Agent Detail - STRESS

Agent Summary

Quick take: Stress during pregnancy may be associated with an increased risk of low birth weight or premature delivery. Some reports have associated stress with an increased risk of congenital anomalies involving cranial neural crest-derived tissues.

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Stress can be defined as a physiologic response to an aversive stimulus. Much of the research on stress effects on reproduction use experimental animals subjected to physical stressors such as noise, restraint, heat, or food deprivation. It is not clear that these stresses adequately model human psychologic stress.

Non-Malformation Endpoints In Experimental Animal Studies

Experimental animal studies have yielded conflicting reports on the effects of stress on resorption, litter size, birth weight, and offspring viability. Rats exposed to noise and flashing lights for 6 min of every hour 24 h/d throughout pregnancy showed an increase in resorptions and an increase in the variability of fetal weights (with a decrease in mean fetal weight) when compared to unstressed controls (1). Restraint stress in rats has been shown to increase fetal loss, especially when the stress is applied late in gestation (2). In mice, a stress treatment consisting of heat, noise, or both applied for 6 min each hour during different 5-d intervals decreased attainment of the two-cell stage when applied prior to mating, decreased implantation sites and mean crown-rump length when applied during days 5 through 9 of gestation, and decreased embryo weight and crown-rump length when applied during days 9-13 (3). A similar study using loud jet engine or claxon noise during gestation days 1-6 or 6-15 in mice showed an increase in embryo and fetal death in treated groups (4). A prospective study reported a decrease in birth weight and behavioral impairment in the offspring of monkeys exposed to mild daily noise stress (39). A series of studies using foot shock avoidance stress in pregnant rats showed a small but significant reduction in birth weight in the offspring of treated dams and an increase in the perinatal death rate associated with the stress (5,6). These data are difficult to interpret because no information was given concerning maternal weight gain or food intake during pregnancy and because weight data for all pups in each generation were combined rather than being examined by litter.

There have been a number of negative experimental animal studies involving stress simulations. Rats and mice exposed to white noise for 6 min of every half-hour during different intervals of pregnancy had offspring with birth weights no different than controls, although poor maternal weight gain and increased resorptions were seen in 2 of the treatment groups (5). Other studies using a variety of stressors during pregnancy in the rat have shown no adverse effects on litter size or birth weight in the offspring (6-9). Immobilization with food and water deprivation for 12 h on one day during embryogenesis in rats and mice had no effect on the number of implantation sites or on fetal viability (a control group was also food and water deprived) (10). Pregnant mice exposed to high frequency white noise on days 6-15 actually showed a decrease in resorptions in one study (11); this finding was assumed to be a statistical fluke. Although the negative and positive studies are difficult to compare due to differences in technique and, in some cases, differences in the adequacy of data handling, it appears likely that a sufficient degree of stress applied for a sufficient length of time in pregnant rodents has the potential to adversely affect some parameters of reproduction such as implantation and embryo viability. Adverse effects on birth weight have not been established.

Malformations in Experimental Animal Studies

Investigations of restraint stress during rat pregnancy (10,12) and studies of noise stress during pregnancy in rats and mice (4,5,11) have given negative results for the induction of birth defects. The only convincing evidence of a teratogenic effect of stress in rats was presented by Geber in 1966 (1). He reported that very disruptive stress consisting of noise and flashing lights for 6 min/h, 24 h/d, throughout pregnancy resulted in an increase in a number of congenital anomalies involving different organ systems. Stressed dams also failed to gain as much weight during pregnancy as controls. These results were considered consistent with intrauterine hypoxia induced to different degrees within the uterus during embryogenesis, perhaps due to catecholamine-mediated vasoconstriction.

By contrast to the situation in rats, the induction of stress-related birth defects in mice has been more readily achieved. Immobilization of pregnant animals for 12 h on a single day gave rise to offspring with an increase in fused or supernumerary ribs and exencephaly (10). A linear relationship was shown between the induction of supernumerary ribs and the loss of maternal body weight during the treatment period, suggesting that the skeletal effects may have been a result of general toxicity of the treatment. High-frequency noise stress for several days during pregnancy has been associated with an increase in the incidence of exencephaly, cleft lip, open eyes, and fused sternebrae in mouse offspring (13). This treatment also increased catecholamine levels in maternal blood (13), adding credence to Geber's theory of intrauterine hypoxia due to vasoconstriction.

