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* Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, The Burns and Allen Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048 and Jefferson Medical School, Philadelphia, PA 19107-5587
2 To whom correspondence should be addressed. E-mail: calvin.hobel{at}cshs.org.
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ABSTRACT |
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 TOP ABSTRACT LITERATURE CITED |
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KEY WORDS: • preterm birth • psychosocial stress • social environment • corticotropin-releasing hormone (CRH) • perinatal infection
This paper reviews the epidemiological and clinical research evidence linking 1) maternal stressors including perceived stress, life event stress, pregnancy-related anxiety and work stress and 2) nutritional stress to adverse outcomes of pregnancy. Plausible biological mechanisms underpinning these associations are presented. The interaction of maternal stress exposure and nutritional deficiency on the risk of adverse birth outcomes and the possible biochemical mechanisms of this interaction are also proposed.
Maternal stress exposure and adverse birth outcomes
Individual maternal psychosocial stress and preterm birth. A growing body of empirical evidence, based on methodologically rigorous studies of pregnant women of different ethnic, socioeconomic and cultural backgrounds, supports the premise that mothers experiencing high levels of psychological or social stress during pregnancy are at significantly increased risk for preterm birth, even after the effects of other risk factors are adjusted for (1– 5). The effect sizes of maternal stress on preterm birth in recent, well-controlled prospective studies with relatively large sample sizes (>1000 subjects) have typically ranged between a 1.5-fold and twofold increase(1, 6, 7). Thus, it is clear that although psychosocial stress is a significant risk factor, not all women reporting high levels of psychosocial stress deliver preterm. This raises questions about vulnerability to stress in pregnancy. Such questions concern the nature of stressful experience; the timing of stress during gestation; the nature of the combined effects of stress; and other risk factors, such as infection, work strain, or micronutrient deficiency, and the nature of the biological and behavioral mechanisms that mediate the effects of stress on gestational outcomes.
With reference to the nature of stressful experiences, a major barrier to the external validity of work to date is the limited presentation of stress as life events, as first measured by Holmes and Rahe's Schedule of Recent Events questionnaire (8). Although these instruments include questions about residential moves, job change, the death of a spouse or the birth of a child, they lack a sensitivity to many of the often endemic and pressing realities of low-income life, such as a chronic lack of resources, unhealthful living conditions, concerns with crime and neighborhood safety and the difficulties of child rearing and arranging suitable child care, particularly for single women. Furthermore, these instruments may be completely inappropriate for use in developing countries.
Not surprisingly, different measures of stress have yielded different, even contradictory results. For example, in their case-control study, Berkowitz and Kasl (9) found that although there was a significant linear trend between life-event stress and preterm delivery for white women, this association did not hold for African-American women. This unexpected result led the authors to conclude that the life-events checklist may be an invalid measure of stress in African-American populations. A more recent study of 2000 pregnant women measured chronic stressors (as opposed to acute life events), including problematic family relationships, employment, neighborhood and housing concerns (10). The authors found that although the prevalence of exposure to these stressors did not vary by race, high exposure to chronic stress was a significant positive predictor of low birth weight within the African-American population. This more context-relevant operationalization of stress appears to offer greater sensitivity to the experiences of low-income and minority women. In fact, Turner et al. (11) suggest that the observed social class differential in psychological distress is as much a function of exposure to chronic conditions as it is to acute stressors. These data suggest that evaluation of chronic stress exposure rather than acute experiences my be more appropriate when assessing the effect of maternal stress on birth outcomes in developing countries.
Recent evidence suggests that pregnancy-specific stress (e.g., maternal fears and anxiety related to the outcome of the pregnancy, the experience of labor, the ability to care of a new infant and the health and well-being of the infant) may be an important independent construct in a comprehensive assessment of stress exposure and its relationship to shortened gestation(2, 3, 12, 13). For example, in bivariate analyses Wadhwa et al. (3) found that pregnancy anxiety was significantly and negatively associated with length of gestation. However, when multivariate techniques were used to adjust for biomedical risk and life-event stress, pregnancy-specific anxiety was no longer a significant predictor of gestational length. Using more sophisticated statistical techniques, Rini et al. (2) also assessed the association between pregnancy specific anxiety and risk of preterm birth. These authors conclude that both anxiety and pregnancy-related anxiety independently contribute to risk of shortened gestation. In keeping with this finding, Dunkel-Schetter (12) reported that findings from numerous prospective studies exploring the association between maternal stress and length of gestation confirm that "the strongest predicator of gestational length and preterm delivery of all stress concepts was a new variable, pregnancy anxiety" (p.41). In all of these studies, biomedical risk factors were carefully controlled as were multiple stress constructs that were simultaneously assessed (e.g., life event stress, anxiety, perceived stress, work strain). These associations were retained across race and ethnic groups as well as socioeconomic strata.
