Obstetric complications in schizophrenic parents

89

Schizophrenia Research, 5 ( 199 I ) 89% IO I Elsevier

SCHIZO

00177

Review article

Obstetric

complications

in schizophrenic

parents

Thomas F. McNeil Lkparin~ent qf’Psychiatry. (Received

Univrrsit~~of Lund, Malm6, Sweden

27 November

1990, accepted

During the last decade, somatic complications occurring in the mother or offspring during pregnancy, labor delivery or the first week after delivery have received increasingly serious consideration as an etiologically relevant factor in the development of schizophrenia (McNeil, 1987; Murray et al., 1988). Much of the impetus for the scientific interest shown in this field resulted from findings obtained within studies of groups at high risk for schizophrenia, which flourished during the 1970s. In the decade that followed, a number of new studies have been published concerning the relationship between such obstetric complications (OCs) and risk for the development of schizophrenia. The purpose of the current review is to provide evidence for and conceptualizations concerning the following three questions: QUESTION 1. Are reproductions by schizophrenic parents attended by increased rates of OCs, as compared with reproductions by control parents? QUESTION 2. Is severity of parental mental illness related to the occurrence of OCs in reproductions by schizophrenic parents? QUESTION 3. Do OCs relate to the development of mental and physical abnormality among the highrisk offspring of schizophrenic parents? QUESTION PARENTS COMPARED

1. ARE REPRODUCTIONS ATTENDED WITH

BY SCHIZOPHRENIC

BY INCREASED REPRODUCTIONS

RATES OF OCS, BY

AS

CONTROL

PARENTS?

(A) Theoretical and practical relevance of question I Question 1 has been the subject of scientific inquiry with surprisingly great frequency, considering the Corwsponduzce 10: T.F. McNeil, University

of Lund.

0920-9964!9l:‘SO3.50

Malmii.

r

Department

of Psychiatry,

Sweden.

1991 Elsevier Science Publishers

B.V.

22 January

1991)

general lack of agreement about the particular relevance of the answer to this question. One can speculate about the various reasons for this interest. Mednick and Schulsinger (1968) presented exciting findings from the first Copenhagen highrisk study, in which OCs were reported to predict serious mental disturbance among their high-risk subjects and to interact with genetic risk for schizophrenia (Mednick, 1970). These results gave much impetus to the inclusion of OCs in studies of risk for schizophrenia. In the wake of Mednick and Schulsinger’s study, many new high-risk studies were initiated by other research teams (Garmezy, 1974; Rieder, 1979), and OC data were collected for many of these new samples. At the initial stage of investigation. the OC data could only be used to compare high-risk and low-risk (control) samples with each other. Furthermore, in the early 1970s comparisons of high-risk and low-risk groups were often being misinterpreted as being of great etiological interest; groups at heightened risk for schizophrenia tended to be viewed as somewhat ‘diluted’ groups of schizophrenics, and the characteristics of high-risk groups were thought to be more or less generalizable to the characteristics of schizophrenics. Some researchers thus reasoned that a significantly elevated rate of OCs among high-risk cases (vs. controls) would represent evidence that OCs cause schizophrenia, while no increase in OC rates among high-risk cases would, correspondingly, indicate that OCs do not cause schizophrenia (see, e.g., Shields and Gottesman, 1977). Such a theoretical position is illogical, and in a major review of the relationship between OCs and schizophrenia, McNeil and Kaij (1978) argued persuasively that studies of the rates of OCs in

90

reproductions by schizophrenic parents could show neither that OCs do contribute nor that OCs do not contribute to the development of schizophrenia in the offspring. To show that OCs do (not) contribute, OCs bud to he studied as antecedents to schizophrenia. In contrast, the answer to the question of whether reproductions by schizophrenic parents are attended by increased OC rates (question 1) has a number of different relevant clinical and theoretical applications: (1) at a clinical level, the answer to the question would indicate whether reproducing schizophrenics require extra obstetric attention and intervention; (2) whether reproduction by schizophrenics would be contraindicated due to an unusually high risk for OCs. endangering both the mothers and the offspring; (3) the answer might suggest whether the increased risk for mental (and possibly physical) pathology found among the offspring of schizophrenics is due at least partially to an increased frequency of OCs; (4) the etiology of schizophrenia could possibly be explained by a serendipitous finding of some special type of OC or other reproductive phenomenon (such as great deviation in offspring sex ratios or birthweights) that would be an expression of the genotype or another etiological factor in schizophrenia. Hopes of making such an etiological breakthrough are apparently still alive. and are found especially in studies concerning low birthweight and other characteristics (see e.g., Marcus et al., 1981); (5) the study of OC rates among schizophrenic parents presents the opportunity to evaluate the possible effect of environmental or mental problems on OCs, this touching upon the field of psychosomatic obstetrics; (6) moreover, one possible explanation for the association between OCs and the later development of schizophrenia, observed in many samples, is that the OCs are merely an expression of genetic influence or a secondary correlate of other parental environmental influences. If this were true, then OCs would be an epiphenomenon, rather than a primary somatic factor contributing to the development of schizophrenia. The best available strategy for testing this epiphenomenon-hypothesis is to study the rates of OCs in groups of individuals at increased genetic (and perhaps environmental) risk for schizophrenia, i.e. the offspring of schizophrenic parents (McNeil and Kaij, 1979). Such studies

thus have considerable importance for theoretical formulations of the role of OCs in the development of schizophrenia. This plethora of different interests and applications regarding the answer to question 1 places somewhat different demands on the studies, especially concerning the particular types of OCs that are most relevant for investigation. OCs that have a purely somatic flavor, that clearly have a detrimental effect on the offspring, and that could occur at least to some extent in mentally normal reproducing women are apparently relevant to most of the different applications of this research. In contrast, the inclusion of obstetric interventions (e.g., elective C sections) due to maternal mental conditions or somatically complicating influences that are clearly an expression of the mother’s schizophrenia (e.g., taking psychopharmaca during pregnancy) may be relevant to questions of schizophrenics’ effect on their offspring, but are clearly irrelevant to the question of rates of naturally occurring somatic abnormalities that might be an expression of genetic or psychosomatic influence. Attention needs to be paid especially to the question of whether or not to include as OCs conditions that have strong mental or psychosocial overtones, e.g., maternal fatigue. third trimester nausea, anxiety, and amount of analgesics in labor. Increased rates of such conditions are likely to be found as naturally occurring phenomena among female mental patients, which may or may not be a relevant or interesting finding, depending upon the goal of the study. Furthermore, researchers need to be aware that conscientious prenatal and obstetric services collect voluminous data on their patients, much of these data representing only backgound information or data only indicating increased risk for (but not the occurrence of) OCs in the current reproduction. Some researchers with access to these data have apparently indiscriminately considered very broad categories of events and conditions as representing OCs, including such variables as deviation on age at first menstruation, problems during previous reproductions, previous illnesses, current unmarried status, current maternal irritability, heart burn and increased number of vaginal examinations as ‘OCs’ worth noting and testing statistically. Inclusion of such OC variables can only be justified if there is some meaningful