The induction of facial clefting by stress in mice has received particular attention. In some studies, maternal stress with either restraint or food deprivation has produced an incidence of cleft palate as high as 69% compared with a 1% rate in controls (14). This effect may be mediated by the elevation of corticosteriods by stress (47). For more information on corticosteroids and clefting in mice, see agent summary #2945, cortisone.

Behavioral abnormalities in the offspring of animals stressed during pregnancy have also been the subject of considerable research. Some investigators have focused on alterations in serotonin(#1695) in the brain tissues of neonatal rats as a possible mechanism to explain stress-related behavioral abnormalities (34). Overall, the effects on male sexual behavior in the offspring of stressed rodents have been among the most reproducible of the behavioral abnormalities. Studies have shown decreases in such endpoints as copulatory behavior in rats (15-18,48) and intermale aggressivity in mice (19), although the latter is markedly strain-dependent (20). The mechanism of altered sexual behavior in male rodents is likely to involve abnormalities in prenatal exposure to androgens, particularly testosterone (#1629). Maternal stress during pregnancy has been shown to alter anogenital distance, an androgen-sensitive parameter, in rats (8) and mice (20). The role of fetal testicular testosterone production in intrauterine development has been investigated in detail in the rat. Studies by Ward and Weisz have shown that stress in the mother perturbs the normal pattern of secretion of testicular testosterone between days 17 and 19 of gestation (21,22). Failure of testosterone to increase on day 18 appears to underlie abnormal subsequent sexual behavior (21).

Human Studies – General Considerations

It has been believed for many years that excessive stress has adverse effects on health, including during pregnancy. A 1961 paper reported that of 200 women tested during pregnancy, 11 demonstrated extreme degrees of anxiety and 10 of these 11 had significant adverse outcomes (4 miscarriages, 5 neonatal deaths, and 1 baby with congenital anomalies) (30). Another study used an anxiety test administered in the third trimester and evaluated Apgar score in the offspring. Mean Apgar scores in the severely anxious group were lower than in the normal group (28). This finding in itself is not meaningful, because Apgar is a ranking system and does not permit comparisons of group means; however, in the normal anxiety group, all Apgar scores were 8 or more while in the severely anxious group Apgars ranged from 0 to 9. The authors concluded that extreme maternal anxiety might jeopardize fetal/neonatal well-being. An alternative explanation for the difference in distribution of Apgar scores is that anxious women receive more analgesic medication during labor (29). Women under stress may alter their dietary patterns and use medications and recreational drugs in attempts to alleviate stress. It is difficult to define and test for the reproductive effects of stress itself (33,35).

In addition, study design may influence outcome. Retrospective designs elicit measures of stress in mothers who already know the outcome of their pregnancies, and investigators may have the luxury of including any number of adverse outcomes as endpoints of interest. In 1 prospective study, data on psychologic state were collected and a limited number of abnormal obstetric outcomes was selected for investigation before rather than after delivery. This report was unable to identify a relationship between maternal emotional state and adverse outcome (31).

Spontaneous Abortion and Malformation

An elevated frequency of negative life events was found among 111 women who spontaneously aborted a normal fetus (49). In this study, the incidence of reported negative life events among 81 women who spontaneously aborted a chromosomally abnormal fetus was used for comparison (49). The small size of this study and the relatively small magnitude of difference between the study groups make the reported findings suggestive at best.