Researchers have also focused on the influence of timing of exposure to stress over the course of gestation. This research has capitalized on naturally occurring acute stressors, such as earthquake, that expose an entire cohort of women at various stages of gestation. Glynn et al. (14) assessed the association between exposure to earthquake and length of gestation by the timing of exposure in 40 women. Results suggest that women exposed to acute stress in early pregnancy are at significantly increased risk of shortened gestation compared with women exposed late in pregnancy. The association between timing of exposure and vulnerability to shortened gestation deserves further attention.
Work during pregnancy: physical and psychosocial strain. When a pregnant woman continues to work by choice or necessity, aspects of the work environment may be harmful to her fetus. The studies that have examined the relationship between work and pregnancy outcome have yielded conflicting results because of inconsistencies in how type of work was defined, what working conditions were assessed and whether psychosocial stress was included in the explanatory model (15, 16). To illustrate these complex issues, several studies published in the past decade are worthy of mention. Barnes et al. (17) studied various activities in 2741 Filipino women and found a significant effect of heavy effort on pregnancy outcome but only in a selected subgroup. In a study of physically active women in the U.S. Army, only women participating in job categories defined as heavily physical were at increased risk of preterm birth (18). In a more recent study by Henriksen et al. (19) of 4259 women, medical information and general lifestyle factors and exposures to work were collected at 16 wk; only women reporting >5 h of both standing and walking had a significantly increased risk of preterm delivery. According to Stein et al. (20) working women in Western societies often manifest the "healthy worker effect," which is a selective bias resulting from the exclusion from employment persons who are ill, handicapped, or at risk because of other factors. Women employed while pregnant tend to be better educated, financially better off and healthier than their unemployed counterparts. Another bias in studies is whether the amount of work in the home is considered as a stressor. Housework itself can be both strenuous and mentally stressful, especially if the women have other children to care for and have little support or help with their chores. In less developed countries, where poor maternal nutrition is an additional stressor, hard physical labor may increase demands on the pregnancy, resulting in a great risk for poor fetal growth and preterm birth.
Physical effort and long-duration standing, often associated with work, can result in poor fetal growth by limiting blood flow to the uterus thereby restricting both oxygen and nutrient delivery (21). Uterine contractions associated with standing during late gestation can cause uterine compression of the pelvic vessels (22). Ambulatory tocodynamometry has shown that walking after the week 30 of pregnancy is associated with increasing frequency of uterine contractions (23). Hobel et al. (24) showed that standing is associated with a significant increase in the release of norepinephrine that can be suppressed by wearing support stockings. Thus, standing is apt to cause compression of the abdominal vessels with a decrease in cardiac output and uterine blood flow as well as hormonal changes that could increase uterine activity (25– 27). On the other hand, mental stress could result in elevations of pituitary peptides such as corticotropin-releasing hormone (CRH) 3 and adrenocorticotropin (ACTH) leading to elevations of cortisol. Elevation in CRH was shown to be positively associated with stress scores in patients who deliver preterm when compared with those who deliver at term (28). Excessive cortisol is known to be associated with decrease fetal growth (29).
Expanded definition of stressful exposure. The notion that community-level conditions can produce profound effects on host susceptibility to disease is derived from the long-standing existence of strong social class gradients in health. Women who live in violent, crime-ridden, physically decayed neighborhoods are more likely to experience pregnancy complications and adverse birth outcomes after adjustments have been made for a range of individual-level sociodemographic attributes and health behaviors (30– 32). The stresses of racism and community segregation are associated with lower birth weights (33– 35). However, whether community-level adversity has a deleterious effect on fetal outcomes independent of individual-level risk factors and whether the predictive power of these individual-level factors depends on community-level conditions was only recently been tested empirically. For example, O'Campo et al. (36) found that the effects of individual poverty on birth outcomes are exacerbated by residence in a disadvantaged neighborhood. Urban African-American women were more likely to deliver low-birth-weight infants when they lived in socioeconomically disadvantaged areas, regardless of individual level poverty and other risk factors (37).
