Reduced Infant Birthweight Consequent Upon Maternal Exposure to Severe Life Events ALI S. KHASHAN, MSC,ROSEANNE MCNAMEE,PHD, KATHRYN M. ABEL, MRCP, MRCPSYCH,PHD, MARIANNE G. PEDERSEN, MSC,ROGER T. WEBB,PHD, LOUISE C. KENNY,PHD, MRCOG, PREBEN BO MORTENSEN, MD, DMSC, AND PHILIP N. BAKER, DM, FRCOG Objective: To investigate the association between maternal exposure to severe life events and fetal growth (birthweight and small for gestational age). Stress has been associated with adverse pregnancy outcome. Methods: Mothers of 1.38 million singleton live births in Denmark between January 1, 1979 and December 31, 2002 were linked to information on their spouses, parents, siblings, and older children. Exposure was defined as death or serious illness in a relative during pregnancy or in the 6 months before conception. Linear regression was used to examine the effect of exposure on birthweight. Log-linear binomial regression was used to assess the effect of exposure on small for gestational age. Results: Death of a relative during pregnancy or in the 6 months before conception reduced birthweight by 27 g (adjusted estimate -27 g, 95% Confidence Interval (CI) =-33, -22). There was a significant association between maternal exposure to death of a relative and risk of a baby weighing below the 10th percentile (adjusted relative risk (RR) = 1.17, 95% CI = 1.13, 1.22) and 5th percentile (adjusted RR = 1.22, 95% CI = 1.15, 1.29). Conclusions: Mothers exposed to severe life events before conception or during pregnancy have babies with significantly lower birthweight. If this association is causal, the potential mechanisms of stress-related effects on birthweight include changes in lifestyle due to the exposure and stress-related dysregulation of the hypothalamic-pituitary-adrenal axis during pregnancy. Key words: stress, pregnancy, birthweight, small for gestational age, severe life events. IUGR = intrauterine growth restriction; CVA = cerebrovascular accident; AMI = acute myocardial infarction; SGA = small for gestational age; VSGA = very small for gestational age; GHQ = general health questionnaire; SES = socioeconomic status. INTRODUCTION I ntrauterine growth restriction (IUGR) in which a baby fails to reach its growth potential is a serious complication of pregnancy. Perinatal mortality rates in IUGR fetuses are four to ten times higher than that of normally grown infants (1) and approximately 5% to 10% of all pregnancies complicated by IUGR will result in either stillbirth or neonatal death (2,3). Suboptimal fetal growth is responsible for at least one quarter of all stillbirths (4) and recent evidence suggests that this figure is probably higher (5). Analysis of over 23,000 fetal deaths in California on population-based percentile curves showed a strong link between low fetal weight for gestational age and fetal demise (6). Of major public concern is the long-term childhood mor- bidity for survivors of pregnancies affected by IUGR. At 2 years of age, 5% of survivors of pregnancies affected by IUGR will have cerebral palsy and this increases to 10% among survivors delivered at 30 weeks’ gestation (3). It is also well established that a hostile intrauterine environment places surviving infants at significant risk of a variety of medical problems in adulthood. Adults who were growth restricted in utero have significantly increased risks of devel- oping chronic hypertension, cardiovascular disease, including chronic hypertension and Type II diabetes (7). The idea that maternal psychosocial stress influences the unborn baby exists in all cultures (8), and previous studies have suggested an association between stress and low birth- weight (2500 g) (9). Anxiety (10), depression (11), distress (9), 9/11 attacks (12), life events (13), lifestyle (14), and work-related stress (15) are among the psychosocial stressors investigated in relationship to low birthweight. The authors of most of these studies reported that maternal exposure to psy- chosocial stress decreases birthweight significantly. Recently, Smits et al. (12) defined stress as exposure to the September 11 attacks via media reporting in a study of Dutch neonates. The authors reported around 50-g reduction in mean birth- weight of the offspring of exposed women compared with those who were unexposed. Pritchard and Teo (16) found a significant association (odds ratio = 4.08) between high levels of household strain at 20 and 30 weeks’ gestation and odds ratio of low birthweight. Karlsson et al. (17) reported a more than three-fold increased odds ratio of small for gestational age (SGA) in relation to poor social network and an almost three-fold increased odds ratio of SGA in relation to poor social support. In contrast, Homer et al. (18) found no signif- icant association between maternal work-related stress and risk of low birthweight. In another study, there was no signif- icant association between maternal exposure to life events and mean birthweight (19). Several reasons may have contributed to the inconsistent results reported from these studies, includ- ing different definitions of psychosocial stress, small sample size, and retrospective designs (20). We used the Danish national registers to investigate the association between maternal exposure to severe life events and fetal growth. We defined severe life events as the expe- rience of death or serious illness in a close relative. Bereaved persons are considered to be at risk of stress (a psychological From the Centre for Women’s Mental Health Research (A.S.K., K.M.A., R.T.W.), University of Manchester, Manchester, UK; Biostatistics Group (R.M.), University of Manchester, Manchester, UK; Maternal and Fetal Health Research Group (A.S.K., L.C.K., P.N.B.), University of Manchester, Manchester, UK; National Centre for Register-Based Research (M.G.P., P.B.M.), University of Aarhus, Aarhus, Denmark; Department of Obstetrics and Gynaecology (L.C.K.), University College Cork, Cork University Mater- nity Hospital, Cork, Ireland. Address correspondence and reprint requests to Ali Khashan, Centre for Women’s Mental Health Research, University of Manchester, Williamson Building, Oxford Road, Manchester M13 9PL, UK. E-mail: ali.khashan@ postgrad.manchester.ac.uk Supported by Tommy’s the Baby Charity (P.N.B.) and the Stanley Medical Research Institute (P.B.M.). Received for publication August 7, 2007; revision received December 5, 2007. DOI: 10.1097/PSY.0b013e318177940d 688 Psychosomatic Medicine 70:688 – 694 (2008) 0033-3174/08/7006-0688 Copyright © 2008 by the American Psychosomatic Society