A Danish report in 2000 focused on possible influence of stress during organogenesis and the incidence of congenital malformations in tissues derived from cranial neural-crest cells (50). The authors of this report posited that since migration of neural crest cells is an important component of normal development, and some agents (including retinoids (#1194) and corticosteroids (#1054)) are known to interfere with this process, the incidence of cranial-neural crest congenital malformations might be increased by the pathophysiological effects stress during early pregnancy (50). Using the detailed Danish medical record system, these authors identified more than 3500 pregnancies that included first trimester exposure to severe life events such as death or first hospital admission for cancer in partners or children. As a control, they used a group of more than 20,000 pregnancies without such exposures. There was a significant elevation in cranial neural-crest malformations in pregnancies exposed to severe life events when compared to those without such exposure (adjusted odds ratio: 1.54 [95% CI 1.05-2.27]. No significant difference was found in the frequency of other malformations between the two groups. Unexpected death of an older child during the first trimester was associated with an adjusted odds ratio of 8.36 [CI 1.63-13.8]. Although medical records have limited sensitivity for monitoring the use of tobacco, alcohol, or other drugs during gestation, the authors attempted to control for these factors, and the data did not suggest that these agents explained the reported increase in malformations in the stress-exposed pregnancies.

A subsequent study (54) that also focused on a possible relationship between stressful life events and cranial-neural crest anomalies found the strongest association in women over 25 years old who had given birth to an infant with cardiac conotruncal defects (OR = 1.53, 95% CI 1.14-2.07), but not for mothers less than or equal to 25 years old (OR = 1.03, 95% CI 0.78-1.35). In another study published in 2000, telephone interviews were conducted with mothers who had given birth to children with a conotruncal heart defect, neural tube defect, or cleft lip. These women were more likely to report a stressful life event such as the death of someone close to them, job loss, or separation/divorce for themselves or someone close to them (51).  This group used a similar research approach with a population in California born between 1999 and 2004 (65).  These findings only showed a statistically significant association between reports of stress and neural tube defects among women who also reported not using folic acid (#1222) supplements, suggesting that stress may not have been the key determinant for an elevated risk of these defects (65).

Birth Weight and Gestational Age

Several studies using retrospective or prospective designs have evaluated the effects of stress on reducing birth weight and gestational age. Three different groups of investigators interviewed women after delivery and found that the mothers of preterm babies had a higher rate of psychologic abnormalities or reported more psychologically adverse life events (23-25). Because interviews were conducted after the pregnancy outcomes were known, recall bias may have been a factor. Two of these studies did not control for family income, maternal smoking (#1062), ethanol (#1290) use, nutrition, or prenatal care (23,24). One of the surveys evaluated a number of pregnancy factors and found several to be associated retrospectively with preterm delivery. These factors included low socioeconomic status, previous preterm delivery, inadequate weight gain (#3870), a history of infertility, a history of induced abortion, bleeding from the vagina during the index pregnancy, abnormal placentation, a lack of leisure-time physical activity, ethanol ingestion, and an undesired pregnancy (25).

Another paper used 2 methods to avoid the biases associated with interviewing women shortly after normal and abnormal births. First, interviews with women delivering preterm or delivering at term after successful treatment for preterm labor were conducted 3 to 9 months postpartum and only when the baby was at home and in good health. Second, a prospective study was conducted wherein women were interviewed at 4 to 6 months gestation and followed for preterm labor. The groups of women who went into premature labor were found to have higher anxiety scores both when measured months after the delivery and when measured prospectively (27). The authors correctly recognized that this association did not show that maternal anxiety causes preterm labor, but they believed that "psychopathological tendencies" might increase the risk of premature labor when superimposed on other factors. A subsequent study also found measures of stress on a standardized instrument to be associated prospectively with a small (16%) but statistically significant increase in risk of premature birth, controlling for maternal demographic factors and for maternal use of cigarettes, alcohol, and illicit drugs (40). Exposure to an earthquake in pregnancy was also shown to be associated with a small decrease in gestation length (53). The largest effect was associated with first trimester exposure, which was associated with a mean gestational age decrement of 1.23 weeks.

A prospective study on the possible association between psychologic state and low birth weight did not find a relationship with maternal anxiety but was able to show that major life events (such as death of a close relative or friend) occurred more often in women who went on to have low birth weight or premature babies. This study also identified an association between major life events, smoking, and low socioeconomic class (32), which may be factors in low birth weight and prematurity. A prospective study that surveyed women in midpregnancy found an increased incidence of prematurity in women who had experienced severe stressful events as categorized by the American Psychological Association (36). This report did not contain sufficient detail to permit a full analysis of its findings. Another prospective study found that events perceived as stressful between the 16th and 30th week of gestation were associated with an increased risk of preterm delivery (58).

