Mild ventriculomegaly detected in utero with ultrasound: clinical associations and implications for schizophrenia1

Schizophrenia Research 33 (1998) 133–140

Mild ventriculomegaly detected in utero with ultrasound: clinical associations and implications for schizophrenia1 J.H. Gilmore a,*, J. van Tol a, M.A. Kliewer b, S.G. Silva a, S.B. Cohen a, B.S. Hertzberg b, N.C. Chescheir c a Department of Psychiatry, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7160, USA b Department of Radiology, Duke University Medical Center, Durham, NC 27710, USA c Department of Obstetrics and Gynecology, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7160, USA Received 6 March 1998; accepted 9 June 1998

Abstract The most consistent structural abnormality of the brain associated with schizophrenia is that of mild enlargement of the lateral cerebral ventricles. Mild ventriculomegaly (MVM ) of the fetal brain detected in utero with ultrasound is associated with developmental delays similar to those described in children at high risk of schizophrenia. Fetal mild ventriculomegaly may be a marker for increased risk of schizophrenia and other neurodevelopmental abnormalities. Given the association between schizophrenia and obstetrical complications, pre- and perinatal complications and pregnancy outcomes were retrospectively reviewed in 51 pregnancies in which the fetus exhibited mild ventriculomegaly on routine ultrasonography and 49 control pregnancies. Mothers of children with MVM were older than controls and had shorter gestations. There were no significant between-group differences in numbers of pregnancy complications or pregnancy outcomes as reflected in gestational age at birth, birthweight, or Apgar scores. Children with isolated mild ventriculomegaly tended to be male. This study indicates that isolated mild ventriculomegaly detected in utero is not associated with pregnancy complications and suggests that isolated mild ventriculomegaly of the fetus is genetically determined or caused by environmental events not routinely considered pregnancy complications. © 1998 Elsevier Science B.V. All rights reserved. Keywords: Brain development; Human; Obstetric complications; Fetus; Pregnancy

1. Introduction Enlargement of the lateral cerebral ventricles is the most common structural brain abnormality * Corresponding author. Tel: +1 919 966 6971; Fax: +1 919 966 9646; e-mail: [email protected] 1Presented in part at the 36th Annual Meeting, American College of Neuropsychopharmacology, Waikoloa, Hawaii, 10 December 1997.

associated with schizophrenia. Enlargement of the lateral ventricles has been detected in both postmortem studies ( Falkai and Bogerts, 1995) and in neuroimaging studies (Chua and McKenna, 1995). A meta-analysis of neuroimaging studies found that 37–41% of the distributions of ventricle size in patients with schizophrenia did not overlap with that of controls (Raz and Raz, 1990). A recent case-control study found that enlarged lateral ventricles increase the likelihood of having schizo-

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phrenia with an odds ratio of approximately 2.0 (Jones et al., 1994b). Therefore, mild ventricular enlargement is likely a risk factor or a marker of increased risk for schizophrenia. While the association between schizophrenia and mild enlargement of the lateral cerebral ventricles is clear, it is not known when this structural abnormality arises. Neuroimaging studies of firstepisode patients with schizophrenia reveal increased lateral ventricle volumes, indicating that the lateral ventricle enlargement precedes the clinical onset of symptoms in schizophrenia ( Weinberger et al., 1982; Owens et al., 1985; Degreef et al., 1992; Nopoulos et al., 1995). Studies of postmortem brain tissue of patients with schizophrenia have revealed a variety of subtle cytoarchitectural abnormalities consistent with abnormal neurodevelopment (Falkai and Bogerts, 1995). In addition, people with schizophrenia are more likely to have had prenatal and/or obstetric complications than controls (Geddes and Lawrie, 1995). Children who ultimately develop schizophrenia have delayed motor milestones, speech problems, lower educational test scores (Jones et al., 1994a), and social maladjustment (Done et al., 1994). Neuropsychological studies of children genetically at risk of schizophrenia have revealed a variety of neuropsychological and motor abnormalities [ for reviews, see Fish et al. (1992) and Kremen et al. (1994)]. The weight of evidence indicates that early brain development is abnormal in at least some forms of schizophrenia [ for review see Gilmore et al. (1997)]. Therefore, it is critical to develop methods of assessing brain development in utero and understanding factors—genetic and environmental— that influence in-utero brain development. One promising methodology is ultrasound. Prenatal ultrasound imaging is a standard, readily available, and inexpensive means of assessing the developing fetal brain. We have used ultrasound to study discordancy of fetal brain development in monozygotic twins (Gilmore et al., 1996). Besides measures of fetal head structure typically used in clinical settings—head circumference and biparietal diameter—it is possible to image and measure lateral cerebral ventricle width. The width of the atrium of the lateral ventricle averages 7.6 mm and is stable throughout gestation