The literature showing an association between stress and preterm birth is largely limited to individual-level psychosocial definitions and measurements of stressful experiences. A more comprehensive multilevel approach that considers the potentially important influences of sociocultural context on reproductive health outcomes may advance this field. Multilevel approaches to assessing the contribution of social context to reproductive health outcomes has been used in developing countries (38– 41).
Advances in statistical techniques that facilitate the modeling of multilevel influences and the growing interest in the use of geographic information systems have also made analyses of community-level variation and influences more feasible (42– 44). However, multilevel studies are still relatively rare compared with individual-level and aggregate-level investigations of health and mortality. The results of these studies nevertheless point to the potential importance of residential context on health. A recent review considered articles published before 1998 on the effect of local area social characteristics on various individual health outcomes in developed countries (45); the 25 studies reviewed controlled for individual socioeconomic status. All but 2 of the 25 studies reported a statistically significant association between at least one measure of social environment and a health outcome despite heterogeneity in study designs, substitution of local area measures for neighborhood measures and probable measurement error.
In sum, epidemiological data consistently demonstrate an association between maternal stress and preterm birth. This literature has been hindered by a rather limited conceptualization of exposure to stress where exposure is assessed only at the individual level. Also, many of these studies were cross-sectional in design or enrolled women in the late second or early third trimester, thus limiting the ability to assess the effect of changes in exposure over the course of gestation on outcome. In addition, this work was largely conducted in westernized countries and therefore findings may not be applicable to developing countries. Little empirical work has explored the interaction between other risk factors such as infection or micronutrient deficiency and the experience of stress on birth outcomes.
Pathophysiology of stress
Role of CRH as the mediator of the stress response. CRH, a neuropeptide isolated from the mammalian brain, has been implicated in the mediation of an integrated physiological response to stress (46). The stress system includes the CRH neurons in the paraventricular nucleus of the hypothalamus and other brain areas and the locus ceruleus/norepinephrine and central autonomic (sympathetic) systems in the brainstem. When CRH is released from the median eminence of the hypothalamus, it exerts a powerful effect on the pituitary by releasing ACTH, thus regulating the glucocorticoid response to stress (46, 47). Adaptive changes in response to stressors can be behavioral (psychosocial, nutritional) or physical (work, prolonged standing). For example, behavioral changes noted in rats that received intra-cerebral-ventricular injections of CRH included increase locomotor activity and aggressiveness in a familiar environment, decreased feeding and sexual activity and the assumption of the freeze posture in a foreign environment (48). These responses were similar to those occurring in stressed rats. Thus, central administration of CRH, like stress, produces anxiogenic-like and anorectic effects (49). Chrousos (47) considered that these data supported the hypothesis that CRH may mediate the metabolic, circulatory and behavioral adaptations that occur in demanding situations.
Role of CRH during pregnancy. Within the pregnant uterus, starting at 7–9 wk gestation, the fetal-placental-decidual unit produces hormones, neuropeptides, growth factors and cytokines and appears to function in a manner resembling the hypothalamic-pituitary-target systems. Pregnancy is associated with major alterations in neuroendocrine function, including changes in hormone levels and control mechanisms (feedback loops), that are crucial in providing a favorable environment within the uterus for cellular growth and maturation (50). It is now well-recognized that a shift in the balance from a progesterone-dominant to an estrogen-dominant milieu results in a sequence of events in the gestational tissues to promote labor, including gap junction formation, expression of oxytocin receptors and synthesis of prostaglandins. It is also known that unlike most other mammals, the human (primate) placenta cannot convert progesterone to estrogen because it does not express the cortisol-responsive enzyme 17–beta hydroxylase required for this conversion. Instead, the fetal adrenal zone produces a precursor hormone, dehydroepiandrosterone sulfate (DHEA-S), that is used by the placenta to synthesize estrogens (51). Estriol, a marker of fetal adrenal activity, is a marker of risk for spontaneous preterm birth (52).