91

reason for determining that schizophrenics do or do not have more of such conditions and events. Our own approach (within the primary context of studying OCs as potential antecedents to schizophrenia in the offspring) has been to limit OCs to somatic complications actuall,v occurring in the current reproduction and having some potential direct relevance for the physical \vell-being of the @I&spring. We have also gathered data on such phenomena as the presence of active mental disturbance and symptoms during pregnancy and at labor/delivery (McNeil et al., 1984; McNeil, 1988a); pregnancy symptoms such as fatigue, dizziness, heart burn, nausea and leg muscle cramps (McNeil et al., 1983); and current life situation and obstetric history, but we have not labelled these phenomena as ‘OCs’, nor included them together with more classical obstetrical variables with established relevance for the fetus/offspring. No single definition of what constitutes ‘OCs’ will likely be optimal for all reasons for asking question 1, but a great variety of different conditions included among ‘OCs’ in the different studies could provide some difficulty in obtaining a single answer to this question. One important task is to determine to what extent the differences in answers obtained to the question are due to differences in the OCs included for investigation on different studies. (B) General expectations for @dings Both researchers and clinicians generally appear to expect increases in OC rates in reproductions by schizophrenic parents, and our initial findings of no differences between schizophrenic and control parents (McNeil and Kaij, 1973) were generally viewed by others as a failure to find what should have been an obvious difference between these groups. Indeed, a number of different reasons exist for expecting at least some positive findings of group differences to appear in the literature on this topic. First, approximately 30 different studies have been conducted regarding OC rates in schizophrenic and control parents, and with the multiple variables (and sometime groups) studied in each investigation, a number of positive findings of differences between schizophrenic and control parents would be expected on the basis of chance alone. Second, positive findings are both more

scientifically rewarding to obtain and easier to publish, and positive findings should thus tend to appear in the literature more often than do negative findings of no difference. Third, both the premorbid personality characteristics of many female schizophrenics (Watt, 1974) and the prodroma1 or residual symptoms of schizophrenia, such as marked social isolation, impairment in personal hygiene and lack of initiative (DSM-III-R, APA 1987) might predict lessened contact with prenatal services and diminished interest in physical health and care; this would tend to increase OC rates (and is even counted as an OC per se in one study) (Wrede et al., 1980, 1984). Fourth, schizophrenics appear to have increased rates of other mental, physical and psychosocial factors and characteristics during pregnancy and at labor/delivery that would tend to increase the occurrence of OCs, e.g., use of psychopharmaca (McNeil, unpublished data; Sameroff et al.. 1984) difficult life situations and problematic interpersonal relationships (McNeil et al., 1983) active mental disturbance (McNeil et al., 1984) greater anxiety during labor/ delivery (McNeil, unpublished data), smoking (McNeil et al., 1983) and drinking to intoxication (Ragins et al., 1975). Fifth, helpful obstetric services may tend (artificially) to increase the rate of obstetric intervention (and thus apparent ‘OCs’) for the generally laudible purpose of assisting women with mental difficulties or with problems in coping with the stress of pregnancy and labor/delivery. Such help might, e.g., include inducing labor near term to get the often unpleasant late stage of pregnancy over, stimulating the course of labor to shorten its duration, offering instrumental deliveries to those women having or anticipated to have difficulties in bearing down, giving more analgetics or anesthetics during labor/delivery to those who are unusually anxious or apparently mentally vulnerable, giving more attention during pregnancy and labor (resulting, e.g., in more vaginal exams and use of more sophisticated medical procedures), etc. Increased observation should increase rates of identified OCs. This additional attention and assistance might result in increased rates of apparent OCs, due purely to mental or psychosocial factors. Such a possibility of increased help for sometimeschizophrenics would not require that the women already be labelled schizophrenic, but rather could

92

occur for women who show difficulties or vulnerability during pregnancy and labor/delivery. The above arguments for expecting increased rates of OCs among schizophrenics are based on the premise that premorbid, prodromal, active or residual schizophrenia could in some manner contribute to the occurrence of OCs. In principle, the directionality of such a hypothetical relationship could be the opposite. Extensive physical illness (like preeclampsia) during pregnancy, great fright and worry elicited by vaginal bleeding and imminent abortion, a physically traumatic delivery, or the death of one’s fetus or newborn child could, in principle, lead to the (re-)development of a psychosis in a mentally vulnerable woman (Brockington et al., 1982; Paffenbarger, 1982). Instead of schizophrenia leading to more OCs, it is theoretically possible that some serious OCs (or basic biological dysfunction associated with them) also could lead to increased rates of mental illness in the parent experiencing the OCs, which in turn would strengthen a relationship between schizophrenia and the occurrence of OCs in reproductions by schizophrenics. Given these many different reasons for expecting increased rates of OCs in reproductions by schizophrenic parents, the frequent findings of no differences between schizophrenic and control parents, reviewed below, are perhaps even more impressive. (C) The data Perhaps the most extensive review conducted of OC rates in reproductions by schizophrenic parents was published by McNeil and Kaij in 1978, in association with a general evaluation of the topic ‘Obstetric factors in the development of schizophrenia’. The authors then reviewed the currently existing data found in 20 studies of reproductions by schizophrenic parents, a vast majority of whom were mothers. These different studies ranged broadly in their diagnostic definitions of schizophrenia and in their sources of data regarding OCs. A number of reports of new results are now available, and the total OC data available are selectively reviewed below concerning offspring birth weight, OCs, malformations and perinatal deaths. Birthweight. A vast majority of the studies conducted found no significant difference in the birthweight of the offspring of schizophrenics vs.