(Monteagudo et al., 1996). Studies of prenatal ventricle development have described a clinical entity designated as ‘mild ventriculomegaly’. Typically defined as the width of the atrium of the lateral ventricle of 10–15 mm, mild ventriculomegaly is associated with developmental abnormalities of the CNS, including trisomy 21, neural tube defects, agenesis of the corpus callosum, and microcephaly (Mahoney et al., 1988; Bromley et al., 1991; Hertzberg et al., 1994; Patel et al., 1994; Tomlinson et al., 1997). More significantly, when mild ventriculomegaly is isolated (not associated with other abnormalities), it is associated with mild developmental abnormalities, including motor and language delays, in about 20% of the children (Bromley et al., 1991; Hertzberg et al., 1994; Patel et al., 1994). A recent study found that children with in-utero isolated mild ventriculomegaly had significantly lower scores on the Bayley mental and psychomotor development indexes than controls at 22 months of age; 36% of children with isolated mild ventriculomegaly met criteria for developmental delay, versus 5% of the control group (Bloom et al., 1997). Isolated mild ventriculomegaly detected in utero is associated with subsequent mild neurodevelopmental abnormalities similar to those observed in children at high risk of schizophrenia. Isolated mild ventriculomegaly detected in utero ultimately may be a risk factor for schizophrenia and other neurodevelopmental disorders associated with enlarged lateral ventricles. It has been hypothesized that pre- or perinatal environmental insults such as infection, hypoxia, or trauma contribute to ventricular enlargement in schizophrenia (Lewis and Murray, 1987). There have been no prior studies of pre- and perinatal complications in children with isolated mild ventriculomegaly detected in utero, although levels of interferonalpha in cord blood of children with mild ventriculomegaly are higher than controls, possibly indicating an association with prenatal viral infection (Dommergues et al., 1996). This study was carried out to characterize associations of isolated mild ventriculomegaly of the fetal brain with pre- and perinatal obstetric complications and with pregnancy outcome. In this way, a better understanding of the nature of isolated mild ventriculomegaly

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that arises in utero and its potential relationship to schizophrenia may be gained.

2. Methods Reports of prenatal ultrasounds performed at Duke University Medical Center during 52 months from 1985 through 1992 (all months not available) were reviewed for reports describing the width of the atrium of the lateral ventricle as ‘mildy prominent’, ‘prominent’, ‘upper limit of normal’, ‘mildly enlarged’, or ‘mild ventriculomegaly’ (see Fig. 1 for representative ultrasound ). The width of the atrium of the lateral ventricle was determined in an axial scan plane obtained at the level of the choroid plexus. The measurement was made perpendicular to the long axis of the ventricle by positioning electronic calipers on the medial and lateral walls of the atrium of the ventricle. Subjective assessment of the degree of filling of the ventricle by the choroid plexus was also considered in assessing ventricle size. A low intra- and interobserver variability has been reported for this assessment (Cardoza et al., 1988). In these clinical scans, the width of the ventricles was not recorded; rather qualitative descriptions of this assessment were reported. The records of all months between these dates were not available; a total of 52 months were

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reviewed. Fifty-one subjects met inclusion criteria: mildly enlarged ventricles in the absence frank hydrocephalus or other congenital abnormalities, complete pregnancy and birth records, and no evidence of ‘normalization’ of ventricle size during pregnancy. Forty-nine control subjects were identified by a random review of subjects scanned in the same week as the mild ventriculomegaly cases, with a similar gestational age and no evidence of congenital abnormalities (three subjects in a twin pregnancy were matched with a randomly chosen control in a multiple gestation pregnancy). For these cases, all available records were reviewed for demographic information, maternal medical history, and prenatal and perinatal complications, as well as birth weight, gestational age at birth, APGAR scores, and head circumference at birth. T-test and chi-squares were performed to test for group differences in the presence of prenatal and perinatal complications, and pregnancy outcome measures. A post-hoc, exploratory analysis was preformed on the presence of individual complications. The level of significance was set at 0.05 for all non-directional tests. Bonferroni corrections for numbers of statistical tests done were not performed as this study is a preliminary, hypothesis generating study. Data analysis was conducted using SAS 6.11 (Cary, NC ).

3. Results

Fig. 1. Representative ultrasound of mild enlargement of the atrium of the lateral ventricle. Cross-hairs indicate electronic calipers.

