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Sociobiological variables and pregnancy outcome
International Journal of Gynecology & Obstetrics 70 Ž2000. 105᎐112
Sociobiological variables and pregnancy outcome R.L. Tambyrajia, M. MongelliU Department of Obstetrics and Gynecology, National Uni¨ ersity of Singapore, Singapore
Abstract Recent advances are beginning to shed light on the mechanisms whereby adverse psychosocial factors can influence pregnancy outcome. High levels of maternal stress have been linked to endocrine disturbances, which in turn increases the risk of preterm labor considerably. These observations have been supported by experimental animal models. Birth weight is subject to considerable ethnic variation, and on its own is a nonspecific indicator of pregnancy outcome. The benefits of social and psychological intervention have been best documented in the intrapartum situation, whereas antenatal intervention is most likely to be of benefit when focused on improving socioeconomic conditions and access to healthcare providers. 䊚 2000 International Federation of Gynecology and Obstetrics. Keywords: Pregnancy; Preterm labor; Social variables; Maternal stress
1. Introduction Poor pregnancy outcome is often linked to a constellation of adverse social circumstances, and of these, stress is the strongest predictor in developed countries. In developing countries, the lack of facilities, poverty and the poor organization of care compound other social problems, thus result-
U
Department of Obstetrics and Gynecology, National University Hospital, Singapore 119074, Singapore. Tel.: q657724277; fax: q65-7794753. E-mail address: [email protected] ŽR.L. Tambyrajia..
ing in high maternal and perinatal mortality and morbidity. Anxiety about the development of the fetus and the wish to optimize pregnancy outcome are universal, deep rooted human emotions, and have been documented since antiquity. Within each culture, one will find sets of beliefs regarding what a pregnant woman should avoid or actively pursue to improve the outcome w1,2x. With the current scientific focus mainly on the recent spectacular advances in molecular biology, there is a real risk that the power of adverse psychosocial factors may be underestimated. Pregnancy and birth complications lend them-
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R.L. Tambyrajia, M. Mongelli r International Journal of Gynecology and Obstetrics 70 (2000) 105᎐112
selves very well to the application of prospective designs, since variables such as ethnic group, birth weight, Apgar scores and umbilical blood gases are usually well documented. The importance of these outcome measures has been highlighted in the recent work by Barker et al. w3x. Their studies suggest that the intrauterine environment may have long term implications on adult health, including common conditions such hypertension and diabetes. In this paper we will review and discuss issues related to the question of whether psychosocial and ethnic factors affect fetal development and birth processes. To achieve this objective, we will assess the experimental evidence from animal research, human observational studies and human interventional studies.
Ž- 2500 g. is significantly smaller w9x, with both groups living in similar socioeconomic conditions and with total healthcare coverage. Similarly, Californian black babies under 3001 g have much lower mortality rates than whites, even though their birth weights are lower w10x. These ethnic variations in fetal growth patterns are detectable in utero from early in the third trimester by ultrasound biometry w11x. Similar influences can be attributed to other maternal characteristics such as maternal weight, height and parity w11x. It is apparent, therefore, that in the clinical assessment of fetal growth, these ethnic differences in fetal growth need to be accounted for.
3. Stress and perinatal outcome: experimental studies 2. Birth weight and ethnic group An extensive description of the variations in birth weight among different ethnic groups was published by Meredith in 1970 w4x. Of the 78 groups considered, the largest newborns were found in Anguilla and Nevis, weighing a mean of 3.88 kg. The smallest babies were those of the Lumi tribe in the Toricelli mountains in New Guinea, with a mean birth weight of 2.4 kg. The extreme variations in birth weight noted in this survey are clearly not entirely attributable to race, with social, geographic and nutritional factors also being possible contributors. Maternal nutrition does not materially affect fetal growth unless extreme deprivation occurs. Babies born at high altitudes are more likely to be lighter and preterm than those born at sea level w5x. Ethnic differences clearly persist in mixed populations from the same location w6,7x, suggesting true genetic differences. In California, large differences in birth weight were shown to be present between different ethnic groups, even after controlling for 22 different physiological and pathological factors w8x. Birth weight variations do not always correlate with trends in perinatal mortality. In Singapore, Malay babies have a much higher perinatal mortality than Indian babies, even though their percentage of low birth weight
There is strong experimental evidence from animal research in various species that maternal exposure to stressful conditions has adverse effects on the offspring w12,13x. Well known stressors such as immobilization, noise, unexpected handling or crowding have resulted in smaller litter size, lower birth weights, increased incidence of malformations, and growth retardation. Most of this research has been performed in rodents and whether these are adequate models for the study of effects on human fetal development remains uncertain. In view of the longer gestation, usually with a single fetus, primates have better in utero protection than rodents. For example, in primates, maternal protein deficiency does not lead to growth retardation and learning difficulties in their offspring, as it does in rodents. However, studies in various monkey species have shown that exposure to stressful events can result in a variety of complications, such as abortion, low birth weight, and a poorly developed placenta w14x. In a recent large retrospective study of pigtailed macaques by Ha et al. w15x, it was found that the presence of the sire and other pregnant females, fewer moves, and lower parity increases the probability of a viable birth. Likewise, gestation length was positively related to contact with the sire and other pregnant females, number of
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moves, and dam age. Sire presence was the single most important factor in nearly all measures of reproductive outcome. In the sheep, stressful conditions during labor Že.g. presence of observers, unfamiliar sounds. can delay the birth process w16x. Hence, the hypothesis is formed that stress reactions can negatively influence human fetal development and the progress of labor is indeed plausible. To understand the possible biological pathways involved requires an understanding of the pathophysiology of stress.