Pregnancy is the only known physiological state in humans in which CRH circulates in plasma at levels that would normally activate the pituitary-adrenal axis (53). In addition, pregnancy is characterized by hypercortisolism to a degree similar to that observed in severe depression and anorexia nervosa. The source of this elevation in cortisol could be in part secondary to increases in free CRH as pregnancy progresses (28). However, to a large extent, circulating CRH in pregnancy appears to be tightly bound to a CRH-binding protein that may limit its bioactivity until the end of pregnancy, when CRH may play a role in the initiation of parturition (4). During human pregnancy the CRH gene is also expressed in the placenta and membranes and results in the increasing production and release of placental CRH into both maternal and fetal compartments over the course of gestation (54, 55). A growing body of empirical evidence supports a central role for placental CRH in orchestrating and coordinating fetal and maternal endocrine events involved in parturition. For example, placental CRH was shown to directly and preferentially stimulate DHEA-S secretion by human fetal adrenal cortical cells (56). Placental CRH also directly acts on the uterus and cervix to augment changes produced by estrogens on these tissues. CRH interacts with both prostaglandins and oxytocin, the two major uterotonins likely responsible for the stimulation and maintenance of myometrial contractility at term and during labor (57– 59).
Role of CRH in preterm birth and poor fetal growth. The overwhelming evidence from clinical studies suggests that women in preterm labor have significantly elevated levels of CRH compared with control subjects matched for gestational age. These elevations precede the onset of preterm labor, in some instances by several weeks(4, 28, 60– 63). Two studies that assessed CRH serially over the course of gestation found that compared with women with term deliveries, women delivering preterm had not only significantly elevated CRH levels but also a significantly accelerated rate of CRH increase over the course of gestation (4, 28). Moreover, the effects of placental CRH on spontaneous preterm birth are independent of other biomedical risk factors (64).
Placental CRH is stress sensitive. A series of in vitro studies by Petraglia et al. (65, 66) showed that CRH is released from cultured human placental cells in a dose-response manner in response to all the major biological effectors of stress, including cortisol and catecholamines. In vivo studies found significant correlations between maternal pituitary-adrenal stress hormones (ACTH, cortisol) and placental CRH levels (53, 67, 68). The maternal environment may also modulate placental CRH via its influence on maternal pituitary-adrenal function.
Maternal psychosocial stress is significantly correlated with maternal pituitary-adrenal hormone levels; both ACTH and cortisol stimulate placental CRH secretion. Some (28, 69) but not all studies (70) also reported direct associations between maternal psychosocial processes and placental CRH function. Thus, depending on the chronicity of the stressor, the resultant increase in CRH production may be a critical factor that contributes to spontaneous preterm labor and impaired fetal growth (54).
Stress and endocrine-immune interaction. A vast literature in both animals and humans supports the notion that stress both increases susceptibility to infection and the consequences of infection (71– 75). The mechanisms underpinning the association between stress and these immunological changes involve the hypothalamic-pituitary-adrenal axis and the autonomic system, glucocorticoids and catecholamines. Under conditions of chronic stress, moderate-to-high levels of glucocorticoids exert several direct effects on the immune system. These include inhibiting the production and response of lymphocytes to proinflammatory cytokines; suppressing the differentiation of T cells, early events in B-cell activation and monocyte-to-macrophage differentiation; and inhibiting the expression of major histocompatibility complex–I (76, 77). The tissues and organs of the immune system are enervated by the autonomic nervous system and contain receptors for several endocrine and paracrine hormones. Cortisol also indirectly affects the immune system by modulating the expression of the parasympathetic and sympathetic components of the nervous system on thymocytes, monocytes and macrophages (77, 78). These effects are believed to be mediated by a large infrastructure of anatomical and physiological connections that allow communication both within and between the endocrine and immune systems. For example, the efferent sympathetic-adrenomedullary system participates in the interactions of the hypothalamic-pituitary-adrenal axis and immune or inflammatory stress by being reciprocally connected with the CRH system, by transmitting humoral and nervous signals to lymphoid organs and by reaching sites of inflammation via postganglionic sympathetic neurons (78, 79). Immune cells contain receptors for and respond to neurotransmitters, neuropeptides and neurohormones secreted by sympathetic neurons and the adrenal medulla.
