Prenatal stress and affective disorders in a population birth cohort

Original ArticlePrenatal stress and affective disorders in a population birth cohortThere is increasing interest in whether the timing of maternal stress during pregnancy determines vul-nerability to specific psychiatric diseases in off-spring (1–4),but it is unclear which periods in pregnancy confer vulnerability.It is also not known whether psychosocial stress alone can increase it.Some have suggested that prenatal stress is associated with a higher risk of affective disorders,and that the timing of the stress may influence the risk for this outcome (2,4–7).The second and third trimesters and the 10weeks prior to conception have all been reported to be the critical periods (2,4–7).To address the question of the relevant timing during gestation,we analyzed data from a large birth cohort to ascertain whether women who were at a specific stage of pregnancy during a war of six days Õduration had offspring with unique incidences of hospitalization for affective disorders.We analyzed data by month of pregnancy to study the precise timing of potential disruption of fetal development.We also analyzed data by trimester so as to augment the power of our analyses by increasing the numbers of offspring exposed during each periodKleinhaus K,Harlap S,Perrin M,Manor O,Margalit-Calderon R,Opler M,Friedlander Y,Malaspina D.Prenatal stress and affective disorders in a population birth cohort.Bipolar Disord 2013:15:92–99.Ó2012John Wiley &Sons A ⁄S.Published by Blackwell Publishing Ltd.Objectives:Pregnant women exposed to an acute traumatic event are thought to produce offspring with an increased incidence of affective disorders.It is not known whether there are specific times in pregnancy which confer increased vulnerability,or if psychosocial stress alone can increase the incidence of affective disorders in offspring.We examined the relationship of the timing of an acute psychosocial threat during pregnancy to the incidence of affective disorders in offspring using data from a large birth cohort.Methods:Using data on 90079offspring born in Jerusalem in1964–1976and linked to Israel Õs psychiatric registry,we constructed proportional hazards models to evaluate the link between gestational age during the Arab–Israeli war of June 1967and incidence of mood disorders.Results:Those in their first trimester of fetal development during the war were more likely to be admitted to hospitals for any mood disorders [relative risk (RR)=3.01,95%confidence interval (CI):1.68–5.39,p =0.0002];for bipolar disorder the risk was doubled (RR =2.44,95%CI:0.996–5.99,p =0.054)and for all Ôother Õmood disorders the risk was tripled (RR =3.61,95%CI:1.68–7.80,p =0.001).Mood disorders were also increased in offspring whose mothers had been in the third month of pregnancy in June of 1967(RR =5.54,95%CI:2.73–11.24,p <0.0001).Conclusions:A time-limited exposure to a severe threat during early gestation may be associated with an increased incidence of affective disorders in offspring.The third month of fetal development was a moment of special vulnerability.Karine Kleinhaus a,b ,SusanHarlap a,b ,Mary Perrin a ,Orly Manor c ,Ronit Margalit-Calderon c ,Mark Opler a ,Yehiel Friedlander c and Dolores Malaspina aDepartments of a Psychiatry,b Obstetrics and Gynecology,New York University School of Medicine,New York,NY,USA,c Hebrew University-Hadassah Braun School of Public Health,Jerusalem,Israeldoi:10.1111/bdi.12015Key words:cohort study –mood disorders –prenatal stressReceived 8March 2012,revised and accepted for publication 1September 2012Corresponding author:Karine Kleinhaus,M.D.,M.P.H.Department of PsychiatryNew York University School of Medicine 550First Avenue New York,NY 10016USAFax:212-263-2935E-mail:kkleinhaus@Bipolar Disorders 2013:15:92–99Ó2012John Wiley and Sons A/S Published by Blackwell Publishing Ltd.BIPOLAR DISORDERS92of development;this also made it easier to compare our work with other studies.MethodsSubjectsSubjects included offspring from the Jerusalem Perinatal Study,a population-based cohort derived from all92408births in1964–1976to mothers residing in West Jerusalem(8).Details of this cohort are given elsewhere(8).The cohort has been linked with IsraelÕs population registry to trace and verify identity(ID)numbers,dates of birth and basic demographic characteristics,and to ascertain vital status and dates of death.In1999,the cohort was linked to IsraelÕs national psychiatric registry which has been run by the Ministry of Health since 1950(9).This registry contains a record of all admissions to psychiatric wards and day facilities and includes the dates of admission and discharge, plus a single discharge diagnosis for each episode assigned to a board-certified psychiatrist.These diagnoses were coded with the International Clas-sification of Diseases(ICD)and codes from previous years have been updated to reflect the 10th revision(ICD-10),and those for psychotic disorders have been recently validated(10).The cohort was re-linked with the psychiatric registry in