control parents (Yarden and Suranyi, 1968; Lane and Albee, 1970; Mednick et al., 1971 (see Mura et al., 1973); McNeil and Kaij, 1973; Mizrahi Mirdal et al., 1974; Rieder et al., 1975; Schachter et al., 1975; Hanson et al., 1976; Zax et al., 1977; Rieder and Nichols, 1979; Wrede et al., 1980, 1984; Marcus et al., 1981, 1984; Marcuse and Cornblatt, 1986; Schachter, Lachin, Spruill, Johan, Saladin, and Williams, unpublished). Apparently only two studies found significantly lower birthweights in the offspring of schizophrenics than controls (Mura et al., 1973; Sameroff et al., 1984) and one other study (Paffenbarger et al., 1961) found significantly lower offspring birthweights for women with postpartum psychoses (less than half of whom were schizophrenic) than for controls. In contrast, the author’s own unpublished data show unusually heavy offspring born to schizophrenic (vs. matched control) mothers, thus representing findings somewhat similar to those of DeHorn and Strauss (1977) of significantly higher birthweights for the offspring of schizophrenic (vs. control) fathers. Studies in this field also suggest that no birthweight differences occur in the offspring of schizophrenic mothers vs. schizophrenic fathers (McNeil and Kaij, 1978). In total, the data indicate no difference in birthweights associated with reproductions by schizophrenic vs. control parents. OCs (pregnancy, birth, and neonatal complications). As was true regarding birthweight, a majority of the studies that have investigated OCs (which are often subcategorized as pregnancy (PCs), labor/delivery/birth (DCs or BCs), or neonatal complications (NCs)) have found no significant differences for reproductions by schizophrenic vs. control parents (Mednick et al., 1971; McNeil and Kaij, 1973; Sameroff and Zax, 1973; Mizrahi Mirda1 et al., 1974; Cohler et al., 1975; Hanson et al., 1976; Rieder et al., 1977; Marcus et al., 1981, 1984; Schachter, Lachin, Spruill, Johan, Saladin and Williams, unpublished). With the general tendency across so many studies for schizophrenic parents not to have increased rates of OCs, special attention should be given to studies showing or cited as showing positive findings of differences between schizophrenic parents and controls, to determine the specific nature of and conditions for these positive findings. A short review of such studies follows.

93

Mednick and Schulsinger (1968) reported more birth complications for their severely ill chronic schizophrenic mothers (n = 207) than for controls (n= 104). Few if any data were reported, and the authors stated that there was a ‘general trend for the birth of the high-risk subjects to have been attended with more difficulties’ (p. 276). As description of this, the authors note that significantly more schizophrenic mothers were unwed (which is not a birth complication), that the birth process took much longer (no data were given), and significantly more vaginal examinations were performed for the schizophrenics (which is not a complication per se). The result that was given the greatest emphasis was the finding of abnormal placentas (mostly infarcts) in 1 I % of the schizophrenics versus 1% of the controls. As presented, these findings do not represent impressive evidence of differences between schizophrenic and control parents. A study often cited as indicating greater rates of BCs among schizophrenic women is that of Sameroff and Zax (1973). In this study, schizophrenic mothers (n = 12) were found to have significantly more BCs than controls (n = 12) if and only if abnormal EEGs in the offspring were combined with traditional birth complications; question may be raised as to whether abnormal EEGs represent evidence of only BCs. Analysis of delivery complications alone provided no significant difference between schizophrenic mothers and controls, and the author considers this study as showing no difference between schizophrenic and control women on OCs. A study by Rieder, Broman and Rosenthal (1977) has often been cited as evidencing differences between schizophrenics vs. controls, but is referred to above as not showing significant differences, for the following reasons. Only one OC variable in their entire study showed increased frequency among schizophrenics, and only when one group of the schizophrenics was compared with unmatched controls: vaginal bleeding was significantly more frequent among ‘continuous’ (but not ‘acute’) schizophrenics, and only when they were compared with a large unmatched population control sample (n=6580) but not when compared with a demographically matched control group with the same sample size as that of the schizophrenics. These results represent little con-

vincing evidence for OC increases among schizophrenic parents. A more recent publication by Sameroff et al. (1984) reports finding increased rates of prenatal complications and lower birth weights among reproductions by schizophrenic mothers (n = 29) than controls (n = 57). The increased prenatal complications resulted entirely from the inclusion of an item concerning ‘chronic medication of the mother’, which for obvious reasons differentiated schizophrenics from controls. Without this item, schizophrenics did not have significantly more prenatal complications than did controls, although the birth weight difference between offspring of schizophrenics and controls still remains, as noted above. A study of Wiedorn (1954) of patients from the 1950s or earlier indicated unprecedentedly high rates of toxemia in women who were hospitalized for schizophrenia and who at some time delivered a child in the same hospital in New Orleans (n= 72). Primiparae black schizophrenics showed a toxemia rate of 83% in reproductions prior to their first psychotic episode, but even the black controls from the same hospital (n = 72) showed high rates of toxemia (about 33% in different subsamples). White schizophrenics showed a rate of toxemia (32%) that was comparable to that for black controls. Both the sample and the results in this study appear unrepresentative for other studies in this area. And finally, a Finnish study by Wrede et al. (1980, 1984) rates special attention, as this study is outstanding in producing positive findings of differences in OC rates between schizophrenic mothers and controls. The index sample consisted of women with a mental hospital diagnosis of schizophrenia and delivering a child in hospital in Helsinki in 1960-1964. Schizophrenics with permanent social deficit were termed ‘chronic schizophrenics’ (n = 54) and those with l-3 psychiatric admissions were termed ‘mild schizophrenics’. Almost all cases (94%) became formally schizophrenic some time after the current delivery, which Wrede et al. interpret as reason not to expect bias in reporting OCs for these cases. A control sample (n= 171) was chosen from the same delivery series. Controls were nor demographically matched with schizophrenics, and notable differences occurred between the chronic schizophrenics and the other

94

two groups on unmarried status (20% chronic, 4% mild, 2% control) and low/lower middle social class (37% chronic, 14% mild, 12% control). The researchers apparently included almost any information obtainable from the obstetric records as representing possible ‘OCs’, a procedure which differentiates this study from most other studies in this field. For example, as pregnancy complications the authors included failure to attend a Well-Baby Clinic (WBC); abnormality on (e.g.) height of the mother, mother’s pulse at time of delivery, age at first menstruation, menstruation duration, and prior deliveries; previous illnesses, treatment for previous illnesses, prior abortions, as well as heart burn, itching, headache, backache, cramps, insomnia, dizziness, digestion complaint, and medication during the pregnancy. The rationality for counting these anamnestic variables as OCs occurring during the current pregnancy is unclear, and question may be further raised as to why such complaints as headache, insomnia or heart burn should be considered as complications scored and weighted in a manner comparable to that for serious pregnancy complications such as bleeding including abortus imminens and toxemia. Nevertheless, the researchers made an unweighted count of all such anamnestic data and minor deviations, together with more serious complications, and the chronic schizophrenics were found to have more total ‘pregnancy complications’ than did the mild schizophrenics or controls. The specific ‘pregnancy complications’ that differentiated the three groups were failure to attend the WBC, nausea and heart burn in the third trimester, suffering from prior illnesses, systolic hypertension, and proteinuria. The chronic schizophrenics had significantly more PCs than did mild schizophrenics on total number of PCs, not attending the WBC, nausea and heart burn in third trimester, and proteinuria; the mild schizophrenics were not different from controls on these variables. Both chronics and mild schizophrenics more often had suffered prior illnesses and had systolic hypertension than had controls (the latter possibly an expression of increased mental distress among schizophrenics). Further, mild schizophrenics had significantly more ‘severe’ delivery complications (DCs) than did controls, while the chronic schizophrenics were quite comparable to controls. The specific ‘delivery