4. Pathophysiology of stress Exposure to stressful conditions can have adverse effects through two basic mechanisms: direct effects on the hormonal or neuroendocrine axis; and by promoting harmful behaviors such as smoking, alcohol and substance abuse. The latter are renowned for their negative effects on pregnancy outcome w17,18x. 4.1. Hormonal pathways It has been proposed that, depending on the individual, a stressful situation may evoke one of two reactions: fight᎐flight, or conservation᎐ withdrawal w19x. If the situation is perceived as being beyond the individual’s control, the release of corticosteroids is stimulated; whereas if it is controllable, a release of epinephrine and norepinephrine is triggered. Strong emotions may be sufficiently powerful to override the neuroendocrine feedback controls that, in normal conditions, maintain homeostasis and pathophysiological processes. In rhesus monkeys w20x adrenaline and noradrenaline decrease the blood flow to the uterus, resulting in fetal hypoxia, hypotension, and bradycardia. In other species, the effects vary from bradycardia and fetal hypoxia, to a variety of malformations w21x. The mechanism of labor is of paramount interest to workers concerned with preterm delivery and termination of pregnancy. Factors regulating its onset are poorly understood, and appear to be related to hormonal changes, including progesta-
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gens, prostaglandins, cortisol and oxytocin. The secretion of these hormones can be influenced by stressful stimuli w21x. Sensitivity to oxytocin is higher in women who deliver preterm than in those that deliver at term, and this suggests that this hormone plays an important role w22x. The increased sensitivity is due to an increased density of oxytocin receptors rather than increased circulating oxytocin w23x. 4.2. Immunological factors Psychological factors can have an influence on the immune system via hormonal and neuronal pathways. Increases in catecholamines or cortisol can suppress immune processes and may also rapidly change the numbers of lymphocytes via redistribution in the circulation w24x. Furthermore, neuropeptides such as beta-endorphin ᎏ itself sensitive to stress w25x ᎏ are known to mediate increases in natural killer cell activity ŽNKCA.. Exposure to chronic stressful situations Žsuch as examination periods and bereavement. has been shown to result in decreased NKCA w24x. Furthermore, the hypothalamus can exert direct neuronal influences on the immune system, by-passing hormonal pathways w26x. The immune system could influence pregnancy outcome by increasing the risk of preterm labor. It is well established that chronic stress leads to increased vulnerability to infectious diseases w27,28x, which may account for a substantial proportion of preterm labors. It is plausible that psychological stress increases the susceptibility to infections such as chorioamnionitis, and thus induces preterm rupture of membranes.
5. Effects of stress on human pregnancy The pregnant state not only renders a woman more vulnerable to a variety of biological threats, but also to psychological stress. In a review by Levin and DeFrank w29x it was suggested that experiencing stressful events is predictive of preterm delivery and antepartum complications and that anxiety is linked to both antepartum and intrapartum complications. A direct demonstra-
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tion of possible biological pathways was presented in a recent study by Teixeira et al. w30x on 100 women undergoing ultrasonography at approximately 32 weeks. It was shown that both state anxiety and trait anxiety were significantly correlated with adverse changes in the Doppler indices of uterine blood flow. 5.1. Preterm labor Most studies that have examined the relation between psychosocial factors and preterm labor have reported positive associations w31᎐34x. Major life events appear more common in pregnancies that result in preterm delivery. In the study by Pritchard and Teo w32x, it was found that chronic stressor exposure may also be an important determinant. They found a strong correlation between experiencing high levels of difficulty with the household at 20 weeks gestation and preterm delivery. A limited number of studies have been published on the possible link between anxiety and preterm birth. Levi et al. w35x found a negative association between trait anxiety and the duration of pregnancy, but could not show an increase in preterm birth in his group. In a prospective study w36x, state anxiety appeared to be unrelated to pregnancy complications, including preterm labor. In contrast, Omer et al. w37x presented evidence that state anxiety was more prevalent in a group with threatened preterm labor or preterm delivery than in a group with full term labor. These contradicting findings may be attributed to differences in methodology. In order to obtain a reliable picture of the influence of psychosocial factors on preterm labor, it is important to study prospectively the psychosocial and background variables in a large number of pregnancies. Such a project was carried out by Hedegaard et al. w34x. They reported a dose᎐response relation between stressor exposure, as assessed in the 30th week of pregnancy, and risk of preterm delivery. Of interest in this study is that the same factors, when measured in the 16th week of pregnancy, did not appear related to preterm delivery. The effect of stress has been linked to elevated
maternal plasma CRH levels. In a prospective case controlled study, Hobel et al. w38x found that mothers from varied socioeconomic strata who had preterm delivery had significantly higher plasma CRH and ACTH levels than did control subjects at all gestational ages examined. It was concluded that activation of the placental maternal pituitary adrenal axis is consistent with the classic endocrine response to stress. 5.2. Complications during labor and deli¨ ery A wide variety of intrapartum complications have been studied in relation to psychosocial factors, with most studies reporting significant correlations between psychosocial factors and intrapartum problems. Prolonged labor and inadequate uterine activity, secondary to stress or other emotional upheavals, have been documented in animal studies and reported for pregnant women in ancient texts w16x. Lederman et al. w39x studied adrenaline blood levels and self reported anxiety amongst women in labor. These variables were found to be positively correlated. High levels of anxiety and adrenaline were associated with a marked decrease in uterine activity, particularly in the second stage of labor. However, this was followed by a rebound effect leading to a pronounced increase in uterine activity at a later stage. 