December of2004.Nuclear families were linked within the cohort,and currently a33–41-year follow-up of offspring has been completed.This research was approved by the institutional review boards at Hebrew University,Jerusalem,and at New York University Medical Center,and exempted from the requirement for written informed consent.Operational definitionsStressor.This study relied on the Arab–Israel(ÔSix DayÕ)War of June1967as a presumed cause of acute maternal stress.As previously described(1), the tension in Israel intensified on May19,1967 when Egypt expelled United Nations peacekeeping forces from the Sinai Peninsula,and escalated until spiking with the outbreak of the conflict on June5. The conflict itself lasted from June5to June10. During thefirst two days,there was heavy shelling of Western Jerusalem(11,12).Afterwards,there were no major displacements of residents from Western Jerusalem,and no changes in their nutri-tion.As a result,this war was chiefly a severe psychological stressor,likely to have been only a few days in duration.This was especially likely because from the third day of the conflict,it became evident that the residents of Western Jerusalem would survive this assault. Psychiatric outcomes.ICD-10codes for mood disorders include diagnoses of types of manic episodes(F30),bipolar affective disorder(F31), depressive episodes(F32),recurrent depressive disorder(F33),and mood disorders that do not meet criteria for the categories of manic episode, bipolar disorder,or major depressive disorders (F34,F38and F39).For this study,we assigned a diagnosis of mood disorder to offspring who had at least one hospital episode with a discharge diag-nosis of a mood disorder(ICD-10=F30–F39) and no admission for schizophrenia(F20).In those individuals meeting these two criteria,we ignored hospital episodes with other diagnoses,including schizophrenia spectrum disorders(F21–F29)and any other conditions coded in the ICD-10:adult personality and behavior;mental retardation; organic,including symptomatic,mental disorders; mental and behavioral disorders due to psychoac-tive substance use;neurotic,stress-related,and somatoform disorders;behavioral syndromes asso-ciated with physiological disturbances and physical factors;disorders of psychological development; behavioral and emotional disorders with onset usually occurring in childhood and adolescence; and unspecified mental disorder.Within the group of mood disorders we also analyzed separately:(i) those with at least one admission for bipolar disorder,regardless of other diagnoses,and(ii) those withÔotherÕmood disorders,i.e.,offspring defined as having a mood disorder,but with no episodes for bipolar disorder.Data analysisBecause offspring were born in different years within the Jerusalem birth cohort and thus fol-lowed for different periods of time,we chose Cox proportional hazards models to analyze the effects of prenatal stress at specific times in pregnancy on the incidence of hospitalization for mood disor-ders.Each psychiatric diagnosis was coded as present or absent.The date of onset was taken as thefirst episode in the psychiatric registry,regard-less of the discharge diagnosis assigned to that episode.Time to event was handled as completed years since birth,i.e.,age,until thefirst hospital admission or death;survivors were censored on December31,2004.Ties were handled by EfronÕs method(13).Gestational month at the time of the war was calculated using date of birth.We counted back by calendar month from date of birth in orderPrenatal stress and affective disorders93to define month-long windows during pregnancy when prenatal stress occurred.We incorporated variables in thefinal model if their inclusion adjusted the crude hazards ratio for admission to hospital after prenatal stress at a specific month of gestation by more than10%,and they were also significantly associated with mood disorders in a multi-variant model.Any identified covariates were then entered into afinal model to examine the incidence of each of these outcomes in the offspring based on the timing of the Six Day War during gestation.The variables evaluated for inclusion were:sex,parental ages,parental region of birth,parental history of admission to hospital for any psychiatric illness,socioeconomic status, and secular trend.Sex was coded as male versus female.Parental ages were coded as continuous variables,in years of deviation from their means (31.5years for the father and27.6years for the mother).The motherÕs and fatherÕs ages were also each defined as a dichotomous variable (<35years old versus‡35years old)for presen-tation in the cross tabulations(Table1).Dummy variables,each variable defined as dichotomous (yes or no),were coded for paternal and maternal country of birth in Israel,North Africa,Western Asia,or Europe,and other developed countries. Maternal or paternal history of admission to hospital for a psychiatric diagnosis was coded as a dichotomous variable(yes or no).Socioeconomic status was coded as low versus medium or high. Secular trend was tested with sine