complications’ that differed among the three groups were deviant mental status (e.g., tense, irritable, restless), deviant physical status (e.g., tired, anemia, vomiting), ‘mother too thin’, preterm delivery (not likely a delivery complication), placental abnormality (calcified, ruptured) and receiving any medication during delivery (sedatives, analgesics and labor-inducing drugs); the other two delivery complications separating the groups were fetal heart rate deviations (five chronic, four mild, one control case) and a ‘massage points’ score reflecting inferred amount of fetal squeezing and tactile stimulation during the delivery (about five chronic, 15 mild and seven control cases). Both chronic and mild schizophrenics differed from controls on these ‘delivery’ variables, with the exception of ‘mother too thin’. which was characteristic only of the chronics. In the author’s opinion, serious question can be raised as to whether most of these significant variables should even seriously be considered as representing ‘PCs’ or ‘DCs’ typical for most studies in this field. Furthermore, pre-schizophrenic women would reasonably be expected to have an increased frequency of such deviations as tension, fatigue, physical thinness and sedatives, without this necessarily reflecting typical OC conditions included in most other studies. The postpartum variables significantly differentiating the groups were child unhealthy at birth (most frequent among mild schizophrenics), child unhealthy during first week (most frequent among chronic schizophrenics) and medication required for mother (two chronics, seven milds and two controls). Of some significance, more perinatal deaths occurred among the offspring of mild schizophrenics (four stillbirths, four neonatal deaths) than the other two groups (zero chronic, one control). Thus, while Wrede et al.‘s study did find a number of significant differences between schizophrenics and controls on PCs, DCs and NCs, most of the differences observed are (in this author’s opinion) either irrelevant to the current reproduction, questionable as typical somatic OCs and/ or quite to be expected to differ between preschizophrenics and control women. Further, the two schizophrenic groups (chronic and mild) were most often different from one another on OC rates, but inconsistently so in relation to controls. This

95

fact tends to be ignored by other reviewers (e.g., Walker and Emory, 1983; Watt, 1984; Hare, 1988) who simply cite the Wrede et al. study as indicating that ‘schizophrenics have more OCs’. In the study by McNeil and Kaij (1987) of schizophrenic and matched control women, the author personally attended and observed most of the labors and births. The author was as blind as possible concerning index-control status of the cases and the psychiatric diagnosis of any apparent index case. (Six different diagnostic categories were included within the total index sample of women with a history of psychosis.) No difference was found between schizophrenics and matched controls on offspring gestational age or offspring body size per gestational age (although the offspring of the schizophrenics tended to be both heavy and long), and a very low rate of instrumental deliveries was found in both groups. The offspring of schizophrenics had a very low rate of fetal distress (lower than that of controls), but a notably high rate of low 1 min Apgar scores; the reason for these deviations on 1 min Apgar is unknown, but the Apgar scores were largely normalized by 5 min. The two groups of offspring were identical on rates of any abnormality notable at birth. As the findings now stand, the high rate of deviations of 1 min Apgar scores among schizophrenics’ offspring have to be weighed against their unusually low rate of fetal distress; the labors and deliveries of schizophrenics did not appear notably different from those of control cases. In contrast, as compared with controls, the schizophrenic mothers were much more anxious during labor/delivery (as assessed by the midwives), had a lower degree of control over their own behavior, and more often asked for medication to diminish pain. The midwives were more often positive toward giving such medication to the schizophrenics, and the schizophrenics received more help and attention from the midwives than did the demographically matched control women. Had these behaviorally or mentally oriented variables been calculated as representing ‘OCs’ (which they were not in this study), then the schizophrenics could well have had more total ‘labor and delivery complications’. In total, a number of differences on OC rates have been found between schizophrenic and control women. While a few of these differences appear

to represent typical somatic OCs, most of the differences were found in studies with either unusual samples, special analysis procedures, or ‘OC’ variables that lie outside the typical realm of somatic obstetrical complications. Enough data exist to permit the conclusion that the pregnancies and births of schizophrenics are more mentally, behaviorally and socially complicated. When the more obvious mental/behavioral consequences and correlates of schizophrenia are removed from ‘OC’ scores, the pregnancies and deliveries of schizophrenics do not typically appear to be notably dcflerent from those of controls on a purely somatic basis. neonatal Malformations and fetal and deaths. Sobel (1961) used psychiatric records to investigate rates of malformations occurring in 222 offspring of schizophrenic women who were in New York state mental hospitals at the time of delivery in 1950-1958. He reported a higher rate of malformations in these offspring (3.2%) than in two separate samples from the general population (about I %). In contrast, Paffenbarger et al. (1961) found no difference between women with postpartum psychosis and controls on rates of congenital defects recognized by time of hospital discharge (no frequencies were given for either group). Hanson et al. (1976) did not report the frequency of malformations among the offspring of schizophrenics, but two of the five case studies for schizophrenics did include evidence of congenital malformations in the offspring. A similar report procedure was found in Wrede et al. (1984) in which no rates of malformations were given but two of the specific conditions noted for the offspring of schizophrenics were malformations (Down’s syndrome, luxatio coxae). In the author’s own study (McNeil et al., 1991) the offspring of schizophrenics did not differ from demographically matched controls on the frequency of congenital malformations noted either by time of discharge from the delivery department or after several years’ follow-up through different pediatric sources. From the data available, it is difficult to draw any certain conclusions about whether the rates of congenital malformations are increased among the offspring of schizophrenics. More data exist concerning fetal and perinatal deaths, and these data suggest at least some inconsistent increases for the offspring of schizophrenics. Perinatal mortality was 8.1% (ten stillbirths and

96

eight neonatal deaths) among Sobel’s 222 offspring of hospitalized cases, which was higher than that for the general population (3.6%) at that time. In Paffenbarger’s study (Paffenbarger et al., 1961) fetal deaths were noted for 5% of the patients with postpartum psychoses (less than half of whom were schizophrenic) and 2% of controls, while 2% of the postpartum cases and 1% of controls had neonatal deaths. Wrede et al. (1984) found significantly more perinatal deaths (four stillbirths and four neonatal deaths= 7%) among the offspring of mild schizophrenics than among chronic schizophrenics (O/54) and controls (one stillbirth/l 7 1). Rieder et al. (1975) obtained data from the collaborative project in Boston and found a nonsignificant tendency for the offspring of schizophrenics to have more fetal and neonatal deaths than did the offspring of ‘possibly schizophrenic’ cases, nonschizophrenic index cases, and control parents. This difference became statistically significant only when limited to deaths with unknown cause (n= 7) but not when spontaneous abortions prior to the 20th week of pregnancy were excluded. On the other hand, Hanson et al. (1976) used data from another part of the collaborative project and found one fetal death and one neonatal death among 33 offspring of schizophrenic parents, as compared with no deaths among 66 control cases; however, two fetal deaths were also found among 36 offspring of psychiatric patients with diagnoses other than schizophrenia. Furthermore, Zax et al. (1977) reported perinatal deaths to have occurred among the offspring of neurotic-depressives but not the schizophrenics. In the author’s own study (McNeil and Kaij, 1987) one perinatal death occurred among the 104 controls, but none among the 88 psychosis cases. Similarly, no fetal or neonatal deaths occurred in the Israel study of Marcus et al. (1984) and those authors interpreted the differences in results for different samples as reflecting differences in prenatal care and the general nutritional and health status of the samples. Both Israelian and Swedish samples rate high on these positive characteristics and low on perinatal deaths, while the opposite was said to be true for the samples in the United States. This argument appears plausible, but consideration has again to be taken to the special findings by Wrede et al. (1984) of more perinatal deaths among the mild schizophrenics than among the chronic

