alterations in Thyroid Function in Preterm Infants).^{29,99,124,129,156,168} T₄ levels are higher in infants of mothers who received a course of antenatal glucosteroids.⁸⁵ The preterm infant may take 3 to 8 weeks to reach term levels of these hormones.¹⁵⁶

Neonatal stress

Although definitions and depictions of the stress response may vary, all or most propose an integrated biologic response pattern during or after stressor exposure. Activation of endocrine and neurotransmitter systems represents the major mechanisms upon which other aspects of this response are built. Responses to stressors are normally of short duration (acute stress) and are aimed at survival followed by a return to a state of dynamic homeostasis.^118,132 Stress responses that go on for extended periods (chronic stress) can produce long-term changes in stress response systems, leading to decreases in adaptive capacity and increased risk for physical and psychological disorders.¹⁷¹

The NICU has the potential for significant stress during a period of critical brain development. There are many sources of stress in the NICU from both internal (e.g., pain, distress, pathologic processes) and external (e.g., physical environment, caregiver interventions, medical or surgical procedures, multiple simultaneous modes of stimulation) demands. Stress and pain (see Chapter 15) interact. Preterm infants may be simultaneously exposed to pain stimuli and other potentially noxious sensations (e.g., handling, light, sound, and temperature changes) that cause further activity in nociceptive pathways and systemic stress responses. An infant’s stress tolerance may be reached or exceeded repeatedly, contributing to short- and long-term morbidity. Infants in the NICU experience both acute and chronic stress. Many handling procedures in small and sick infants lead to stress, which if not controlled, may cause cumulative harm.⁶

Baseline responses to stress are set early in life and can influence later responses and adaptation.^{13,33,41,109,159} Stress activates the HPA axis with release of catecholamines, CRH, adrenocorticotropin (ACTH), β-endorphins (BEs), and cortisol. Stress responses affect many systems: cardiovascular (increased blood pressure and heart rate), gastrointestinal (increased gut motility and splanchnic vasoconstriction), renal (sodium and water retention), and respiratory (increased oxygen consumption, decreased tidal volume, and functional residual capacity or ventilation-perfusion mismatch). Stress can alter coagulation, immune function, and cytokine production. Stress has profound metabolic consequences; metabolic stability may be more difficult to maintain in the stressed neonate, especially in immature infants.⁶ Stress can lead to hyperglycemia or hypoglycemia. Stress increases counterregulatory hormones (e.g., glucagon, ACTH, catecholamines, cortisol) that decrease insulin secretion. Glucagon, fat, and protein are converted to glucose, which—in the face of insulin resistance from the counterregulatory hormones—results in hyperglycemia. In immature infants, this response and the infant’s nutrient stores may become exhausted, so over time the infant becomes hypoglycemic.⁶

Term infants, whether healthy or ill, have an intact HPA axis and can identify and respond to stress.¹¹⁷ Healthy preterm infants older than 28 weeks’ gestational age respond to stress with increased cortisol secretion, although at lower levels than in term infants.¹¹⁷ Healthy term infants have relatively low basal cortisol levels that rapidly increase with stress.⁵⁰ Salivary cortisol has been used to examine responses of both term and preterm infants to stressful or soothing events.^{46,91,137,146,147}

However, in preterm infants who are ill or younger than 28 weeks’ gestational age, the HPA is suppressed during the first few weeks after birth. These VLBW infants seem unable to “recognize” stress and to respond by increasing cortisol secretion.⁵⁰ Preterm infants—especially those who are ill or weigh less than 1000 g—have lower basal cortisol levels and are less able to increase cortisol production with stress. In these infants there is an increase in precursors but not in cortisol, suggesting immature activity of enzymes to convert these precursors to cortisol. In very immature infants, this may reflect the persistence of fetal protective responses against higher maternal cortisol levels.⁵²