and cosine transformations of time together with theirfirst harmonics;variables were coded for sine,cosine,2·sine and2·cosine.Results are given as relative risk(RR)of mood disorders,bipolar disorder,or other mood disorders,along with the 95%confidence intervals(CIs).We compared the RR for bipolar disorder to that for other mood disorders in offspring whose mothers were in their third month of pregnancy during the Six Day War in order to determine if they were significantly different.Calculations of the ratio of RR were performed using the method described by Altman and Bland(14)(a multi-step process described in detail in their paper).We used this method because one cannot assume that,when two CIs overlap,the two estimates are not significantly different(14, 15).There was no adjustment for multiple testing. We hypothesized that there would be a difference in effect on incidence according to month of gestation during which the stressor occurred because of earlierfindings regarding the incidence of schizophrenia in this cohort,mentioned above. SAS(SAS Institute Inc.,Cary,NC,USA)was used for the analyses.ResultsOf the original cohort of92408there were949 (1.0%)stillbirths and1380(1.5%)whose ID numbers could not be traced in the Population Registry,leaving90079offspring available for this study.Table1summarizes the demographic char-acteristics of the updated cohort as a whole,as well as of those offspring who were in utero during the first,second,or third trimester of gestation during the Arab–Israeli war of June1967.Table2shows the number and percent of offspring admitted to hospital for any mood disorder,bipolar disorder, other mood disorders,or schizophrenia in the Jerusalem Cohort as a whole and by trimester of exposure to the war.In the cohort there were also 89offspring admitted for organic mental disorders (F00–F09),100for mental disorders due to drug use(F10–F19),195for mental disorders due to stress(F40–F48),44for behavioral symptoms associated with physiologic disturbances(F50–F59),353offspring admitted for personality Table1.Number of offspring and percent distribution of selected variables by trimester of pregnancy in June1967TotalTrimester123(n=90079)(n=1423)(n=1409)(n=1466) SexMale51.552.849.749.4 Female48.547.250.350.6 Paternal age(years)<3570.867.069.869.0‡3529.233.030.231.0 Maternal age(years)<3586.482.385.386.4‡3513.617.714.713.6 Paternal region of birthIsrael16.917.016.816.3 North Africa20.825.021.422.8 West Asia30.531.333.432.7 Europe andother31.826.728.528.2Maternal region of birthIsrael15.615.616.015.6 North Africa22.524.622.924.6 West Asia29.333.233.333.2 Europe andother32.726.727.826.7Paternal admissionYes 1.40.50.50.7 No98.699.599.599.3 Maternal admissionYes 1.3 1.00.40.5 No98.799.099.699.5 Socioeconomic statusLow25.635.830.433.6 Medium37.432.336.937.4 High37.0032.729.1Kleinhaus et al. 94disorders(ICD-10code F60–F69),80for mental retardation(F70–F79),37for behavioral disorders childhood⁄adolescent onset(F90–F98),25for disorders pertaining to psychological development (F80–F89),and10for unspecified mental disorder (F99).Table3shows the number of offspring admitted with any mood disorders,bipolar disorders,or other mood disorders by month of exposure to the war.Evident in Table4,only those offspring whose mothers were in thefirst trimester of pregnancy during the war had a significantly increased RR for mood disorders as compared to other trimesters.For thatfirst trimester,our Cox model showed a significantly increased incidence of admission to hospital for any mood disorders (RR=3.01,95%CI: 1.68–5.39,p=0.0002), bipolar disorder(RR=2.44,95%CI:0.996–5.99,p=0.051),and other mood disorders (RR=3.61,95%CI:1.68–7.80,p=0.001)com-pared to the rest of the cohort.The RRs for our subcategories did not differ significantly from each other.Stress in either the second or third trimester was linked to a decreased incidence of all three diagnoses as seen in Table4,although none of these decreases were statistically significant.Off-spring in utero during month3of pregnancy at the time of the war subsequently experienced a very high incidence of admission for all mood disorders (RR=5.54,95%CI: 2.7–11.24,p<0.0001), bipolar disorder(RR=5.45,95%CI: 2.01–14.79,p=0.0009),and other mood disorders (RR=5.64,95%CI:2.07–15.34,p=0.0007)in comparison to other months of pregnancy;effects for these groups did not differ significantly from each other.Although thefindings for the third month are based on small numbers,we report them because they are highly significant.The RR for hospital admission for male off-spring did not differ substantially from that for female offspring for all mood disorders (RR=1.18,95%CI:0.91–1.53,p=0.21),or for bipolar disorder(RR=0.92,95%CI:0.64–1.32,p=0.66).Male offspring had only65%of the incidence in female offspring of other mood disorders(RR=0.65,95%CI:0.44–0.95, p=0.02).However,the RRs of male versus female offspring for bipolar disorder and other mood disorders did not differ significantly from each other(RR=1.04,95%CI:0.61–1.75).There were too few cases when analyzing risk