Schizophrenia Research 157 (2014) 305–309
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Adverse obstetric and neonatal outcomes in women with severe mental illness: To what extent can they be prevented? Fiona Judd a,b,⁎, Angela Komiti a,b, Penny Sheehan c, Louise Newman d, David Castle a,e, Ian Everall a,f,g a
Department of Psychiatry, The University of Melbourne, Melbourne, Australia The Centre for Women's Mental Health, Royal Women's Hospital, Melbourne, Australia Pregnancy Research Centre, Royal Women's Hospital, Melbourne, Australia d Centre for Developmental Psychiatry & Psychology, Monash University, Melbourne, Australia e St Vincent's Hospital, Melbourne, Australia f Florey Institute of Neuroscience and Mental Health, Melbourne, Australia g North West Mental Health, Melbourne, Australia b c
a r t i c l e
i n f o
Article history: Received 10 September 2013 Received in revised form 29 April 2014 Accepted 17 May 2014 Available online 13 June 2014 Keywords: Schizophrenia Bipolar disorder Pregnancy Pre-eclampsia Pre-term birth
a b s t r a c t Background: Women with schizophrenia and bipolar disorder are at a higher risk of obstetric and neonatal complications. The aim of this study was to better understand the factors that may influence these adverse outcomes. Method: We examined obstetric and neonatal outcomes of pregnant women with schizophrenia and bipolar disorder and factors possibly influencing these outcomes. A retrospective review of the medical history of 112 women with a DSM-IV diagnosis of schizophrenia or bipolar disorder was undertaken. Data for controls were extracted from the hospital's electronic birth record data. Results: Women with schizophrenia and bipolar disorder presented later for their first antenatal visit and had higher rates of smoking and illicit drug use than the control group. They also had higher rates of pre-eclampsia and gestational diabetes. Their infants were less likely to have Apgar scores 8–10 at both 1 and 5 minutes and were more likely to be admitted to special care/neonatal intensive care nursery than the infants of controls. The rate of pre-term birth was significantly increased in the women with schizophrenia and bipolar disorder. Pre-term birth and admission to special care/neonatal intensive care were predicted by smoking and illicit drug use. Conclusion: These data point to potentially modifiable factors as significant contributors to the high rate of adverse obstetric and neonatal outcomes in women with mental illness. Comprehensive management of women with mental illness prior to, during pregnancy and in the postnatal period may have long-term benefits for their offspring. © 2014 Elsevier B.V. All rights reserved.
1. Introduction Pregnancy and birth complications may result in a range of injuries extending from fetal and neonatal death to developmental compromise including later emotional, cognitive and behavioral problems in the child (Verdoux and Bourgeois, 1993; Schetter and Tanner, 2012; Unterscheider et al., 2014). Data linkage studies have shown that women with schizophrenia (Bennedsen et al., 2001; Nilsson et al., 2002; Jablensky et al., 2005) and bipolar disorder are at increased risk of a range of obstetric and neonatal complications (MacCabe et al., 2007; Lee and Lin, 2010; Bodén et al., 2012). Women with
⁎ Corresponding author at: The Centre for Women's Mental Health, The Royal Women's Hospital, Locked Bag 300, Grattan St & Flemington Rd, Parkville, VIC 3052, Australia. Tel.: +61 3 8345 2077; fax: +61 3 8345 2070. E-mail address: fi[email protected] (F. Judd).
http://dx.doi.org/10.1016/j.schres.2014.05.030 0920-9964/© 2014 Elsevier B.V. All rights reserved.