Exposure of VLBW infants to significant early pain and stress has been reported to alter later cortisol response patterns with a “resetting” of the basal arousal system postulated.⁴⁶ Early stress in the fetus and neonate may produce permanent changes in neural pathways, increasing the risk of later disorders such as adult psychopathology and hypertension (see Maternal Stress Responses and Fetal Endocrine Programming).^{6,13,41,136,159} Maternal stress in the third trimester is associated with increased ACTH and cortisol and increased placental CRH. Because CRH is a primary factor in labor onset, this may lead to preterm labor and decrease the sensitivity of the fetal-neonatal anterior pituitary to CRH, with permanent elevations in cortisol and BEs.¹³⁶

Thyroid function and thermoregulation

Thyroid function and neonatal temperature regulation are interrelated (see Chapter 20). T₃ and T₄ increase basal metabolic rate and heat production, whereas T₄ and norepinephrine stimulate metabolism of brown adipose tissue. Occlusion of the umbilical cord activates brown adipose tissue catabolism via a catecholamine surge and withdrawal of placental prostaglandins and adenosine.^28,29 T₄ enhances the effects of catecholamines to increase oxygen consumption (and metabolic rate) and increases brown adipose tissue lipolysis. Within 6 hours of birth, the term neonate can respond to cold stress by increasing his or her metabolic rate 100%; by 6 to 9 days, this increase may be 170%. The preterm infant responds similarly to cold stress, although at a slower rate and lower percentage increase (∼40%).⁴²

Transient alterations in thyroid function in preterm infants

In healthy preterm infants, cord blood T₄ levels range from 5.5 to 6 mcg/dL (72 to 77 nmol/L), increasing to 7 to 9 mcg/dL (90 to 116 nmol/L) by 21 to 28 days and reaching values similar to those of term infants by 4 to 6 weeks or perhaps sooner.¹⁷ As a result, preterm infants are more likely to have below normal values on thyroid screening tests compared with term infants.^131,141,156 Thyroid hormone values after birth are correlated with gestational age. For example, infants of 25 to 27 weeks’ gestation have free T₄ levels that are two to three times lower than those of term infants.²⁹ Maturation of thyroid function in VLBW infants is illustrated in Figure 19-10.

Early loss of placental transfer of maternal T₄, which at that point in gestation may account for 30% of fetal T₄, along with iodine deficiency from inadequate stores and intake, may alter thyroid homeostasis in preterm infants, especially ELBW infants.^7,29,168 As a result some preterm infants develop transient thyroid alterations in the early weeks after birth as T₄ and T₃ levels fall in the first week to values lower than at birth. Other factors in the etiology of these alterations include decreased liver thyroxine-binding globulin (TBG) production, immaturity of the hypothalamic-pituitary-thyroid axis, inadequate nutrition, decreased MDI-I, decreased brown adipose tissue, and immature tissue thyroid systems (Table 19-7).^29,129 Thyroid function tends to return to normal as the infant matures or recovers from the underlying illness, with achievement of stable serum T₄ values by 6 to 7 weeks.¹³¹ Three transient patterns of altered thyroid function have been described in preterm infants: physiologic hypothyroxinemia, transient primary hypothyroidism, and transient secondary/tertiary hypothyroidism.^29,63 These are more likely to occur in VLBW infants who weigh less than 1000 g and infants who are ill or stressed. Ill preterm, such as those with respiratory distress syndrome, patent ductus arteriosus, necrotizing enterocolitis, and prolonged oxygen dependence, may also develop nonthyroidal illness syndrome.^29,168 This disorder is similar to the euthyroid sick syndrome seen in severely ill adults and children.¹⁴⁰

Physiologic hypothyroxinemia of prematurity is seen in many preterm infants younger than 35 weeks’ gestational age and referred to as transient hypothyroxinemia of prematurity (THOP).^29,168 There is a lack of consensus regarding what values define THOP.^168,169 These infants have low T₄ levels with low to normal TBG and thyroid-stimulating hormone (TSH) levels.^29,129,168 This is a transient phenomenon that usually resolves within 2 to 3 weeks, although it may last for 2 to 3 months.^29,63 Thus most preterm infants are hypothyroxinemic. The frequency increases with decreasing gestational age. The mechanism and pattern of this disorder vary with gestational age.²⁹ 