Certain cytokines, especially tumor necrosis factor-alpha (TNF-
), interleukin (IL)-1 and IL-6, activate the stress system in vivo (78). The observations that stress hormones, particularly glucocorticoids, inhibit lymphocyte and leukocyte proliferation, migration and cytotoxicity as well as the secretion of certain cytokines such as IL2 and interferon-
, support the conclusion that stress is generally immunosuppressive. Recent evidence suggests that stress-induced concentrations of glucocorticoids and catecholamines may also influence the immune response. Immune responses are regulated by antigen-presenting cells such as monocytes and macrophages, which are components of innate immunity, and by T-helper (Th) lymphocyte subclasses Th1 and Th2, which are components of acquired or adaptive immunity. Th1 cells promote cellular immunity whereas Th2 cells promote humoral immunity. Naive CD4+ (antigen-inexperienced) Th0 cells are bipotential and are precursors of Th1 and Th2 cells. Cytokines produced by the cells of the innate immune system (monocytes and macrophages) are among the most important factors currently known to influence differentiation of Th0 cells toward the Th1 or Th2 subsets to drive cellular and humoral immune responses. Th1 and Th2 responses are mutually inhibitory. Recent evidence strongly suggests that stress hormones differentially regulate Th1 and Th2 patterns and type1 and type2 cytokine secretion, thereby potentially altering the balance between these two acquired immune responses. This may be adaptive in an acute situation but maladaptive in a chronic situation (perhaps including pregnancy) because it results in increased vulnerability to infectious agents that are defended against primarily via innate and cellular immune responses (78,
79).
Stress, infection and preterm birth.
Microbial infection and inflammation in the gestational tissues has emerged as one of the major risk factors for preterm birth (80). The most common organisms associated with preterm birth are relatively low-virulence bacteria associated with a condition known as bacterial vaginosis (81). Maternal infections may trigger parturition by activating the monocyte and macrophage system in peripheral blood and human decidua, resulting in the release of inflammatory cytokines. Enhanced expression of the proinflammatory cytokines IL1, IL6 and TNF- are associated with preterm birth (82,
83). Proinflammatory cytokines promote spontaneous labor and rupture of membranes via synthesis and release of prostaglandins and metalloproteases in the gestational tissues; the production of inflammatory cytokines, cortisol and DHEA-S, in the fetus; and CRH synthesis in the placenta (66,
84–
86).
Very little research has examined the nature of the stress-infection-immune relationship in human pregnancy. In fact, a review of the relevant literature found only two studies of stress and immunity in human pregnancy. In one study, a cross-sectional investigation of a sample of 72 pregnant women, high levels of maternal psychological stress and low levels of social support were significantly associated with depression of lymphocyte activity (87). In the second study, psychosocial stress was assessed in 94 women with a confirmed diagnosis of first trimester spontaneous abortion. The decidua of women with high stress scores was found to have altered immune parameters, including higher numbers of MCT+, CD8+ T cells and TNF- cells (immune mediators of miscarriage), than the decidua of women with low stress scores (88). Moreover, an in vivo study reported that women in preterm labor with microbial invasion of the amniotic cavity had significantly higher CRH levels than those in preterm labor without infection (63). Maternal psychosocial stress may produce increased risk of preterm birth via 1) a neuroendocrine pathway (maternal ACTH, cortisol) to ultimately result in premature activation, greater degree of activation or both of the placental-fetal endocrine systems (CRH, estrogens) that promote parturition or 2) immune mechanisms regulated by Th1, Th2 and inflammatory cytokines, wherein maternal stress may modulate immune responses (Th1-Th2 ratio) to increase susceptibility to maternal infection (bacterial vaginosis) and intrauterine or fetal inflammatory processes (ascertained by placental histopathology), thereby promoting preterm birth through proinflammatory mechanisms.
Nutrition deprivation and adverse outcome of pregnancy
Before we consider poor nutrition as a stressor we must understand whether pregnancy itself affects nutritional metabolic pathways. For example, for years it has been known that pregnancy is associated with hypersecretion of and peripheral resistance to insulin (89). Using the 24-h metabolic clock for monitoring circulating fuels and hormones has been helpful to delineate metabolic profiles in pregnancy to identify abnormalities in maternal metabolism. In 1980 Cousins et al. (90) contributed significantly to our understanding of the progressive effects of normal pregnancy on plasma glucose and insulin levels when compared with postpartum nonpregnant control subjects. During the day they observed a diurnal rhythm of plasma glucose (increments above the 24-h mean) in response to meal intake that was small, ranging between 1.6 and 1.9 mmol/L (30 and 35 mg/100 mL) in the postpartum state and were not significantly modified by pregnancy. The corresponding insulin levels were similarly small but there was a mean increase of 31% in pregnant subjects. In addition Cousins et al. observed that in the third but not the second trimester the peak anabolic values for both plasma glucose and insulin were significantly increased. When values were compared with those of the postpartum state, there was a progressive increase in the degree of catabolic excursion of plasma glucose during sleeping hours from the second to third trimester of pregnancy. This resulted in a state of relative hypoglycemia with significantly reduced fasting plasma glucose and 24-h integrated glucose levels. Studies by Meis et al. (91) found that a daytime fast of 8 h resulted in significantly lower glucose concentrations than did a nighttime fast of 8 h.