5.3. Birth weight The use of low birth weight ŽF 2500 g. as a marker of adverse outcome is rather nonspecific, as it can result from either preterm delivery Ž- 37 weeks., fetal growth restriction, or a combination of both w40x. Yet birth weight is one of the most important measures we have of the health status of a population, being a strong predictor of both mortality and morbidity, and reflecting nutritional status and growth rates. Neonatal size can be influenced by a large number of variables. Kramer w41x, in a lengthy review on low birth weight, listed 43 potential causes, subdivided into seven groups, while admitting that his literature search may not have been complete. Known pathological factors that may depress birth weight include hypertensive disease, chronic maternal illness, maternal
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addictions, high altitude, malnutrition, placental disorders, infection, and chromosomal defects. Physiological variables include maternal height and weight, parity, ethnic group and sex of the baby w18x. Given the nonspecific nature of birth weight as an outcome variable, it is not surprising that reports have been conflicting. Some studies found a negative correlation between birth weight and maternal exposure to stress, anxiety and excessive work load, whereas others found none. Only a few studies w42᎐44x have controlled birth weight for maternal characteristics such as height and weight, parity, gestational age, gender of the newborn, and smoking; all of which can have significant effects on birth weight. Most investigators have focused on exposure to stressful life events w42,45,46x or chronic stress w47x. A few have performed studies combining anxiety and stressor exposure w31,48x. The association between psychosocial factors and birth weight is strongest in multivariate models, when several factors are combined such as exposure to stressors, level of social support, risk behavior and anxiety w31,43,44,49x. On a large scale, in a prospective study among clerical female workers in Denmark w13x, the level of control in work situations was examined in relation to pregnancy outcome. Odds ratios for low birth weight were found to be significantly higher among those women working in jobs characterized by high demands and low control. The high odds ratios for light-for-date birth weight were statistically significant, and remained so even after replacement of the self reported soft data on job stress by more hard data based on occupational title. In another report w32x, a strong association between high levels of perceived difficulty with household duties and low birth weight was observed even after smoking had been controlled for.
6. Benefits of social intervention While it is clear that extreme socioeconomic deprivation is a main determinant of maternal mortality in developing countries w50x, there is
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still controversy as to whether social or psychological support measures have beneficial effects on pregnancy outcome in more developed countries. The type of interventions that have been studied can be divided into two broad categories: Ž1. relaxation techniques; and Ž2. psychosocial counselling. In pioneering studies, hypnosis was used in Russia for the prevention of preterm birth with some promising results w37x, but there was too little information available for detailed evaluation. Papiernik w51x was one of the earliest advocates of a comprehensive social intervention program, specifically to reduce preterm delivery, and data from historical controls did support his approach. In contrast, at least three large studies have shown that social support provided by family workers who regularly visited women at home did not have a positive influence on birth weight w52᎐54x. A possible confounding factor could be patient selection. In recent work on selected high risk patients such as drug abusers w55x or unmarried teenagers w56x, social or psychological support did result in significant reduction of preterm delivery rates. There is a stronger case for the beneficial effect of psychological support during labor and delivery. Sosa et al. w57x, working in Guatemala, investigated the effects of a supportive lay woman on the length of labor in healthy primigravidae. The local hospital policies did not allow any relatives, friends, or nurse caretakers to be present in the labor ward, due to limited space and facilities. It was found that the duration of labor was shorter in the supported groups than in the control groups, with more mother᎐infant interactions observed. In similar studies, Klaus et al. w58x and Kennell et al. w59x found fewer perinatal complications in the supported groups as compared with the controls. A possible explanation is that a supportive companion may reduce circulating catecholamines by decreasing maternal anxiety, thus improving uterine contractility and perfusion. In terms of reducing maternal mortality and morbidity in developing countries, the provision of transport, healthcare facilities and education are probably the most urgent and effective inter-
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ventions w50x. The implementation of these measures is, however, strongly dependent on the integrity of the local political leadership and medical establishment.
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7. Conclusions Animal and human studies have provided strong evidence that maternal psychological disturbances can affect several pregnancy outcome measures such as fetal growth, preterm labor and intrapartum performance. Intrauterine growth patterns and birth weight have been linked to an increased risk of coronary disease and diabetes in adulthood. Intervention measures such as psychological support appear most beneficial in the intrapartum period rather than in the antenatal period. Social intervention in the antenatal period is most likely to be effective at the level of provision of services and education. Improving the social status of women is a key objective, given that in developing countries they still suffer from gross discrimination and inferior social standing. This, together with improved levels of education, should also lead, in the long term, to a reduction in unwanted pregnancies and a fall in overall fertility rate.