schizophrenics or controls in Finland in the 1960s. If general health status influenced perinatal death rates in that study, then the death rates would likely have been higher among the offspring of the chronits than the mild schizophrenics. At present, the total evidence concerning perinatal deaths, while somewhat inconclusive, would generally tend to support the conclusion that the offspring of schizophrenics, as well as other mental patients, do under some societal circumstances have increased rates of perinatal deaths. QUESTION

2. IS

NESS RELATED DUCTIONS

SEVERITY

OF PARENTAL

TO THE OCCURRENCE

BY SCHIZOPHRENIC

MENTAL

OF 0’3

ILL-

IN REPRO-

PARENTS?

One major reason for asking this question is that the varying answers to question I obtained in different studies might be due to some extent to varying psychiatric characteristics of the samples. A reasonable hypothesis is that very severely ill schizophrenics should show differentially more OCs than less ill schizophrenics, and therefore more often differ from normal control cases. The data provide no singular confirmation of this hypothesis. Sameroff and Zax (1973) found that the more severely mentally disturbed sample halves among both schizophrenics and neuroticdepressives had more pregnancy complications and birth complications than did the less disturbed schizophrenics and neurotic-depressives. Zax et al. (1977) also reported that greater severity of mental illness was positively associated with increased OCs, such as low birth weight, prematurity and low Apgar scores. Subsequent data analyses by Sameroff et al. (1984) showed that more severe or chronic mental illness in the mother was associated with more prenatal, infant. and total complications, as well as with short labor, low Apgar score and low birth weight, within a total sample including cases with schizophrenia, neurotic-depression and personality disorder. All these data from the same research group support an association between severity of disturbance and increased OC rates. Furthermore, studies by Rieder and colleagues found that ‘continuous’ schizophrenics tended to have more vaginal bleeding than did ‘acute’ schizophrenics (Rieder et al., 1977), and that schizophrenics tended to have more perinatal deaths than

97

did ‘possibly schizophrenic’ cases (Rieder et al., 1975). In another study (Goodman, personal communication, 1987) more severe disturbance among schizophrenic mothers was related to increased frequency of premature births, lower offspring birth weight, and higher total OC scores. In contrast, studies by McNeil et al. (1974) and Schachter, Lachin, Spruill, Johan, Saladin and Williams (unpublished manuscript) found no relationship at all between active maternal mental disturbance during the current reproduction and OC rates in reproductions by female mental patients, most of whom were schizophrenic. In the study by Wrede et al. (1984) the chronic schizophrenics tended to have more pregnancy complications than did the mild schizophrenics (consistent with the hypothesis), but (opposite to the hypothesis) the mild schizophrenics had more delivery complications and perinatal deaths than did the chronic schizophrenics. The data concerning the relationship between severity of maternal mental illness and OC rates are thus somewhat inconclusive, but with a tendency for greater accumulated severity of mental illness to be related to more OCs.

QUESTION

3.

DO OCS RELATE

OF MENTAL AND PHYSICAL HIGH-RISK

OFFSPRING

TO THE

DEVELOPMENT

ABNORMALITY

OF SCHIZOPHRENIC

AMONG THE PARENTS?

Evidence pertaining to this question (Mednick, 1970) re-awakened much of researchers’ previous interest in OCs as antecedents to the development of schizophrenia (e.g., Pollack and Greenberg, 1966; Pollin and Stabenau, 1968) and also stimulated new studies that have now obtained even stronger evidence that OCs antecede the development of such psychopathology in many different types of schizophrenic samples (McNeil and Kaij, 1978; Jacobsen and Kinney, 1980; Parnas et al., 1982; Lewis and Murray, 1987). The answer to question 3 has relevance for the issues of (a) explaining the mechanisms for the development of pathology among groups at heightened genetic risk, (b) identifying risk groups and risk criteria for use in prediction and possible intervention, and (c) identifying the origins of other conditions or phenomena that appear to be related to schizophrenia, such as pandysmatura-

tion (Fish, 1984) or poor sensorimotor performance (Marcus et al., 1984). The event that elicited the wave of modern studies of OCs and schizophrenia was Mednick’s publication in 1970, in which ‘severe abnormality’ developing among the offspring of schizophrenic women in the Mednick and Schulsinger longitudinal study (1968) was reported to be clearly associated with OCs. At least one OC was reported for 70% of the high-risk subjects who evidenced severe abnormality, as compared with only 15% of normal high-risk subjects and 36% of the low-risk subjects. The two OCs that were most discriminative of the disturbed vs. nondisturbed high-risk groups were prolonged labor and prematurity, i.e., OCs that are associated with schizophrenia in randomly selected patient samples (McNeil, 1987). Mednick interpreted these findings within a framework of selective damage to the hippocampus, resulting from anoxia. These findings were later the object of some criticism (McNeil and Kaij, 1978; McNeil, 1988b), but the results have set much of the tone for the studies that followed in this field. Parnas et al. (1982) published follow-up data for the Mednick and Schulsinger sample, concentrating on the relationship between OCs and the subsequent development of schizophrenia (n = 12) borderline schizophrenia (DSM-III schizotypal personality) (n = 25), and no mental illness (n = 55) occurring w,ithin the high-risk sample by an average of 24 years of age. Those high-risk offspring developing schizophrenia had significantly more OCs and more severe OCs than did high-risk cases developing a borderline disorder. However, neither of the high-risk subgroups differed significantly from nondisturbed high-risk cases on OC rates, and the nondisturbed cases fell in between the schizophrenics and borderlines on OC rates. The researchers interpreted their findings as possibly suggesting that the normal high-risk individuals (who had a medium frequency of OCs) had a lower genetic predisposition for schizophrenia than did the other high-risk cases; among the more genetically predisposed high-risk individuals, the OCs that occurred contributed to the development of schizophrenia, while the absence of OCs left these individuals simply as borderline cases. Further follow-up of these subjects, now in progress, should yield interesting answers as to