The relative hypoglycemia described by the above two studies by Cousins et al. and Meis et al. were not observed by Phelps et al. (92) in studies of diurnal profiles of glucose, insulin, free fatty acid, triacylglycerols and amino acids in late pregnancy. An overnight fast of 14 h was insufficient to show a heightened propensity for accelerated fat mobilization, as shown by free fatty acid levels. A significant elevation of triacylglycerols was found throughout the 24 h, with elevations after each meal. The extra triacylglycerols were viewed as supporting facilitated anabolism to spare ingested glucose from oxidation by the mother. Fasting and premeal values of individual amino acids, except threonine, were generally significantly lower in pregnant subjects.
These data may suggest that the observed night-day fasting differences are caused by the cumulative glucose demands of daily activity added to those of the fetus and placenta proving too great for glucose regulatory mechanism to maintain euglycemia. Thus, the metabolic demands of pregnancy establish a state of relative hypoglycemia and leave little margin of safety for the additional effects of stress or self-induced reductions in caloric intake or fasting. It maybe important for pregnant women to establish appropriate meal patterns during daytime hours to maintain euglycemia and to avoid fasting during daytime or nighttime hours.
Metabolic changes during fasting and energy restriction
The fasted or starved state necessitates two major metabolic adaptations: first, energy expenditure must be reduced to conserve energy, and second, fuel stores must be mobilized to maintain vital functions. In animals and humans, sympathetic nervous system activity is reduced by fasting or energy restriction (93, 94). Suppression of the sympathetic activity may contribute to a decrease in metabolic rate with energy restriction. One postulated mechanism linking diet and sympathetic nervous system activity involves insulin-mediated glucose metabolism in glucose-sensitive neurons of the hypothalamus that regulate an inhibitory pathway governing central sympathetic outflow (95). The adrenal medulla, in contrast, is stimulated modestly during fasting (94). Epinephrine is important for the mobilization of glucose from glycogen and it may also foster mobilization of triacylglycerols from adipose tissue. Lipolysis is sensitive to variations in plasma epinephrine levels within the physiological range and fasting enhances the lipolytic effect of catecholamines (96, 97). The combination of sympathetic nervous system suppression and adrenomedullary stimulation allows substrate mobilization with a minimal increase in energy expenditure.
Nutrition deprivation and low birth weight. There is most likely a continuum of nutritional deprivation ranging from mild to severe, and it is not clear how much deprivation is needed to influence pregnancy outcome. For example the maternal depletion syndrome is commonly used to explain poor maternal and infant health in developing countries (98). The syndrome has been attributed to the nutritional stresses of successive pregnancies, lactation, inadequate weight gain and poverty. The maternal depletion syndrome may help us understand the various energy pathways leading to depletion or repletion, but it does not provide us with an understanding of the complexities of altered nutrition before and during crucial times during pregnancy. Moderate alterations in nutrition are more likely to be associated with patterns of change, the timing of which could affect outcome.