schizophrenia have an increased risk of pre-term birth, low birth weight and small for gestational age babies (Bennedsen et al., 2001; Nilsson et al., 2002; Jablensky et al., 2005), greater risk of placental abruption (Jablensky et al., 2005) and of infants with cardiovascular congenital abnormalities (Jablensky et al., 2005), stillbirth and infant death (Nilsson et al., 2002). Women with schizophrenia have also been shown to be at greater risk of interventions such as cesarean section, vaginal assisted delivery, and pharmacological stimulation of labor (Bennedsen et al., 2001). Women with bipolar disorder have an increased risk of preterm birth (MacCabe et al., 2007; Lee and Lin, 2010) and small or growth retarded babies (MacCabe et al., 2007; Lee and Lin, 2010; Bodén et al., 2012) as well as increased risk of placenta previa and antepartum hemorrhage (Jablensky et al., 2005). Studies have also shown that pregnancy outcomes are worse for women with schizophrenia than those with bipolar disorder (Verdoux and Bourgeois, 1993; Jablensky et al., 2005). The cause(s) of these complications and the potential to prevent them is unclear. Possible causative factors include an abnormality in
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fetal development due to a genetic predisposition, the effects of maternal mental illness and stress, co-morbid problems such as sociodemographic disadvantage, poor nutrition and associated lifestyle factors, poor attendance at antenatal care, or the effects of prescribed drugs (Sacker et al., 1996; Jablensky et al., 2005; McColl et al., 2013). It is likely that multiple factors influence risk and mediate poor outcomes. Data sets vary in the range and detail of information available to explore causal hypotheses and the effects of potential confounding factors. In particular, information about the quality and quantity of both obstetric and mental health care provided to women during their pregnancy is usually scant. Recently, Nguyen et al. (2012) compared obstetric and neonatal outcomes of a sample of women with severe mental illness (SMI) with general population data. Consistent with previous studies, women with SMI had a lower rate of spontaneous vaginal delivery and a higher rate overall of complications of pregnancy. In contrast with some earlier studies, women with SMI had a greater risk of gestational diabetes mellitus and pre-eclampsia. In addition, the birth weights of infants of women with SMI were similar to those in the control group, and risk of preterm birth was not significantly greater compared with controls. A changed profile of obstetric and neonatal outcomes suggests that factors other than or in addition to genetic predisposition, may account for the higher rates of complications seen in women with SMI. If this is so, these complications may be preventable, with the potential to reduce later emotional, cognitive and behavioral problems in the children of women with SMI. The current study was undertaken to further explore the nature of obstetric and neonatal outcomes of pregnant women with schizophrenia and bipolar disorder, as well as determine factors possibly influencing these outcomes. 2. Methods 2.1. Setting The Royal Women's Hospital (RWH) in Melbourne, is Australia's largest specialist women's hospital, providing care to women with ‘high risk’ pregnancies as well as to all women living in a local catchment area. Care is delivered by four multidisciplinary teams (Teamcare) comprising midwives, obstetricians, a social worker, dietician, physiotherapist, physician and psychiatrist. The hospital has a multidisciplinary consultation-liaison mental health team. Women with mental health problems are seen in Teamcare rather than in a stand-alone or specialist clinic. All women identified in the antenatal period as having a mental health problem by maternity staff are referred to the team psychiatrist who then provides direct care to the woman and/or is involved in ongoing liaison with the woman's usual mental health care provider. The study received ethical approval by the institutional review board. 2.2. Subjects Women who delivered a baby at the hospital were included in the study if a diagnosis of schizophrenia or bipolar disorder was made following clinical interview with the maternity team psychiatrist between August 2008 and September 2012. Diagnoses were made using DSM-IV criteria. Data were collected by retrospective file audit. A comparison sample was obtained from the hospital's electronic birth record data for the period 2009–2012. The Centricity Perinatal data recording system (GE) was first introduced at RWH in October 2009 and contains information regarding antenatal course as well as labor and delivery. Our control sample comprised all women seen for antenatal care who delivered at the hospital from 2009 to September 2012, but excluding those with schizophrenia or bipolar disorder. Hereafter, the women with schizophrenia and bipolar disorder and the comparison sample will be referred to as the study group and control group, respectively.