In infants born at greater than 30 to 32 weeks’ gestational age, T₄ and free T₄ increase transiently after birth in conjunction with the TSH surge (which is similar to the pattern seen with term infants) and then decrease. This is followed by a gradual increase in TBG, T₄, free T₄, and T₃, reaching term values by 38 to 42 weeks.²⁹ These infants probably have immaturity of the thyroid’s ability to respond to TSH and ability to convert T₄ to T₃.²⁹

In VLBW infants younger than 30 weeks’ gestational age, there is a limited TSH surge and increase in T₄, followed by a decrease in T₄ and free T₄ to a nadir at 1 to 2 weeks.^29,156 These infants usually achieve cord blood levels of serum T₄ by 3 to 4 weeks.²⁹ The greatest fall is seen in the lowest gestation infants.¹⁵⁶ As T₄ decreases, TSH rises, but often remains below 20 μU/L (the cutoff value for hypothyroidism).¹⁵⁶ The etiology of the hypothyroxinemia in these infants is not completely understood but probably due to immaturity of the HPT axis, interruption of transfer of maternal thyroid hormones and iodine across the placenta, iodine deficiency, immaturity of MDI enzymes, decreased TBG and probably an inability to increase iodine uptake and T₄ production with extrauterine adaptation.^7,29,63 Because of immaturity, these infants also have inefficient production of thyroglobulin and a decreased ability to convert T₄ to T₃ due to low levels of liver MDI-I activity (see Box 19-3 on page 630).²⁹

Transient primary hypothyroidism is less common.²⁹ These infants have low T₄ and free T₄, with increased TSH levels during the first 2 to 3 weeks after birth.⁶³ Thyroglobulin and iodine stores are low, with increased T₄ utilization and demand. The frequency of transient secondary/tertiary hypothyroidism is unknown but may occur in up to 10% of VLBW infants. These infants have low T₄ and free T₄ levels without changes in TSH during the first 1 to 2 weeks after birth.²⁹ There may be some benefit to treating these infants in that low thyroid hormone may contribute to later neurologic problems, although it is unclear if supplementation improve outcomes.^155,156

The decision of whether to treat healthy or ill preterm infants with THOP is controversial.^{29,63,66,131,155} Exogenous TRH significantly increases serum T₄ and TSH levels. However, most studies of use of T₄ for thyroid hormone replacement do not demonstrate significant differences in the age at which serum T₄ values normalize or in infant growth parameters.^130,155,160 Some observational evidence suggests that THOP is associated with adverse developmental outcomes, although trials with thyroid hormone replacement have had mixed results.^{22,29,155,157,168,169} Osborn and Hunt concluded that prophylactic thyroid hormone administration did not reduce neonatal mortality or morbidity or improve neurodevelopmental outcomes, and there was insufficient evidence regarding the effect of thyroid hormone replacement on neonatal mortality, morbidity, and improvement in neurodevelopmental outcomes.^110,111

Neonatal hyperthyroidism

Neonatal hyperthyroidism is rare and is usually a transient disorder associated with transplacental passage of maternal thyroid-stimulating immunoglobulins (TSIs) in women with Graves’ disease (see Chapter 13). This may occur even in euthyroid women after thyroid removal or ¹³¹I thyroid ablation, because TSIs are still present in the woman’s system. TSI levels correlate positively with development of neonatal hyperthyroidism; thus maternal screening can identify the infant at risk. An increased fetal heart rate (greater than 160 beats/min) after 22 weeks is of concern.⁷² The mother may be treated with antithyroid drugs, if she is not already being treated, to maintain the fetal heart rate around 140. The incidence of neonatal effects is 0.6% to 9.5%.⁷² Although this disorder is usually transient, increased mortality has been reported, usually as a result of respiratory obstruction or a difficult delivery due to the enlarged thyroid, or high-output cardiac failure secondary to tachycardia (heart rates greater than 200 beats/min).⁷² If the disorder is recognized prior to birth, infants have been treated by giving medications such as propylthiouracil (PTU) to the mother.^120,154