A prospective study in upper middle class women with a low self-reported incidence of tobacco and ethanol use showed that standard indices of stress during pregnancy correlate negatively with infant birth weight and gestational age (38). Although medical complications of pregnancy occurred in some of the subjects, the stress indices were independently correlated with a decrease in birth weight and gestational length, making more plausible the association between stress and premature delivery that has been noted in other reports. Medical illness may increase both stress and prematurity; that is, women suffering medical complications of pregnancy may be more anxious about their health or about their pregnancy outcome. One study found that anxiety during pregnancy was associated with preterm delivery but that the strength of the association decreased when adjusted for medical comorbidities (55).

If stress is associated with preterm delivery or low birth weight, race or poverty may be mediators of the association. Low birth weight was found to be associated in low-income women with chronic stressors including food insecurity, another child with a chronic illness, crowding in the home, and unemployment (56). A case-control study of African American women found an association between delivering a very low birth weight and 3 or more stressful life events (57).

Not all studies have identified an association between stress and preterm birth or low birth weight. A case-control study of preterm delivery in North Carolina was unable to show a significant association with job stress (46). A Danish study used a questionnaire in mid-pregnancy to ascertain stress and found no significant association with preterm delivery or intrauterine growth retardation after adjustment for cigarette and alcohol use (59). In spite of the statistical results, the authors concluded that preterm delivery was increased by stress, but the attributable risk was only 3%. A study of racial and ethnic disparities in preterm birth found that African American and native American women experienced more stressful life events but that these stresses did not make a significant independent contribution to preterm birth risk (60). A study of pregnant women with medical comorbidities such as hypertension and diabetes found that an optimistic disposition was inversely correlated with birth weight and gestational age at delivery, and that after controlling for optimism, stress had no significant impact on pregnancy outcome (61).

Corticotropin-Releasing Hormone

If stress has an effect on preterm delivery and birth weight, the effect may be mediated by corticotropin-releasing hormone, which is released by the pituitary and the placenta. A case-control study used stored midtrimester sera to evaluate maternal corticotropin releasing hormone as a predictor of preterm delivery (52). A small but statistically significant association was identified. The odds ratios (95% CI) for white and black women were 2.3 (1.1, 5.1) and 5.0 (1.8, 13.3), respectively. An increase in corticotropin-releasing hormone in response to stress has been theorized to result in the release of uterine prostaglandins, inflammatory mediators, and vasoactive factors that increase the risk of preterm labor and low birth weight (62-64).

Fertility

The association between stress and fertility was evaluated in 38 women coming for inability to conceive (37). Women with infertility due to "functional" problems, such as ovulatory disorders, had higher indices of stress on standardized tests than did women with infertility due to anatomic disorders (e.g. tubal obstruction) or male factors, suggesting that in some women, stress may contribute to functional fertility problems.

Stress has been reported to decrease serum testosterone concentration in men (41-43). Some studies have shown decreased fertility in stressed men (reviewed in 44), but an evaluation of sperm parameters using computer-assisted imaging did not show semen quality to be related to stress at work or to life events (45). There was, however, an adverse effect of recent death of a close family member on sperm velocity parameters.

Selected References

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2. Euker JS, Riegle GD: Effects of stress on pregnancy in the rat. J Reprod Fertil 34:343-346, 1973.

3. Zakem HB, Alliston CW: The effects of noise level and elevated ambient temperatures upon selected reproductive traits in female Swiss-Webster mice. Lab Anim Sci 24:469-475, 1974.

4. Nawrot PS et al: Embryotoxicity of various noise stimuli in the mouse. Teratology 22:279-289, 1980.

5. Kimmel CA et al: Teratogenic potential of noise in mice and rats. Toxicol Appl Pharmacol 36:239-245, 1976.

6. Ader R, Plaut SM: Effects of prenatal maternal handling and differential housing on offspring emotionality, plasma corti-costerone levels, and susceptibility to gastric erosions. Psychosom Med 30:277-286, 1968.

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