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and susceptibility to the common cold. N Eng J Med 1991;325:606᎐612. Jabaaj L, Grosheide PM, Heijtink RA, Duivenvoorden HJ, Ballieux RE, Vingerhoets AJJM. Influence of perceived psychological stress and distress on antibody response to low dose rDNA Hepatitis B vaccine. J Psychosom Res 1993;37:361᎐369. Levin JS, Defrank RS. Maternal stress and pregnancy outcome: a review of the psychosocial literature. J Psychosom Obstet Gynaecol 1988;9:3᎐16. Teixeira JMA, Fisk NM, Glover V. Association between maternal anxiety in pregnancy and increased uterine artery resistance index: cohort based study. Br Med J 1999;318:153᎐157. Lobel M, Dunkel-Schetter C, Scrimshaw SCM. Prenatal maternal stress and prematurity: a prospective study of socioeconomically disadvantaged women. Health Psychol 1992;11:32᎐40. Pritchard CW, Teo PYK. Preterm birth, low birth weight and the stressfulness of the household role for the pregnant women. Soc Sci Med 1994;38:89᎐96. Gunter LM. Psychopathology and stress in the life experience of mothers of premature infants. Am J Obstet Gynaecol 1963;86:405᎐420. Hedegaard M, Brink Henriksen T, Sabroe S, Secher NJ. Psychological distress in pregnancy and preterm delivery. Br Med J 1993;307:234᎐239. Levi R, Lundberg U, Hanson U, Frankenhauser M. Anxiety during pregnancy after the Chernobyl accident as related to obstetric outcome. J Psychosom Obstet Gynaecol 1989;10:221᎐230. Norbeck JS, Tilden VP. Life stress, social support, and emotional disequilibrium in complications of pregnancy: a prospective, multivariate study. J Health Soc Behav 1983;24:30᎐46. Omer H, Elizur Y, Barnea T, Friedlander D, Palti Z. Psychological variables and premature labor: a possible solution for some methodological problems. J Psychosom Res 1986;30:559᎐565. Hobel CJ, Dunkel-Schetter C, Roesch SC, Castro LC, Arora CP. Maternal plasma corticotropin-releasing hormone associated with stress at 20 weeks gestation in pregnancies ending in preterm delivery. Am J Obstet Gynecol ;180 1999;Ž1 Pt 3.:S257᎐263. Lederman RP, Lederman E, Work BA, McCann DS. The relationship of maternal anxiety, plasma catecholamines and plasma cortisol to progress in labor. Am J Obstet Gynaecol 1978;132:495᎐500. Gardosi J, Mongelli M, Mul T. ‘Intrauterine growth retardation’ In: Steegers EAP, Eskes TKAB, Symonds EM, editors. Preventive Care in Obstetrics and Gynaecology. Bailliere’s Clinical Obstetrics and Gynaecology, 9Ž3.:445᎐463. Kramer MS. Determinants of low birth weight: methodological assessment and meta-analysis. Bull WHO 1987;65Ž5.:663᎐737.
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w42x Brooke OG, Anderson HR, Bland JM, Peacock JL, Stewart CM. Effects on birth weight of smoking, alcohol, caffeine, socioeconomic factors, and psychological stress. Br Med J 1989;298:795᎐801. w43x Reeb KG, Graham AV, Zyzanski SJ, Kitson GC. Predicting low birth weight and complicated labor in urban black women: a biopsychological perspective. Soc Sci Med 1990;30:597᎐604. w44x Mutale T, Creed F, Maresh M, Hunt LP. Life events and low birth weight ᎏ analysis by infants preterm and small for gestational age. Br J Obstet Gynaecol 1991;98:166᎐172. w45x Aurelius G, Radestad A, Nylander I, Zetterstrom R. Psychosocial factors and pregnancy outcome. Part two of a prospective longitudinal study of children in a New Stockholm Suburb. Scand J Soc Med 1987;15:79᎐85. w46x Newton RW, Hunt LP. Psychosocial stress in pregnancy and in relation to low birth weight. Br Med J 1984; 288:1191᎐1194. w47x Aarts MCG, Vingerhoets AJJM. Psychosocial factors and intrauterine fetal growth: a prospective study. J Psychosom Obstet Gynaecol 1993;14:249᎐258. w48x Wadhwa PD, Sandman CA, Porto M, Dunkel-Schetter C, Garite TJ. The association between prenatal stress and infant birth weight and gestational age at birth: a prospective investigation. Am J Obstet Gynecol 1993;169:858᎐865. w49x Cliver SP, Goldenberg RL, Cutter GR et al. The relationships among psychosocial profile, maternal size, and smoking in predicting fetal growth retardation. Obstet Gynecol 1992;80:262᎐267. w50x Viegas OAC, Singh K, Ratnam SS. Magnitude and causes of maternal mortality as a basis for its prevention. In: Proceedings: Third International Congress for Maternal and Neonatal Health, 1987 Lahore, Pakistan, p. 80᎐90 w51x Papiernik E, Grange G. Prenatal screening with evaluated high risk scores. J Perinat Med 1999;27Ž1.:21᎐25. w52x Villar J, Farnot U, Barros F, Victora C, Langer A, Belizan JM. A randomized trial of psychosocial support during high-risk pregnancies. N Eng J Med 1992; 327:1266᎐1271. w53x Spencer B, Thomas H, Morris J. A randomised controlled trial of the provision of a social support service during pregnancy. Br J Obstet Gynaecol 1989;96: 281᎐288. w54x Heins HC, Nance NW, Efird CM. A randomised trial of nurse-midwifery prenatal care to reduce low birth weight. Obstet Gynaecol 1990:341᎐345. w55x Kukko H, Halmesmaki E. Prenatal care and counseling of female drug-abusers: effects on drug abuse and perinatal outcome. Acta Obstet Gynecol Scand Jan 1999;78Ž1.:22᎐26. w56x Rogers MM, Peoples-Sheps MD, Suchindran C. Impact of a social support program on teenage prenatal care