by month for us to adjust our Cox models for sex,but thereTable2.Number of offspring with psychiatric diagnoses by trimester ofgestation in June1967Trimester123Offspring withAny mood disorder2311213Bipolar disorder120511Other mood disorders111702Schizophrenia56814910Other diagnoses822171322Any psychiatric admission1621432335Total no.offspring90079142314091466Table3.Number of offspring with all mood disorders,other mood disorders,and bipolar disorders in the Jerusalem Cohort and by month of gestation during the Arab–Israeli war of June1967Gestational month123456789 All mood disorders228001012 Bipolar disorder104001001 Other mood disorders104000011 Total no.offspring419498506452480477492486488Table4.Relative risk(RR),95%confidence interval(CI)and p-values for hospital admission for mood disorders according to trimester of gestation during the Arab–Israeli War of June1967Trimester during warFirst Second ThirdRR95%CI p-value RR95%CI p-value RR95%CI p-valueAny mood disorders 3.01 1.68–5.390.00020.230.33–1.670.140.690.22–2.150.52 Bipolar disorder 2.44 1.00–5.990.0540.460.07–3.330.440.450.63–3.220.42 Other mood disorders 3.61 1.68–7.800.001–––a0.940.23–3.790.94 a No admissions for other mood disorders during second trimester.Prenatal stress and affective disorders95were sufficient numbers for us to analyze incidence by trimester.Sex of offspring did not influence the relationship of trimester of stress and mood disorders(data not shown),so thefinal propor-tional hazards model for trimesters was not adjusted for sex.No other covariates that we evaluated met criteria(described above)for inclu-sion in thefinal model,including parental age, country of birth and history of hospitalization for psychiatric illness,socioeconomic status,and secular trend.DiscussionWomen in our cohort who were in theirfirst trimester of pregnancy during the Six Day War of June1967delivered children with an increased incidence of hospital admission for mood disor-ders.This effect was particularly noticeable in the offspring of those women who had been in their third month of pregnancy.The short and discrete duration of the war made residual stress in our population unlikely because relief due to IsraelÕs military victory immediately followed the war.This enabled us to pinpoint a narrow window of vulnerability.In other work the stressors studied were likely to have a chronic component so that effects of acute stress on the incidence of mood disorders would be hard to disentangle from those of ongoing stress.Our study is also distinctive because the war of1967was chiefly a psychosocial stressor unaccompanied by environmental disrup-tion or famine.In many other studies additional types of significant stress accompanied mental stress.Several researchers have reported an increase in mood disorders in offspring of mothers who experienced a stressful event in their second or third trimester.Brown et al.(16)studied the incidence of hospitalization for affective psychosis in children who had been in utero during a severe famine that occurred during the winter of1944–1945in Holland.Affective psychosis was defined as diagnostic code296in ICD-9[severe disturbances of mood(mania and⁄or depression)accompanied by mood-congruent psychotic symptoms](16).The researchers found that a severe nutritional depri-vation in the second trimester was associated with an increase in the incidence of affective psychosis in male offspring.However,a re-analysis of data from the same population,but with the addition of newly defined cases,showed that the incidence increased when famine began during the second and the third trimesters,for both sexes,and for both unipolar and bipolar affective disorders(5). This work is difficult to compare with ours because of the different definitions of outcome.Brown et al. used ICD-9codes to designate their groups for analysis;their two main groups,a priori,were affective psychosis(all296ICD-9codes)and neurotic depression(ICD-9code300.4),and these are not directly equivalent to our outcome groups. Furthermore,our cohort did not suffer significant nutritional deprivation,which triggers different physiologic responses than psychosocial stress alone.Khashan et al.(2)found that the male offspring of women who experienced death of a close relative or diagnosis of a close relative with serious disease during the second trimester had a 55%increase in the incidence of affective disorders. In that population,in contrast to ours,psychoso-cial disturbance was likely to continue after the initial event.An increase in admission to hospital for affective disorders,and especially for unipolar disease,was reported by Machon et al.