Patterns of poor nutrition and the risk of intrauterine growth restriction and preterm birth. The Dutch famine in 1944–1945 is the best example of the effect of timing of poor nutrition on low birth weight (99). Third trimester exposure accounted for the whole of the famine effects on birth weight whereas first trimester exposure affected the length of gestation. The later is of special interest today because the first trimester pregnant woman is thought to be more vulnerable to stress and during the famine the stress of war may have been the stressor affecting gestational length but not birth weight. Several recent large-scale epidemiological studies showed that inadequate weight gain in the second half of pregnancy (after 20–24 wk gestation) is associated with preterm birth (99, 100). However, many of these studies did not adequately control for several potential confounders such as maternal physical activity (work) and emotional stress (psychosocial). In 1997 Carmichael and Abrams (100) reviewed the literature on the relationship between gestational weight gain and preterm delivery. Siega-Riz et al. (101) studied a large population of women of Hispanic origin and found that women who delivered preterm had patterns of weight gain similar to women delivering term infants; however, underweight status before pregnancy nearly doubled the likelihood of delivering preterm. In addition, inadequate weight gain in the third trimester increased the risk of preterm birth regardless of body mass index. Siega-Riz posits two mechanisms. First, women with low body mass index as well as those who have preterm labor have lower plasma volume measurements. Without adequate vascular volume expansion, uterine perfusion is limited and there is inadequate delivery of substrate to the fetus. Second, underweight status also serves as an indictor of chronic undernutrition, which may have occurred early in childhood.
Micronutrient deficiency and stress. Our review fails to identify a relationship between micronutrient status and stress; however, there are some promising developments. There is a growing body of evidence that deficiency in (n-3) fatty acids (a macronutrient) is associated with depression, an important component of the stress syndrome (102). In addition (n-3) fatty acid deficits may affect the central nervous system during early development and lead to increased vulnerability to depression (103). A relationship between omega-fatty acid metabolism and a deficiency in the micronutrient zinc has been identified. In depression, a positive correlation exists between serum zinc (an antioxidant and cofactor for synthesis of (n-3) fatty acids) and the proportions of the two (n-3) fractions—eicosapentaenoic and docosahexanoic fatty acids—and an inverse relationship exists between serum zinc and the ratio of (n-6) to (n-3) fatty acids in phospholipids (104). These relationships suggest that abnormal omega-3 metabolism may increase the inflammatory response (by increased oxidative potential resulting from lower zinc levels), resulting in depressive symptoms. Thus, (n-3) fatty acid and zinc deficiencies during pregnancy may have a role in the development of perinatal and postpartum depression (105). This area of investigation should be considered.
Fasting and the risk of preterm birth. In 1970 Felig and Lynch (106) were the first to study the difference in the metabolic effect of fasting between pregnant and nonpregnant women. A group of women undergoing termination of pregnancy at 16–20 wk fasted for 84 h and were compared with a group of nonpregnant women who also fasted. Pregnant subjects had significantly lower blood sugars as early as 12 h into the fast compared with nonpregnant subjects and mean levels fell to hypoglycemic levels (<2.8 mmol/L [50 mg/100 mL]) by 60 h. In concert with significant lower glucose levels at 12 h, insulin levels were significantly lower and acetoacetate and ß-hydroxybutryrate levels were significantly higher, suggesting early ketosis. This study suggested that pregnant women were vulnerable to heightened ketonemia after a brief period of fasting (12 h). Subsequently Metzger et al. (107) reassessed fasting by studying both lean and obese women who skipped breakfast (12-h fast) and on the next day skipped lunch (18-h fast). By 16 h the pregnant group had significantly lower glucose levels and significantly higher free fatty acids and ß-hydroxybutyrate levels. Both lean or obese women showed similar changes. As a result of these findings they coined the term accelerated starvation. Because of the concern about ketonemia on fetal well-being, these authors suggested the common practice of skipping breakfast whether by personal preference or for doctor-initiated laboratory testing should be avoided during pregnancy.
More recently Siega-Riz et al. (108) reported that meal patterns of pregnant women and the frequency of food intake during pregnancy are relevant to the relationship between maternal nutrition status and preterm birth. Women who ate fewer than three meals and two snacks per day had a 30% higher risk for delivering preterm compared with pregnant women who met this level. In addition, pregnant women who reported not eating for >13 h/d had a threefold greater risk of delivering preterm at <34 wk gestation when compared with women who reported <13 h/d without food. This observation, along with the work of Metzger noted above, led Herrmann et al. (109) to analyze the dietary habits of 237 women participating in a study of behavior in pregnancy. They examined the relationship between prolonged periods without eating and CRH concentrations using multivariate logistic regression analysis in 237 pregnancies. These investigators found that periods without food lasting 13 h compared with periods <13 h were associated with elevated maternal CRH concentrations; they controlled for pregravid body mass index, energy intake, income, race, smoking and maternal age. In addition they found an inverse linear relationship between maternal CRH concentrations and gestational age at delivery. Thus, for the first time a plausible mechanism for the relationship between fasting and a greater risk of preterm birth was identified via the expression of placental CRH. This study contributed significantly to our understanding of the link between altered nutrition (fasting) and a neuroendocrine mechanism for preterm birth. A few studies suggest that improving nutritional status may be a plausible intervention for reducing preterm birth(110– 112).