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use and pregnancy outcomes. J Adolesc Health 1996;19Ž2.:132᎐140. w57x Sosa R, Kennel JH, Klaus MH, Robertson SS, Urrutia J. The effect of a supportive companion on perinatal problems, length of labour and mother᎐infant interaction. N Eng J Med 1980;303:597᎐600. w58x Klaus MH, Kennel JH, Robertson SS, Sosa R. Effects of
social support during parturition on maternal and infant morbidity. Br Med J 1986;293:585᎐587. w59x Kennel JH, Klaus MH, McGrath S, Robertson SS, Hinkley C. Continuous emotional support during labour in a US hospital. A randomised controlled trial. J Am Med Assoc 1991;265:2197᎐2201.
Sociobiological variables and pregnancy outcome R.L. Tambyrajia, M. MongelliU Department of Obstetrics and Gynecology, National Uni¨ ersity of Singapore, Singapore
Abstract Recent advances are beginning to shed light on the mechanisms whereby adverse psychosocial factors can influence pregnancy outcome. High levels of maternal stress have been linked to endocrine disturbances, which in turn increases the risk of preterm labor considerably. These observations have been supported by experimental animal models. Birth weight is subject to considerable ethnic variation, and on its own is a nonspecific indicator of pregnancy outcome. The benefits of social and psychological intervention have been best documented in the intrapartum situation, whereas antenatal intervention is most likely to be of benefit when focused on improving socioeconomic conditions and access to healthcare providers. 䊚 2000 International Federation of Gynecology and Obstetrics. Keywords: Pregnancy; Preterm labor; Social variables; Maternal stress
1. Introduction Poor pregnancy outcome is often linked to a constellation of adverse social circumstances, and of these, stress is the strongest predictor in developed countries. In developing countries, the lack of facilities, poverty and the poor organization of care compound other social problems, thus result-
U
Department of Obstetrics and Gynecology, National University Hospital, Singapore 119074, Singapore. Tel.: q657724277; fax: q65-7794753. E-mail address: [email protected] ŽR.L. Tambyrajia..
ing in high maternal and perinatal mortality and morbidity. Anxiety about the development of the fetus and the wish to optimize pregnancy outcome are universal, deep rooted human emotions, and have been documented since antiquity. Within each culture, one will find sets of beliefs regarding what a pregnant woman should avoid or actively pursue to improve the outcome w1,2x. With the current scientific focus mainly on the recent spectacular advances in molecular biology, there is a real risk that the power of adverse psychosocial factors may be underestimated. Pregnancy and birth complications lend them-
0020-7292r00r$20.00 䊚 2000 International Federation of Gynecology and Obstetrics. PII: S 0 0 2 0 - 7 2 9 2 Ž 0 0 . 0 0 2 2 6 - 5
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selves very well to the application of prospective designs, since variables such as ethnic group, birth weight, Apgar scores and umbilical blood gases are usually well documented. The importance of these outcome measures has been highlighted in the recent work by Barker et al. w3x. Their studies suggest that the intrauterine environment may have long term implications on adult health, including common conditions such hypertension and diabetes. In this paper we will review and discuss issues related to the question of whether psychosocial and ethnic factors affect fetal development and birth processes. To achieve this objective, we will assess the experimental evidence from animal research, human observational studies and human interventional studies.
Ž- 2500 g. is significantly smaller w9x, with both groups living in similar socioeconomic conditions and with total healthcare coverage. Similarly, Californian black babies under 3001 g have much lower mortality rates than whites, even though their birth weights are lower w10x. These ethnic variations in fetal growth patterns are detectable in utero from early in the third trimester by ultrasound biometry w11x. Similar influences can be attributed to other maternal characteristics such as maternal weight, height and parity w11x. It is apparent, therefore, that in the clinical assessment of fetal growth, these ethnic differences in fetal growth need to be accounted for.