The mean (±s.d.) gestational age at which MVM was first noted on ultrasound was 26.9±4.2 weeks. Maternal and offspring demographics are shown in Table 1. Mothers of children with MVM were significantly older than control mothers ( p=0.002). Offspring with MVM tended to be male, though this did not reach statistical significance ( x2=1.9, df=1, p=0.16). There were no differences in the numbers of pregnancies with pre- or perinatal complications between the MVM and control groups (see Table 2). The average numbers (mean±s.d.) of prenatal complications (MVM, 2.2±1.7; vs. control, 2.5±1.6; p=0.47), or perinatal complications (MVM, 2.4±1.7 vs. control, 2.4±1.6; p=0.96) per pregnancy were not significantly different

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Table 1 Group demographic information

Maternal ethnicity African-American Caucasian Other Maternal age (mean±s.d.)a Parity (mean±s.d.) Gender of child Male Female

Mild ventriculomegaly (n=51)

Control (n=49)

18 (35%) 31 (61%) 2 (4%) 29.3 (6.2) 2.1 (1.1)

26 (53%) 22 (45%) 1 (2%) 25.7 (5.2) 1.8 (1.1)

35 (69%) 16 (31%)

27 (55%) 22 (45%)

at-test; p=0.002.

Table 2 Complications during pregnancy: subjects with one or more complications during pregnancy

Prenatal complications Perinatal complications Maternal medical problemsa

Mild ventriculomegaly

Control

44 (86%) 43 (90%) 19 (45%)

46 (94%) 39 (85%) 30 (68%)

x2=4.6; adf=1; p=0.032.

Table 3 Prenatal complications

Preterm labor Pregnancy induced hypertension Pregnancy induced diabetes Colds/fever Infections Bleeding Placental problems Premature rupture of membranes Polyhydramnios Oligohydramnios Rubella risk Small for gestational age Large for gestational age Other

Mild ventriculomegaly

Control

7 5 5 3 18 15 7 4 3 8 0 3 13 19

10 7 5 7 17 10 4 3 1 7 2 4 8 25

(14%) (10%) (10%) (6%) (35%) (29%) (14%) (8%) (6%) (16%) (6%) (25%) (37%)

(20%) (14%) (10%) (14%) (35%) (20%) (8%) (6%) (2%) (14%) (4%) (8%) (16%) (51%)

Percentages may not reflect total numbers in each group due to some missing data.

between the MVM and control group. Control mothers were more likely to have had a medical condition during pregnancy ( x2=4.6, df=1, p= 0.03). Frequencies of individual pre- and perinatal complication are presented in Tables 3 and 4,

respectively. Percentages may not reflect the total numbers in each group due to some missing data. Measures of pregnancy outcome are presented in Table 5. Pregnancies with children with MVM tended to be shorter than control pregnancies ( p=

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J.H. Gilmore et al. / Schizophrenia Research 33 (1998) 133–140 Table 4 Birth complications

Induced labor Caesarean section Forcepts Vacuum Breech Meconium-stained amniotic fluid Abnormal cardiotocography Nuchal cord Meconium aspiration Oxygen required Asphyxia Rh incompatibility Other

Mild ventriculomegaly

Control

11 15 12 5 1 6 16 8 1 28 0 8 5

15 14 5 6 2 4 21 8 0 26 0 8 6

(26%) (30%) (24%) (10%) (3%) (13%) (32%) (17%) (2%) (17%) (17%) (10%)

(39%) (29%) (10%) (12%) (6%) (9%) (46%) (17%) (57%) (17%) (13%)

Percentages may not reflect total numbers in each group due to some missing data. Table 5 Pregnancy outcome

Gestational age at birth (weeks)a Mean birth weight (g) Head circumference APGAR 1 min APGAR 5 min

Mild ventriculomegaly (mean±s.d.)

Control (mean±s.d.)

37.8±3.2 (n=51) 3085±823 (n=51) 34.1±2.3 (n=17) 7.9±1.6 (n=50) 8.9±0.6 (n=51)

38.8±1.9 (n=49) 3149±627 (n=49) 34.6±2.0 (n=39) 8.08±1.2 (n=47) 9.0±0.5 (n=47)

ap=0.056.