Clinical findings such as low birth weight, irritability, hunger, tachycardia, diarrhea, sweating, and arrhythmias may be present at birth. T₄ and free T₄ levels are increased, but they are also increased in the normal newborn. If the mother is on antithyroid medication, manifestations may be delayed for 2 to 10 days.⁴³ These infants have an advanced bone age and occasionally craniosynostosis. Clinical effects, although transient, last for 1 to 5 months (generally 2 to 3 months) or up to 10 months in some infants.⁴³

Neonatal hypothyroidism

The most common cause of congenital hypothyroidism in North America is thyroid dysgenesis, with an incidence of 1 in 3500 to 4000 live births.^76,131 The cause is often unclear. In some infants, the hypothyroidism is due to a single gene defect or familial autoimmune factors. In the majority (85%) of infants, the cause is a nonfamilial embryogenic defect.⁶⁷ This may be due to mutations in gene coding transcription factors that are needed for thyroid or pituitary gland morphogenesis and differentiation.^63,67 Females are affected twice as often as males. Hypothyroidism and cretinism secondary to endemic goiter are rare in North America. Infants with intrauterine hypothyroidism may not experience significant impairment of somatic or brain growth before birth, because maternal T₄ crosses the placenta and is catabolized to T₃ for normal fetal brain development.²⁸

Most infants appear normal at birth, with clinical signs apparent in fewer than 5% to 30%. Common findings such as a large fontanel, hypotonia, macroglossia, and umbilical hernia may not develop for several weeks or months.^43,74,131 By the time these findings are apparent, significant neurologic damage has already occurred, because inadequate thyroid hormone during fetal life and early infancy alters CNS development. The exact mechanism of injury is not well understood, but the degree of neurologic abnormality correlates with the duration and severity of the hypothyroidism.⁴³ Even with relatively early diagnosis and treatment after birth, these individuals may have subtle, selective neurologic impairments.¹³³ 

Congenital adrenal hyperplasia

Congenital adrenal hyperplasia (CAH) is the most common cause of ambiguous genitalia and adrenal insufficiency.¹²⁷ CAH comprises a group of autosomal recessive genetic disorders, characterized by enzymatic defects in adrenal cortex hormone synthesis (see Figure 2-10), with a frequency of 1 in 15,000 live births in North America.¹⁰² These infants have a defect in cortisol synthesis. Without adequate cortisol negative feedback, ACTH levels are elevated, especially in the last half of gestation. The excess ACTH stimulates the adrenal glands to overproduce precursors for cortisol and leads to adrenal hyperplasia.^{96,102,131,153}

CAH is due to a complete or partial block in one of the enzymes involved in synthesis of adrenal cortex hormones (see Figure 19-8). Symptoms vary from mild to severe depending on the enzyme defect. Depending on the enzyme involved and the severity of the enzyme block, some female infants may have ambiguous genitalia due to virilization. Because some of the same enzymes are found in the gonads as the adrenals, both tissues are affected.⁹⁶ Prenatal therapy with maternal dexamethasone may prevent or reduce virilization of female genitalia if therapy is begun by 6 to 7 weeks’ gestation.^{68,97,106,154} This glucocorticoid crosses the placenta, suppressing fetal ACTH secretion (see Chapter 7).^68,97 In infants with partial enzyme defects, results may not be apparent until later in childhood or adolescence.

Table 19-8 summarizes the effects of various enzyme blocks that can lead to CAH. The most common block (90% to 95%) is in the cytochrome P-450–type enzyme 21-hydroxylase (21-OH) located on the short arm of chromosome 6, in which multiple types of mutations and clinical phenotypes are seen.^96,102,127 The 21-OH mutations block conversion of progesterone to precursors needed for production of aldosterone and cortisol (see Figure 19-8), leading to lower levels of these hormones. The excess precursors are instead converted to androgens that therefore increase. CAH is one of the disorders evaluated in newborn screening. Screening is done by measuring plasma levels of 17-hydroxy-progesterone, which is elevated in CAH. High rates of false positives to true positives have been reported, especially in stressed preterm and low–birth weight infants.¹² Treatment involves glucocorticoid therapy to suppress ACTH. Aldosterone may be needed if the infant has a salt-wasting form of the disorder (see Table 19-8).