3. Stress and perinatal outcome: experimental studies 2. Birth weight and ethnic group An extensive description of the variations in birth weight among different ethnic groups was published by Meredith in 1970 w4x. Of the 78 groups considered, the largest newborns were found in Anguilla and Nevis, weighing a mean of 3.88 kg. The smallest babies were those of the Lumi tribe in the Toricelli mountains in New Guinea, with a mean birth weight of 2.4 kg. The extreme variations in birth weight noted in this survey are clearly not entirely attributable to race, with social, geographic and nutritional factors also being possible contributors. Maternal nutrition does not materially affect fetal growth unless extreme deprivation occurs. Babies born at high altitudes are more likely to be lighter and preterm than those born at sea level w5x. Ethnic differences clearly persist in mixed populations from the same location w6,7x, suggesting true genetic differences. In California, large differences in birth weight were shown to be present between different ethnic groups, even after controlling for 22 different physiological and pathological factors w8x. Birth weight variations do not always correlate with trends in perinatal mortality. In Singapore, Malay babies have a much higher perinatal mortality than Indian babies, even though their percentage of low birth weight
There is strong experimental evidence from animal research in various species that maternal exposure to stressful conditions has adverse effects on the offspring w12,13x. Well known stressors such as immobilization, noise, unexpected handling or crowding have resulted in smaller litter size, lower birth weights, increased incidence of malformations, and growth retardation. Most of this research has been performed in rodents and whether these are adequate models for the study of effects on human fetal development remains uncertain. In view of the longer gestation, usually with a single fetus, primates have better in utero protection than rodents. For example, in primates, maternal protein deficiency does not lead to growth retardation and learning difficulties in their offspring, as it does in rodents. However, studies in various monkey species have shown that exposure to stressful events can result in a variety of complications, such as abortion, low birth weight, and a poorly developed placenta w14x. In a recent large retrospective study of pigtailed macaques by Ha et al. w15x, it was found that the presence of the sire and other pregnant females, fewer moves, and lower parity increases the probability of a viable birth. Likewise, gestation length was positively related to contact with the sire and other pregnant females, number of
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moves, and dam age. Sire presence was the single most important factor in nearly all measures of reproductive outcome. In the sheep, stressful conditions during labor Že.g. presence of observers, unfamiliar sounds. can delay the birth process w16x. Hence, the hypothesis is formed that stress reactions can negatively influence human fetal development and the progress of labor is indeed plausible. To understand the possible biological pathways involved requires an understanding of the pathophysiology of stress.
4. Pathophysiology of stress Exposure to stressful conditions can have adverse effects through two basic mechanisms: direct effects on the hormonal or neuroendocrine axis; and by promoting harmful behaviors such as smoking, alcohol and substance abuse. The latter are renowned for their negative effects on pregnancy outcome w17,18x. 4.1. Hormonal pathways It has been proposed that, depending on the individual, a stressful situation may evoke one of two reactions: fight᎐flight, or conservation᎐ withdrawal w19x. If the situation is perceived as being beyond the individual’s control, the release of corticosteroids is stimulated; whereas if it is controllable, a release of epinephrine and norepinephrine is triggered. Strong emotions may be sufficiently powerful to override the neuroendocrine feedback controls that, in normal conditions, maintain homeostasis and pathophysiological processes. In rhesus monkeys w20x adrenaline and noradrenaline decrease the blood flow to the uterus, resulting in fetal hypoxia, hypotension, and bradycardia. In other species, the effects vary from bradycardia and fetal hypoxia, to a variety of malformations w21x. The mechanism of labor is of paramount interest to workers concerned with preterm delivery and termination of pregnancy. Factors regulating its onset are poorly understood, and appear to be related to hormonal changes, including progesta-
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gens, prostaglandins, cortisol and oxytocin. The secretion of these hormones can be influenced by stressful stimuli w21x. Sensitivity to oxytocin is higher in women who deliver preterm than in those that deliver at term, and this suggests that this hormone plays an important role w22x. The increased sensitivity is due to an increased density of oxytocin receptors rather than increased circulating oxytocin w23x. 4.2. Immunological factors Psychological factors can have an influence on the immune system via hormonal and neuronal pathways. Increases in catecholamines or cortisol can suppress immune processes and may also rapidly change the numbers of lymphocytes via redistribution in the circulation w24x. Furthermore, neuropeptides such as beta-endorphin ᎏ itself sensitive to stress w25x ᎏ are known to mediate increases in natural killer cell activity ŽNKCA.. Exposure to chronic stressful situations Žsuch as examination periods and bereavement. has been shown to result in decreased NKCA w24x. Furthermore, the hypothalamus can exert direct neuronal influences on the immune system, by-passing hormonal pathways w26x. The immune system could influence pregnancy outcome by increasing the risk of preterm labor. It is well established that chronic stress leads to increased vulnerability to infectious diseases w27,28x, which may account for a substantial proportion of preterm labors. It is plausible that psychological stress increases the susceptibility to infections such as chorioamnionitis, and thus induces preterm rupture of membranes.