whether the data still support this interpretation, or whether the original findings might be an expression of a relationship between early trauma (OCs) and early age at onset of schizophrenia, seen in other samples (McNeil, 1988b). A number of other reports by the MednickSchulsinger group concerned OCs. The 1970 paper by Mednick also presented findings that OCs in the high-risk group were related to rapid onset and recovery, poor habituation of response, and poor extinction of response in study of the galvanic skin response (GSR). OC-rate differences appeared to account for the differences noted in GSR parameters for the mentally deviant vs. normal high-risk subjects. Furthermore, some sex differences were noted, OCs being more important in males: Mednick et al. (1978) reported that OCs were significantly positively related to the development of schizophrenia in male high-risk offspring, but negatively related to the development of schizophrenia in female high-risk offspring. OCs were also related primarily to delusions and hallucinations (i.e. ‘positive’ symptoms) among high-risk males who became schizophrenic. Later publications concerned OCs and cerebral ventricular size in adulthood among high-risk subjects. Silverton et al. (1985) reported that ventricular enlargement was not related to a composite OC score, but was related to shorter body length and lower weight at birth, as well as a rating of prematurity. Schulsinger et al. (1984) published similar data showing that the correlation between increased ventricle-brain ratio (VBR) and lower birthweight was statistically significant, while the correlations between VBR and total OCs, longer duration of birth, and body length at birth were not statistically significant. To my knowledge, no other high-risk study has progressed as far as that of Mednick and Schulsinger in relating OCs to psychopathology in the offspring in adulthood. Fish (1984), who began a longitudinal high-risk study in the 1950s has concentrated on the development and significance of pandysmaturation (PDM) in high-risk offspring. Fish has concluded that PDM occurs with increased frequency in the offspring of schizophrenic women and is clearly related to the development of schizophrenia later in life. However, PDM was found to be unrelated to OCs, and Fish believes PDM to be genetically determined.

The few other high-risk studies with published data relevant to question 3 have related OCs to subject characteristics at much younger ages. For example, Marcus et al. (1981, 1984) presented a very complicated series of analyses and results that possibly can be summarized in the following manner: no consistent relationship was found between OCs and poor motor or sensorimotor development within their total sample of offspring of schizophrenics. However, a subgroup of the offspring of schizophrenics were notable for their repeatedly very poor development during the first year of life. This subgroup did not have more OCs but did tend to have more cases with a low-normal birthweight (2300-2900 g). These lower birthweights tended to be associated with both OCs and the subsequent poor performance of this subgroup. Low birthweight in the offspring of a schizophrenic was always associated with poor development, but in few cases could the low birthweight be traced to another OC. Those researchers concluded that the low birthweight was due to some factor leading to mild intrauterine growth retardation, which was associated with the type of neurological dysmaturation described by Fish (1984). OCs were judged as not totally irrelevant for deviations in the highrisk offspring, as OCs did appear to contribute to poorer development when they occurred. The OC scores from the pregnancy and infant OC categories were in fact related to developmental problems only among the offspring of schizophrenics and not among the offspring of other psychiatric patients or controls. The finding of relationships between OCs and other characteristics only among the offspring of schizophrenics represents an appealing opportunity to identify something unique about schizophrenia, and the literature on OCs has a history of such apparent findings (see McNeil and Kaij, 1978). Mednick’s (1970) finding that OCs related to GSR characteristics (almost) only within the high-risk sample is one example. In another study, Mednick et al. (1971) found that birthweight below 3000 g was related to retarded motor development only among the offspring of schizophrenics. Studies by Schachter et al. (1975) and Rieder et al. (1977) found one or more among many specific OCs to be related to neonatal heart rate acceleration and to IQ at 7 years. respectively. The impor-

99

tance of such singular findings is difficult to determine. In the author’s own longitudinal study of highrisk offspring (McNeil and Kaij, 1987) no systematic relationship was found between a four-point summary OC score (representing entire normality to extreme abnormality on labor/birth/neonatal OCs) and a number of other characteristics of offspring of schizophrenics, i.e., neonatal neurological condition, infant temperament, attachment to the mother, or fear of strangers during the first year of life. Furthermore, this four-point scale for OCs was unrelated to offspring mental disturbance, psychosocial adjustment, developmental scale scores and motor coordination at 6 years of age (McNeil, 198&b). Within the total high-risk sample of offspring of women with six different types of psychoses, mental disturbance at 6 years of age did tend nonsignificantly to be related to prolonged labor and low Apgar score (McNeil and Kaij, 1987). Interestingly, two other, more mentally oriented variables from the pregnancy period, i.e., maternal anxiety and negative maternal attitude toward pregnancy, were highly significantly related to offspring mental disturbance at 6 years of age. Thus far, these data have only been partially analyzed, and further analyses may shed more light on the degree of relevance of OCs occurring in these different risk groups. Summary

and conclusions

Some evidence indicates that OCs may be an etiological factor of importance in the development of schizophrenia. A currently important question not addressed by this review is whether OCs replace other etiological factors, or in some way interact with other factors such as genetic influence (Murray et al., 1988). The data relevant to question 3 are of considerable importance for testing possible interactions of OCs and implied genetic influence, particularly if one can show that increased obstetric complications in a low genetic risk control group does not increase the risk for schizophrenia. The findings from Mednick and Schulsinger’s longitudinal study clearly suggest that OCs are related in a special manner to the characteristics of the offspring of schizophrenics, including the development of schizophrenia in the offspring. This would speak for an interaction between OCs and genetics. However, other high-risk studies have not (at least

yet) contributed much evidence that OCs strongly interact with or add to the implied genetic vulnerability found in the offspring of schizophrenics. With time, some of the other longitudinal highrisk studies may be at least partially able to confirm or disconfirm the Mednick-Schulsinger results. Some of the recent uncertainty in this field concerns not so much the data but rather the concepts and terminology surrounding ‘OCs’. Surprisingly great interest has been focussed on offspring birthweight, possibly because of its ease and reliability of measurement and its relationship to early developmental retardation and adult ventricular enlargement. Obstetricians view low often birthweight as an obstetric ‘OC’, but researchers within psychopathology may tend to consider low birthweight among high-risk offspring as being due to genetic influence (Marcus et al., 1981) or to a prenatal virus hypothetically related to schizophrenia (Machon et al., 1983). Adequate tests of these interpretations (hypotheses) await the identification of the bearers of the schizophrenia gene(s) and of the relevant virus(es), to determine whether these persons have more ‘OCs’ as obstetricians know them. Until that time, the vast data indicating no substantial increases in OCs or low birthweight offspring in reproductions among schizophrenic parents will serve as the best possible available evidence that these OCs are not genetically determined (McNeil and Kaij, 1978; McNeil, 1987, 1988b). If this argument can be accepted, then the vast amount of empirical work concentrated on question 1 will have contributed not only to clinically applicable knowledge, but also to theoretical positions on the etiology of schizophrenia.