0.056). There were no differences in birthweight, APGAR scores at 1 or 5 min, or head circumference at birth between the MVM and control groups (all t-tests p>0.05). Because of the significant group differences in maternal age, additional ANCOVA analyses were performed. Controlling for maternal age, there remained no significant differences in the average numbers of prenatal or perinatal complications per pregnancy between the MVM and control group. Gestational age at birth in the MVM group was significantly shorter than the control group controlling for maternal age ( p=0.045). Other group differences in pregnancy outcome remained nonsignificant. 4. Discussion In this retrospective chart review study, isolated mild ventriculomegaly detected in utero with ultra-

sound was not more likely to be associated with pre- or perinatal complications or poor neonatal outcome. MVM was associated with a greater maternal age and lower gestational age at birth. If confirmed in a prospective study, the lack of association of pre- and perinatal complications and isolated mild ventriculomegaly of the fetal brain would indicate that isolated mild ventriculomegaly is genetically determined or associated with subtle environmental factors not usually considered obstetric risk factors. Twin and family studies indicate that ventricle size in people with schizophrenia is in part genetically determined ( Weinberger et al., 1981; Reveley et al., 1982, 1984; DeLisi et al., 1986), and it is likely that ventricle size in the general population is also genetically determined. Subtle environmental events may also contribute to isolated mild ventriculomegaly of the fetal brain. Advancing maternal age is associated with a variety of poor

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pregnancy outcomes, including obstetrical bleeding, spontaneous abortions, prematurity, and low birth weight, as well as with chromosomal abnormalities (Cunningham et al., 1997). The older maternal age in the MVM group may be associated with subtle environmental insults that contribute to a larger ventricle size in utero. However, the fact that the control group had significantly more maternal medical problems than the MVM group, which would also be an indicator of increased risk for subtle insults to the developing fetus, makes this hypothesis less tenable. The older maternal age in the MVM group is consistent with studies showing an association of schizophrenia with older maternal age (Dalen, 1988). Males appear to be more likely to have mildly enlarged ventricles in utero. Males tend to have larger ventricles than females in utero (Patel et al., 1995). The male predominance in the mild ventriculomegaly group is very interesting, considering that enlarged ventricles are more frequent in males with schizophrenia (Raz and Raz, 1990). It is also consistent with the increased risk that males have for neurodevelopmental disorders associated with mildly enlarged ventricles, including autism and mental retardation ( Kaplan and Sadock, 1988). Efforts have been made to determine how genetic and environmental factors contribute to the enlarged lateral ventricles observed in schizophrenia. However, most studies have not found any association between ventricle size and prenatal or obstetrical complications in adults with schizophrenia (DeLisi et al., 1988; Nimgaonkar et al., 1988; Jones et al., 1994a; O’Callaghan et al., 1995). Studies of a high-risk cohort found that larger ventricular size was associated with both a genetic risk of schizophrenia and the presence of birth complications (Cannon et al., 1989, 1993). Overall, studies have not consistently related ventricle enlargement in adults with schizophrenia with a positive family history of schizophrenia [Jones et al., 1994b; O’Callaghan et al., 1995; for a review, see Roy and Crowe (1994)]. Mild enlargement of the lateral ventricles observed in adults with schizophrenia is likely caused by a variety of genetic and environmental factors that operate over the developmental spectrum. The ventricular enlargement detected in

this study was present by the end of the second trimester, prior to birth. This form of mild ventricular enlargement was not associated with prenatal or perinatal complications, and is thus more likely caused by genetic or subtle environmental factors that influence in-utero brain development. There are limitations to these data, as the study was a retrospective chart review and relied on a qualitative description of ventricle width to classify subjects. However, archived films with a ventricular width were available for 32 subjects in the MVM group. The width of the atrium of the lateral ventricle in the scan taken at the greatest gestational age was measured by a board-certified radiologist (MAK ). The mean width (±s.d.) was 10.1±1.7 mm, indicating that the subjects classified as MVM did have mildly enlarged ventricles. The study population, both MVM and controls, had rather high rates of pre- and perinatal complications, consistent with a high-risk population drawn from an urban tertiary medical center. However, this should not invalidate the lack of association between MVM and pre- and perinatal complications. While it remains to be shown that isolated mild enlargement of the lateral ventricles in the fetus is a marker for increased risk of schizophrenia, it has been demonstrated that it is associated with other neurodevelopmental delays (Bromley et al., 1991; Hertzberg et al., 1994; Patel et al., 1994; Bloom et al., 1997). Subtle abnormalities of fetal brain development have been implicated in a variety of neurodevelopmental disorders, including schizophrenia. It is likely that fetal mild ventriculomegaly is a marker of abnormal brain development that is associated with an increased risk of a range of neurodevelopmental problems, including mental retardation, autism, and learning disorders, and is not specific to schizophrenia. Ultrasound offers a non-invasive, relatively inexpensive way of assessing subtle abnormalities of fetal brain development. A follow-up study of children with MVM is currently underway.

Acknowledgment Supported by the Foundation of Hope, Raleigh, NC, and Center Grant MH 33127.

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