5. Effects of stress on human pregnancy The pregnant state not only renders a woman more vulnerable to a variety of biological threats, but also to psychological stress. In a review by Levin and DeFrank w29x it was suggested that experiencing stressful events is predictive of preterm delivery and antepartum complications and that anxiety is linked to both antepartum and intrapartum complications. A direct demonstra-
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tion of possible biological pathways was presented in a recent study by Teixeira et al. w30x on 100 women undergoing ultrasonography at approximately 32 weeks. It was shown that both state anxiety and trait anxiety were significantly correlated with adverse changes in the Doppler indices of uterine blood flow. 5.1. Preterm labor Most studies that have examined the relation between psychosocial factors and preterm labor have reported positive associations w31᎐34x. Major life events appear more common in pregnancies that result in preterm delivery. In the study by Pritchard and Teo w32x, it was found that chronic stressor exposure may also be an important determinant. They found a strong correlation between experiencing high levels of difficulty with the household at 20 weeks gestation and preterm delivery. A limited number of studies have been published on the possible link between anxiety and preterm birth. Levi et al. w35x found a negative association between trait anxiety and the duration of pregnancy, but could not show an increase in preterm birth in his group. In a prospective study w36x, state anxiety appeared to be unrelated to pregnancy complications, including preterm labor. In contrast, Omer et al. w37x presented evidence that state anxiety was more prevalent in a group with threatened preterm labor or preterm delivery than in a group with full term labor. These contradicting findings may be attributed to differences in methodology. In order to obtain a reliable picture of the influence of psychosocial factors on preterm labor, it is important to study prospectively the psychosocial and background variables in a large number of pregnancies. Such a project was carried out by Hedegaard et al. w34x. They reported a dose᎐response relation between stressor exposure, as assessed in the 30th week of pregnancy, and risk of preterm delivery. Of interest in this study is that the same factors, when measured in the 16th week of pregnancy, did not appear related to preterm delivery. The effect of stress has been linked to elevated
maternal plasma CRH levels. In a prospective case controlled study, Hobel et al. w38x found that mothers from varied socioeconomic strata who had preterm delivery had significantly higher plasma CRH and ACTH levels than did control subjects at all gestational ages examined. It was concluded that activation of the placental maternal pituitary adrenal axis is consistent with the classic endocrine response to stress. 5.2. Complications during labor and deli¨ ery A wide variety of intrapartum complications have been studied in relation to psychosocial factors, with most studies reporting significant correlations between psychosocial factors and intrapartum problems. Prolonged labor and inadequate uterine activity, secondary to stress or other emotional upheavals, have been documented in animal studies and reported for pregnant women in ancient texts w16x. Lederman et al. w39x studied adrenaline blood levels and self reported anxiety amongst women in labor. These variables were found to be positively correlated. High levels of anxiety and adrenaline were associated with a marked decrease in uterine activity, particularly in the second stage of labor. However, this was followed by a rebound effect leading to a pronounced increase in uterine activity at a later stage. 5.3. Birth weight The use of low birth weight ŽF 2500 g. as a marker of adverse outcome is rather nonspecific, as it can result from either preterm delivery Ž- 37 weeks., fetal growth restriction, or a combination of both w40x. Yet birth weight is one of the most important measures we have of the health status of a population, being a strong predictor of both mortality and morbidity, and reflecting nutritional status and growth rates. Neonatal size can be influenced by a large number of variables. Kramer w41x, in a lengthy review on low birth weight, listed 43 potential causes, subdivided into seven groups, while admitting that his literature search may not have been complete. Known pathological factors that may depress birth weight include hypertensive disease, chronic maternal illness, maternal
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addictions, high altitude, malnutrition, placental disorders, infection, and chromosomal defects. Physiological variables include maternal height and weight, parity, ethnic group and sex of the baby w18x. Given the nonspecific nature of birth weight as an outcome variable, it is not surprising that reports have been conflicting. Some studies found a negative correlation between birth weight and maternal exposure to stress, anxiety and excessive work load, whereas others found none. Only a few studies w42᎐44x have controlled birth weight for maternal characteristics such as height and weight, parity, gestational age, gender of the newborn, and smoking; all of which can have significant effects on birth weight. Most investigators have focused on exposure to stressful life events w42,45,46x or chronic stress w47x. A few have performed studies combining anxiety and stressor exposure w31,48x. The association between psychosocial factors and birth weight is strongest in multivariate models, when several factors are combined such as exposure to stressors, level of social support, risk behavior and anxiety w31,43,44,49x. On a large scale, in a prospective study among clerical female workers in Denmark w13x, the level of control in work situations was examined in relation to pregnancy outcome. Odds ratios for low birth weight were found to be significantly higher among those women working in jobs characterized by high demands and low control. The high odds ratios for light-for-date birth weight were statistically significant, and remained so even after replacement of the self reported soft data on job stress by more hard data based on occupational title. In another report w32x, a strong association between high levels of perceived difficulty with household duties and low birth weight was observed even after smoking had been controlled for.