ACKNOWLEDGMENTS

Our research has been supported by grants from the Swedish Medical Research Council (nos. 3793 and 6214) the NIMH, USA (MHl8857) and the W.T. Grant Foundation, Inc., U.S.A.

REFERENCES

American Psychiatric Association (I 9X7) Diagnostic and Statistical Manual of Mental Disorders 3rd ed revised. Washington, DC.

100 Brockington. I.F., Winokur, G. and Dean. C. (1982) Puerperal psychosis. In: I.F. Brockington and R. Kumar (Eds.), Motherhood and Mental Illness. Academic Press, London. pp. 37-69. Cohler, B.J.. Gallant. D.H., Grunebaum, H.U.. Weiss, J.L. and Gamer, E. (1975) Pregnancy and birth complications among mentally ill and well mothers and their children. Sot. Biol. 22, 269-278. DeHorn. A.B. and Strauss. M.E. (1977) Birthweights of male and female schizophrenics’ offspring. Acta Psychiatr. Stand. 55, 321-329. Fish, B. (1984) Characteristics and sequelae of the neurointegrative disorder in infants at risk for schizophrenia: 1952-1982. In: N.F. Watt, E.J. Anthony, L.C. Wynne and J.E. Rolf (Eds.), Children at Risk for Schizophrenia. A Longitudinal Perspective. Cambridge University Press, Cambridge. pp. 423-439. Garmezy. N. (1974) Children at risk: The search for the antecedents of schizophrenia. Part 2: Ongoing research programs, Issues and intervention. Schizophr. Bull. 9. 55-125. Hanson, D.R.. Gottesman, 1.1. and Heston. L.L. (1976) Some possible childhood indicators of adult schizophrenia inferred from children of schizophrenics. Br. J. Psychiatry 129, 142Z 154. Hare. E. (1988) Temporal factors and trends, including birth seasonality and the viral hypothesis. In: M.T. Tsuang and J.C. Simpson (Eds.), Handbook of Schizophrenia Vol. 3. Nosology, Epidemiology and Genetics of Schizophrenia. Elsevier. Amsterdam. pp. 345-377. Jacobsen, B. and Kinney. D.K. (1980) Perinatal complications in adopted and non-adopted schizophrenics and their controls: preliminary results. Acta Psychiatr. Stand. 62 (suppl. 285). 337-346. Lane, E.A. and Albee. G.W. (1970) The birth weight of children born to schizophrenic women. J. Psychol. 74. 157-160. Lewis, S.W. and Murray, R.M. (1987) Obstetric complications. neurodevelopmental deviance and risk of schizophrenia. J. Psychiatr. Res. 2 I, 413-421. Machon, R.A., Mednick, S.A. and Schulsinger. F. (1983) The interaction of scasonality, place of birth. genetic risk and subsequent schizophrenia in a high risk sample. Br. J. Psychiatry 143. 383-388. Marcus, J.. Auerbach. J., Wilkinson. L. and Burack, C.M. (1981) Infants at risk for schizophrenia. The Jerusalem infant development study. Arch. Gen. Psychiatry 38. 703-713. Marcus, J., Auerback. J.. Wilkinson, L. and Burack, C.M. (1984) Infants at risk for schizophrenia: the Jerusalem infant development study. In: N.F. Watt, E.J. Anthony, L.C. Wynnc and J.E. Rolf (Ed%), Children at Risk for Schizophrenia. A Longitudinal Perspective. Cambridge University Press, Cambridge. pp. 440-464. Marcuse. Y. and Cornblatt. B. (1986) Children at high risk for schizophrenia: Predictions from infancy to childhood functioning. In: L. Erlenmeyer-Kimling and N. Miller (Eds.). Life Span Research on the Prediction of Psychopathology. Earlbaum, Hillsdale, NY. McNeil. T.F. (1987) Perinatal influences In the development of schizophrenia. In: H. Helmchen and F.A. Henn (Eds.), Biological Perspectives of Schizophrenia. Wiley, Chichester, pp. 125-138.

McNeil, T.F. (1988a) A prospective study of postpartum psychoses in a high-risk group. 5. Relationship to psychosocial aspects of labor and delivery. Acta Psychiatr. Stand. 78. 47 I-477. McNeil, T.F. (1988b) Obstetric factors and perinatal injuries. In: M.T. Tsuang and J.C. Simpson (Eds.). Handbook of Schizophrenia Vol. 3. Nosology. Epidemiology and Genetics of Schizophrenia. Elsevier, Amsterdam, pp. 3 19-344. McNeil. T.F. and Kaij, L. (1973) Obstetric complications and physical size of offspring of schizophrenic, schizophreniclike. and control mothers. Br. J. Psychiatry 123. 341-348. McNeil. T.F. and Kalj. L. (1978) Obstetric Factors in the development of schizophrenia: complications in the births of preschizophrenics and in reproduction by schizophrenic parents. In: L.C. Wynne. R.L. Cromwell and S. Matthyssc (Eds.). The Nature of Schizophrenia. New Approaches to Research and Treatment. Wiley. New York, pp. 401-429. McNeil. T.F. and Kaij. L. (1987) Swedish high-risk study: sample characteristics at age 6. Schizophr. Bull. 13. 373-38 I. McNeil. T.F., Kaij, L. and Malmquist-Larsson, A. (1983) Pregnant women with nonorgamc psychosis: life situation and experience of pregnancy. Acta Psychiatr. Stand. 68. 445-457. McNeil. T.F., Persson-Blennow. I. and Kaij. L. (1974) Reproduction in female psychiatric patients: severity of mental disturbance near reproduction and rates of obstetric complications. Acta Psychiatr. Stand. 50. 23-32. McNeil, T.F.. Kaij, L. and Malmquist-Larsson. A. (1984) Women with nonorganic psychosis: mental disturbance during pregnancy. Acta Psychiatr. Stand. 70. I27- 139. McNeil. T.F., Blennow. G. and Lundberg, L. (1991) Congenital malformations and structural developmental anomalies in psychiatric high-risk and low-risk groups. In preparation. Mcdnick. S.A. (1970) Breakdown in individuals at high risk for schizophrenia: possible predispositional perinatal factors. Ment. Hyg. 54. 50-63. Mednick, S.A. and Schulsinger, F. (1968) Some premorbid characteristics related to breakdown in children with schizophrenic mothers. In: D. Rosenthal and S.S. Kety (Eds.). The Transmission of Schizophrenia (1st ed). Pergamon Press. Oxford. pp. 267-291. Mednick. S.A.. Mura, E.. Schulsinger, F. and Mednick. B. (1971) Perinatal conditions and infant development in children with schizophrenic parents. Sot. Biol. IX. 103-I 13. Mednick, S.A.. Schulsinger, F., Teasdale, T.W.. Schulsinger. H.. Venables, P.H. and Rock, D.R. (197X) Schizophrenia in high-risk children: sex differences in predisposing factors. In: G. Serban (Ed.), Cognitive Defects in the Development of Mental Illness. Brunner/Mazel, New York, pp. 169~ 204. Mizrahi Mirdal, G.K., Mednick. S.A.. Schulsinger. F. and Fuchs, F. (1974) Pcrinatal complications in children of schizophrenic mothers. Acta Psychiatr. Stand. 50. 553-568. Mura. E.. Mednick. S.. Schulsinger. F. and Mednick. B. (1973) Erratum and further analysis. Perinatal conditions and infant development in children with schizophremc parents. Sot. Biol. 20, 111-112. Murray, R.M.. Reveley, A.M. and Lewis, S.W. (1988) Family history. obstetric complications and cerebral abnormality in schizophrenia. In: M.T. Tsuang and J.C. Simpson (Eds.), Handbook of Schizophrenia, Vol. 3, Nosology, Epidemiolog>