(4)in a population exposed to an influenza epidemic dur-ing the second trimester of pregnancy.An infection would have affected the mother and her pregnancy differently than a purely psychosocial stress and this could account for their conflictingfindings. Although none of the RRs were significant,in our analyses prenatal stress in both the second and third trimesters was linked to slight decreases in incidence for all three diagnoses.It is interesting to note this consistent reversal of direction for the effect of prenatal stress for the second and third trimesters.We can speculate that perhaps fetuses in later stages of development react to physiologic signals of maternal psychosocial trauma in ways that differ from reactions in thefirst trimester, resulting in different effects on long-term mental health outcomes.Affective disorders are currently divided into several distinct diagnostic subgroups in the ICD-10,as noted above,and the same is true in the DSM–IV.Some consider bipolar disorder to be distinct from the other kinds of mood disorders, however,and bipolar disorders and schizophrenia are sometimes conceptualized as components of a clinical continuum with overlapping symptoms and etiologies(17).In consideration of these views we examined the subgroups of bipolar disorders and other mood disorders separately in some of our analyses.We did notfind evidence for a substantial difference in effects of stress during specific time periods on bipolar disorder as compared to other mood disorders,although the increased incidence of other mood disorders,after in utero exposure to the war in thefirst trimester,was1.5times that of the increase measured for bipolar disorders. Machon et al.(4),as noted above,reported a larger increase in unipolar depression than bipolarKleinhaus et al. 96disorder after prenatal stress.He concluded that there was a difference because one effect was significant and one was not;this approach is not necessarily definitive and statistical tests should be used to confirm this difference(14).There are several biological mechanisms that could theoretically contribute to ourfindings.One process might be the actions of elevated levels of cortisol in the developing fetal brain.Increased levels of corticosteroids are part of the stress response.When a pregnant woman experiences stress,her levels of corticosteroids rise and result in a transfer of higher than normal amounts to the fetus.Although some of the cortisol secreted by pregnant women is inactivated by11-beta-hydrox-ysteroid dehydrogenase-2(11b-HSD-2)in the placenta,some maternal cortisol crosses into the fetus(18,19).Increased levels in pregnant women are thought to cause increases in adverse neuro-behavioral outcomes in offspring(20).This is not surprising because cortisol plays an important role in maturation of the human fetal brain,and glucocorticoid receptors are present throughout the fetal brain from early in development in both humans and rodents(18).There is plentiful11b-HSD-2in the human fetal brain as well as in the placenta.11b-HSD-2 appears to be silenced during specific time periods in gestation and active in others(21),which suggests an intricate,time-specific regulation of cortisolÕs influence on neuronal development.This supports the idea of the importance of timing of increased levels of cortisol during the process of fetal development.Cortisol could also affect fetal neurodevelopment via the placenta rather than through direct action on the fetusÕcentral nervous system.Glucocorticoids have multiple actions on the placenta and fetus,each of which varies by period of gestation(18,22).Another possible mechanism is suggested by studies in fetal rats showing that early prenatal stress can reduce expression of glucocorticoid receptors in the hip-pocampus of offspring(23,24),a brain structure involved in the pathology of bipolar disorder(25, 26).Elevated cortisol during early pregnancy could also potentially affect the mother in some way so that she raises her child differently.This possibility was suggested in one animal study in which high levels of synthetic glucocorticoids were adminis-tered to pregnant rats during early pregnancy.It was found that the treated dams displayed different nursing behaviors as compared to controls(27). Epigenetic regulation of gene expression is yet another potential biological mechanism for our findings.DNA methylation has been shown to vary due to environmental factors including nutri-tion,chemical exposure or psychosocial problems (28–31).Differences in DNA methylation were also shown in adult offspring who were in utero during the Dutch famine of1944–1945.These variations were found to vary by sex of offspring and timing of the famine during gestation(32,33).DNA methylation in the central nervous system has been connected to neural development and neuropsy-chiatric disorders(34).Theoretically,changes in methylation could follow prenatal exposure to stress.All of these hypothesized mechanisms require further study.Stress,particularly during the third month,may be tied to an increased incidence of mood disorders in particular for two reasons.Firstly,during the third month of fetal development,neuroblasts that proliferated earlier begin to differentiate into spe-cific neuronal cell types or into microglia(35),and neurons that are the source of all of the GABAer-gic neurons in the mature brain migrate to the developing cerebral cortex and thalamus(35).This critical process starts and