Stress and weight gain. Beginning in the 1970s, interest developed in the role of psychosocial stress and the absence of an adequate social support network on the outcome of pregnancy (113, 114). In 1982, Picone et al. (115) were the first investigators to attempt to determine the effect of stress on energy use in pregnancy. These investigators found that stress negatively correlated with pregnancy weight gain, suggesting that the use of dietary energy was less efficient in women under stress. At that time stress was well known to cause an increased secretion of corticoids, catecholamines, growth hormone and prolactin; now these hormones are known to impair insulin release, stimulate glycogenolysis and lipolysis and increase metabolic rate. These data were the first to suggest that stress-induced metabolic changes may explain the impaired conversion of dietary calories to maternal weight gain.
Stress and poor fetal growth. The only study that has definitively shown a relationship between psychosocial stress and fetal growth restriction is that of Cliver et al. (116). These investigators showed that there was a significant relationship between poor scores on five of six psychosocial scales and a higher risk of fetal growth restriction only in thinner women who had a body mass index less than the median. The poor psychosocial profile had a greater association with fetal growth restriction in nonsmokers than in smokers. An important finding in this study was that psychosocial stress did not have a uniform effect across the entire population. Greater prepregnant weight for height seems to protect against the adverse effect of having a poor psychosocial profile, and in the population studied it reduced the negative effect of smoking on birth weight. The mechanism or causal pathway could be through increased production of catecholamines, resulting in vasoconstriction, or indirectly via the negative health behaviors such as alcohol consumption, poor eating and smoking (117). More recent studies showed that maternal stress is associated with higher maternal cortisol concentrations, and the placental transfer of cortisol could affect fetal growth (28). At midgestation the placenta lacks the enzyme11b-hydroxysteroid dehydrogenase, which converts cortisol to the less potent glucocorticoid cortisone, and cortisol is known to reduce fetal growth (29).
Conclusions
This paper explores and defines the nature of stressful experiences during pregnancy and how they contribute to poor pregnancy outcome. The timing of stressors appears to be most important, with early pregnancy being the most vulnerable period. Stressors present early in pregnancy are most likely present before pregnancy and if we are to improve pregnancy outcome, interventions will have to begin before conception. The risk of preterm birth and poor fetal growth is multifactorial and the maternal stress response appears to be influenced by other conditions such as work strain and poor nutrition. These interactions are further influenced by the role of stress on neuro-endocrine-immune interactions increasing the risk for infections, which are thought to play an important role in the pathophysiology of preterm labor. Poor nutrition by itself has emerged as a very important component of the stress syndrome that needs further characterization in the pathways for the risk of infection, poor fetal growth and preterm birth. Poor nutrition before pregnancy, during early pregnancy and during the third trimester influences the timing of delivery and the birth weight of the fetus.
When the fetus is exposed to maternal stress or poor nutrition, maternal and fetal adaptations prepare it (fetal programming) for early delivery and survival in a hostile environment. However, the fetus pays a price for this chance to survive. Intrauterine programming significantly increases the risk for the early onset of adult diseases (known as the fetal origins of adult diseases). Barker and Osmund (118) were the first to show that low birth weight increased the risk of coronary heart disease in adult life. Subsequently, different profiles of poor fetal growth for each trimester were found to be associated with hypertension and/or diabetes and stroke (119). Even infants born preterm are at elevated risk of coronary heart disease (120).
We believe that health care prevention programs for the future must focus on improving the intrauterine environment of the fetus; however, caution must be exercised because interventions during pregnancy may be too late. Serious consideration should be given toward improving the health of children during adolescence and for women before pregnancy. Directing attention toward improving nutrition and reducing psychosocial and environmental stressors has promise as an intervention strategy.
Knowledge gaps
Identified knowledge gaps are the following:
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3 Abbreviations used: ACTH, adrenocorticotropin; CRH, corticotropin-releasing hormones; DHEA-S, dehydroepiandrosterone sulfate; IL, interleukin; Th, T-helper; TNF-, tumor necrosis factor-.
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