101 and Genetics in Schizophrenia. Elsevier, Amsterdam, pp. 563-571. Paffenbarger, R.S. (1982) Epidemiological aspects of mental illness associated with childbearing. In: I.F. Brockington and R. Kumar (Eds.), Motherhood and Mental Illness. Academic Press. London, pp. 19-36. Paffenbarger, R.S., Steinmetz. C.H., Pooler. B.C. and Hyde, R.T. (1961) The picture puzzle of postpartum psychoses. J. Chron. Dis. 13, 161-173. Parnas, J., Schulsinger, F.. Teasdale, T.W., Schulsinger, H., Feldman, P.M. and Mednick, S.A. (1982) Perinatal complications and clinical outcome within the schizophrenia spectrum. Br. J. Psychiatry 140, 416-420. Pollack, M. and Greenberg, I.M. (1966) Paranatal complications in hospitalized schizophrenic and nonschizophrenic patients. J. Hillside Hosp. 15, 19ll204. Pollin, W. and Stabenau. J.R. (1968) Biological, psychological and historical differences in a series of monozygotic twins discordant for schizophrenia. In: D. Rosenthal and S.S. Kety (Eds.). The Transmission of Schizophrenia, 1st edn. Pergamon Press, London. pp. 3 177332. Ragins. N., Schachter, J.. Elmer, E., Preisman, R., Bowes, A. and Harway, V. (1975) Infants and children at risk for schizophrenia. J. Am. Acad. Child Psychiatry 14, 150-l 77. Rieder, R.O. (1979) Children at risk. In: L. Bellak (Ed.). Disorders of the Schizophrenic Syndrome. Basic Books, New York, pp. 2322263. Rieder, R.O. and Nichols, P.L. (1979) The offspring of schizophrenics. 3. Hyperactivity and neurological soft signs. Arch. Gen. Psychiatry 36, 6655674. Rieder, R.O., Rosenthal, D., Wender, P. and Blumenthal, H. (1975) The offspring of schizophrenics. Fetal and neonatal deaths. Arch. Gen. Psychiatry 32, 200%211. Rieder. R.O.. Broman, S.H. and Rosenthal, D. (1977) The offspring of schizophrenics. II. Perinatal factors and IQ. Arch. Gen. Psychiatry 34, 7899799. Sameroff, A.J., Barocas, R. and Seifer, R. (1984) The early development of children born to mentally ill women, In: N.F. Watt, E.J. Anthony, L.C. Wynne and J.E. Rolf (Eds.). Children at Risk for Schizophrenia. A Longitudinal Perspcctive. Cambridge University Press. Cambridge, pp. 482-5 14. Sameroff, A.J. and Zax. M. (1973) Perinatal characteristics of the offspring of schizophrenic women. J. Nerv. Ment. Dis. 157, l9lll99. Schachter, J., Kerr, J., Lachin, J.M. and Faer, M. (1975) Newborn offspring of a schizophrenic parent: cardiac reactivity to auditory stimuli. Psychophysiology 12, 4833492. Schachter, J.. Lachin. J., Spruill, L., Johan. M., Saladin, L.

and Williams, T.A. (1991) Maternal psychopathology and complications of pregnancy and delivery. Unpublished manuscript. Schulsinger. F.. Parnas. J., Petersen, E.T.. Schulsinger, H., Teasdale, T.W.. Mednick, S.A., Moller, L. and Silverton, L. (I 984) Cerebral ventricular size in the offspring of schizophrenic mothers. A preliminary study. Arch. Gen. Psychiatry 41. 602-606. Shields, J. and Gottesman, 1.1. (1977) Obstetric complications and twin studies of schizophrenia: clarifications and affirmations Schizophr. Bull. 3. 351-354. Silverton, L.. Finello. K.M., Mednick, S.A. and Schulsinger, F. (1985). Low birthweight and ventricular enlargement in a high-risk sample. J. Abnorm. Psychol. 94, 405-409. Sobel, D. (I 96 I) Infant mortality and malformations in children of schizophrenic women. Psychiatr. Q. 35, 60-64. Walker. E. and Emory, E. (1983) Infants at risk for psychopathology: Offspring of schizophrenic parents. Child Dev. 54, 126991285. Watt, N.F., (1974) Childhood and adolescent routes to schizophrenia. In: D.F. Ricks, A. Thomas and M. Roff (Eds.). Life History Research in Psychopathology, Vol. 3. The University of Minnesota Press, Minneapolis. MN, pp. 194421 I. Watt. N.F. (1984) In a nutshell: the first two decades of highrisk research in schizophrenia. In: N.F. Watt, E.J. Anthony, L.C. Wynne and J.E. Rolf (Eds.), Children at Risk for Schizophrenia. A Longitudinal Perspective. Cambridge University Press, Cambridge, pp. 5722595. Wiedorn, W.S. (1954) Toxemia of pregnancy and schizophrenia. J. Nerv. Ment. Dis. 120, l-9. Wrede. G., Mednick, S.A., Huttunen, M.O. and Nilsson, CC. (1980) Pregnancy and delivery complications in the births of an unselected series of Finnish children with schizophrenic mothers. Acta Psychiatr. Scand. 62, 3699381. Wrede, G.. Mednick, S.A., Huttunen. M.O. and Nilsson. CC. (1984) Pregnancy and delivery complications in the births of an unselected series of Finnish children with schizophrenic mothers: II. In: N.F. Watt, E.J. Anthony, L.C. Wynne and J.E. Rolf (Eds.), Children at Risk for Schizophrenia. A Longitudinal Perspective. Cambridge University Press, Cambridge, pp. 5 155525. Yarden, P.E. and Suranyi, I. (1968) The early development of institutionalized children of schizophremc mothers. Dis. Nerv. Syst. 29, 380-391. Zax, M., Sameroff, A.J. and Babigian, H.M. (1977) Birth outcomes in the offspring of mentally disordered women. Am. J. Orthopsychiatry 47, 218-230.