progresses throughout the third month,although these migrations peak from gestational week12to week20(35).Since disruption in GABAergic mechanisms is associated with mood disorders(36),one could hypothesize that disturbances during the third month would disrupt the migration of neurons that are the source of GABAergic neurons in the brain,thereby influencing the risk for these disorders.Secondly, the third month of gestation is a crucial period of development of portions of the brain that are directly related to affect and affective disorders. During the third and fourth months the major nuclei complete development in the limbic system (e.g.,the hippocampus and amygdala)and limbic regions of the cortex(e.g.,the anterior cingulate cortex)(37).Strengths of our study include use of data from a large population-based cohort with over three decades of follow-up,and a clear source of severe psychological stress that began and ended in a well-defined and discrete time period.In studies of longer-term stressors,such as famine within the context of a long conflict,bereavement or natural disasters,it would be difficult to disentangle the effects of the exposure to stress at a specific point in gestation from exposure to chronic stress during the rest of a pregnancy.Prenatal stress and certain outcomes may be associated due to post-natal conditions including the mental health of the mother and the environment in which the infant is raised(38).Stress during infancy has itself been shown to potentially affect risk for mood disorders later in life(39,40).Therefore,if one studies anPrenatal stress and affective disorders97ongoing stress,though it began during pregnancy its effects may be difficult to differentiate from effects of an altered environment after birth.A limitation of our study,as well as of other studies that use data from national registries for hospitalization,is that people with mood disorders do not all require hospitalization.Although Israel has a very high rate of admission to hospital for mental health conditions(41),it is likely that for some these disorders manifested prior tofirst hospitalization,and that others in the cohort were never admitted for their disorder;therefore,this study informs solely on the incidence of hospital-ization.It seems unlikely,however,that those exposed to war prenatally would be hospitalized at different rates than others in the population.In addition,any variation of incidence over time and season was considered in the analyses.Another limitation is the small numbers of cases in the cohort.Small numbers for each diagnosis in each trimester or month make it possible that we could not detect some confounders or mediators.Never-theless,despite smaller numbers in the month-by-month analyses in particular,ourfindings are highly significant.Finally,we cannot analyze data on those offspring with an older age of onset. Currently a33–41-year follow-up of offspring has been completed so that the cohort data are truncated in the late thirties.The cohort will have to mature before this question can be addressed. While completing this study we confirmed the results of earlier work that showed a link between prenatal exposure to the war of1967during early gestation and the incidence of hospitalization for schizophrenia(1).In our updated cohort,exposure to the Six Day War in the second month of gestation,as in the earlier work,was associated with a significantly increased incidence of schizo-phrenia in offspring.Here we used a narrower definition of schizophrenia(ICD-10code F20)in our models,which we will be using going forward, while the earlier work defined schizophrenia as hospitalization for any schizophrenia spectrum disorder(F20–F29).A narrower definition of schizophrenia should designate a more specific group of patients,which is likely to be more useful in studying the diseaseÕs etiology.Major depression is a leading cause of disability worldwide(42).Few genes have yet been found to explain the large proportion of the population with major depression or bipolar disorder(43–45).It has been proposed that environmental factors might interact with genetic ones to affect the risk for these diseases(46).Our work supports the hypothesis that an acutely stressful event occurring early in a womanÕs pregnancy might increase the incidence of mood disorders in her offspring. Additional research on this topic is essential because of its implications for public health.As many women continue to experience acute psycho-social traumas during pregnancy,it is necessary to understand the relationship between fetal exposure to this stress at certain points in gestation and the later risk of mood disorders as afirst step in developing interventions to reduce negative effects of traumatic events on the subsequent generation. AcknowledgementsWe acknowledge support for this project from grants K08 MH085807(KK),K07CA131094(MP),and K01MH080114 (MO),and the National Alliance for Research of Schizophre-nia and Depression(NARSAD)(DM,SH,and MP). 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