6. Benefits of social intervention While it is clear that extreme socioeconomic deprivation is a main determinant of maternal mortality in developing countries w50x, there is
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still controversy as to whether social or psychological support measures have beneficial effects on pregnancy outcome in more developed countries. The type of interventions that have been studied can be divided into two broad categories: Ž1. relaxation techniques; and Ž2. psychosocial counselling. In pioneering studies, hypnosis was used in Russia for the prevention of preterm birth with some promising results w37x, but there was too little information available for detailed evaluation. Papiernik w51x was one of the earliest advocates of a comprehensive social intervention program, specifically to reduce preterm delivery, and data from historical controls did support his approach. In contrast, at least three large studies have shown that social support provided by family workers who regularly visited women at home did not have a positive influence on birth weight w52᎐54x. A possible confounding factor could be patient selection. In recent work on selected high risk patients such as drug abusers w55x or unmarried teenagers w56x, social or psychological support did result in significant reduction of preterm delivery rates. There is a stronger case for the beneficial effect of psychological support during labor and delivery. Sosa et al. w57x, working in Guatemala, investigated the effects of a supportive lay woman on the length of labor in healthy primigravidae. The local hospital policies did not allow any relatives, friends, or nurse caretakers to be present in the labor ward, due to limited space and facilities. It was found that the duration of labor was shorter in the supported groups than in the control groups, with more mother᎐infant interactions observed. In similar studies, Klaus et al. w58x and Kennell et al. w59x found fewer perinatal complications in the supported groups as compared with the controls. A possible explanation is that a supportive companion may reduce circulating catecholamines by decreasing maternal anxiety, thus improving uterine contractility and perfusion. In terms of reducing maternal mortality and morbidity in developing countries, the provision of transport, healthcare facilities and education are probably the most urgent and effective inter-
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ventions w50x. The implementation of these measures is, however, strongly dependent on the integrity of the local political leadership and medical establishment.
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7. Conclusions Animal and human studies have provided strong evidence that maternal psychological disturbances can affect several pregnancy outcome measures such as fetal growth, preterm labor and intrapartum performance. Intrauterine growth patterns and birth weight have been linked to an increased risk of coronary disease and diabetes in adulthood. Intervention measures such as psychological support appear most beneficial in the intrapartum period rather than in the antenatal period. Social intervention in the antenatal period is most likely to be effective at the level of provision of services and education. Improving the social status of women is a key objective, given that in developing countries they still suffer from gross discrimination and inferior social standing. This, together with improved levels of education, should also lead, in the long term, to a reduction in unwanted pregnancies and a fall in overall fertility rate.
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w42x Brooke OG, Anderson HR, Bland JM, Peacock JL, Stewart CM. Effects on birth weight of smoking, alcohol, caffeine, socioeconomic factors, and psychological stress. Br Med J 1989;298:795᎐801. w43x Reeb KG, Graham AV, Zyzanski SJ, Kitson GC. Predicting low birth weight and complicated labor in urban black women: a biopsychological perspective. Soc Sci Med 1990;30:597᎐604. w44x Mutale T, Creed F, Maresh M, Hunt LP. Life events and low birth weight ᎏ analysis by infants preterm and small for gestational age. Br J Obstet Gynaecol 1991;98:166᎐172. w45x Aurelius G, Radestad A, Nylander I, Zetterstrom R. Psychosocial factors and pregnancy outcome. Part two of a prospective longitudinal study of children in a New Stockholm Suburb. Scand J Soc Med 1987;15:79᎐85. w46x Newton RW, Hunt LP. Psychosocial stress in pregnancy and in relation to low birth weight. Br Med J 1984; 288:1191᎐1194. w47x Aarts MCG, Vingerhoets AJJM. Psychosocial factors and intrauterine fetal growth: a prospective study. J Psychosom Obstet Gynaecol 1993;14:249᎐258. w48x Wadhwa PD, Sandman CA, Porto M, Dunkel-Schetter C, Garite TJ. The association between prenatal stress and infant birth weight and gestational age at birth: a prospective investigation. Am J Obstet Gynecol 1993;169:858᎐865. w49x Cliver SP, Goldenberg RL, Cutter GR et al. The relationships among psychosocial profile, maternal size, and smoking in predicting fetal growth retardation. Obstet Gynecol 1992;80:262᎐267. w50x Viegas OAC, Singh K, Ratnam SS. Magnitude and causes of maternal mortality as a basis for its prevention. In: Proceedings: Third International Congress for Maternal and Neonatal Health, 1987 Lahore, Pakistan, p. 80᎐90 w51x Papiernik E, Grange G. Prenatal screening with evaluated high risk scores. J Perinat Med 1999;27Ž1.:21᎐25. w52x Villar J, Farnot U, Barros F, Victora C, Langer A, Belizan JM. A randomized trial of psychosocial support during high-risk pregnancies. N Eng J Med 1992; 327:1266᎐1271. w53x Spencer B, Thomas H, Morris J. A randomised controlled trial of the provision of a social support service during pregnancy. Br J Obstet Gynaecol 1989;96: 281᎐288. w54x Heins HC, Nance NW, Efird CM. A randomised trial of nurse-midwifery prenatal care to reduce low birth weight. Obstet Gynaecol 1990:341᎐345. w55x Kukko H, Halmesmaki E. Prenatal care and counseling of female drug-abusers: effects on drug abuse and perinatal outcome. Acta Obstet Gynecol Scand Jan 1999;78Ž1.:22᎐26. w56x Rogers MM, Peoples-Sheps MD, Suchindran C. Impact of a social support program on teenage prenatal care
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social support during parturition on maternal and infant morbidity. Br Med J 1986;293:585᎐587. w59x Kennel JH, Klaus MH, McGrath S, Robertson SS, Hinkley C. Continuous emotional support during labour in a US hospital. A randomised controlled trial. J Am Med Assoc 1991;265:2197᎐2201.