2.3. Data analysis Prior to analysis, the data were examined for the assumptions of normality required for parametric tests. No violations of assumptions were found. Independent sample t-tests were used to compare groups on continuous measures and Pearson chi-square tests were employed for categorical data. Two separate logistic regression analyses were conducted. The first was to test predictors of the antenatal complication of pre-eclampsia and the second to test for predictors of the neonatal complication of pre-term birth. Four predictors (smoking, alcohol use, illicit drug use and having a diagnosis of either schizophrenia or bipolar disorder) were used for both logistic regression analyses. Direct logistic regression method was used whereby all four predictors were entered simultaneously into each equation. Significant predictors were identified by examining the resultant Wald test statistics, odds ratios (OR) and 95% confidence intervals (CI). A multiple regression analysis was then performed to identify whether the same set of predictors used in the logistic regression, predicted birth weight in the combined study and control group. Differences for all analyses were considered statistically significant at p b .05. For the chi-square tests, Fisher's exact test was reported when cell numbers were less than expected. All statistical analyses were performed using the statistical software package IBM SPSS for Windows release 21.0. 3. Results 3.1. Antenatal care Sixty-three women with schizophrenia and 49 women with bipolar disorder were seen during the period of interest. The pregnancies resulted in 110 singleton births and two twin births. One twin in one of the sets was stillborn. The control sample identified comprised 19,755 women. As can be seen in Table 1, the women in the study group were, on average, older and presented for their first antenatal visit significantly later in their gestation (18.8 weeks) compared to the control group (15.1 weeks). Women in the study group attended a mean of 8.8 (±3.6) antenatal visits. This same information regarding the control population was unavailable for comparison. Smoking, alcohol use and illicit drug use were all significantly higher among the study group compared to the controls. The same comparison was then undertaken between the women with schizophrenia and bipolar disorder. There were few differences between the two groups except that antenatal therapeutic drug exposure was significantly different between the two disorders. Although antipsychotic medications were the most commonly prescribed drug for both groups, the women with schizophrenia were significantly more likely to take these medications than the bipolar group (65% vs. 43%, p = .02). Women with schizophrenia attended their first antenatal visit a little later than did those with bipolar disorder (19.7 ± 8.4 weeks vs. 17.6 ± 7.0) and alcohol use, smoking and illicit drug use in pregnancy was higher in the group with schizophrenia than those with bipolar disorder, but these differences did not reach statistical significance. Just under 10% of women with schizophrenia or bipolar disorder, were admitted to an acute psychiatric unit during their pregnancy (12.7% with schizophrenia and 6.1% with bipolar disorder). Following the birth of their baby, 20.6% of women with schizophrenia and 10.2% with bipolar disorder were admitted with their infant to a mother baby psychiatric unit. Statutory child welfare services were significantly (p b .001) more likely to be involved with women with schizophrenia (34.9%) than those with bipolar disorder (8.2%). 3.2. Obstetric outcomes The study group had significantly more obstetric complications than controls. Women with schizophrenia and bipolar disorder had
F. Judd et al. / Schizophrenia Research 157 (2014) 305–309
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Table 1 Antenatal care: Comparing study and control groups.
Mean age (SD) Alcohol use (%) Smoking—b20 weeks (%) Illicit drug use (%) Mean gestation at 1st AN appt. (SD)
Study (n = 112)
Control (n = 19,755)
χ2/t-test
p
31.7 (6.1) 20.6 38.3 17.9 18.8 (7.8)
30.4 (5.3) 0.6 6.6 2.6 15.1 (6.6)
−2.3 625 171 95.5 −5.0
.02 b.001 b.001 b.001 b.001
Note: AN = antenatal.
significantly higher risk of pre-eclampsia (11.0% vs. 2.6%, p b .001) and gestational diabetes (12.7% vs. 6.4%, p = .007); the incidence of gestational diabetes (14.5% v 10.4%) and pre-eclampsia (11.4% vs. 10.6%) was not significantly different between the schizophrenia and bipolar disorder groups. Outcomes for labor and delivery were similar for both the study and control groups.
reveals a significant difference in babies born under the 25th centile. Even when smokers were excluded, the difference in birth weights (for term infants) between the two groups remained significant (3299 ± 521 gm vs. 3591 ± 482 gm; p = .04).
3.3. Predictors of pre-eclampsia
The results of the logistic regression analysis (Table 4) indicated that smoking and illicit drug use in pregnancy were the only independent significant predictors of preterm (b 37 weeks) birth in this cohort. Smoking doubled the risk of delivering a pre-term infant and illicit drug use increased the risk by almost one and half times.
Logistic regression analysis was used to determine whether smoking, alcohol use, illicit drug use and having a diagnosis of schizophrenia or bipolar disorder predicted the pregnancy complication of pre-eclampsia. Having a diagnosis of schizophrenia or bipolar disorder was the only significant predictor (p b .001), conferring a five-fold increased risk of having pre-eclampsia. A summary of the logistic regression is presented in Table 2. 3.4. Neonatal outcomes Data regarding the rates of congenital abnormality were not available for the control group. In the study group, one infant was still-born and six infants (5.4%) were born with congenital abnormalities, including echogenic intracardiac focus (EIF) in papillary muscle, two cases of clicky hip, two cases of ventricular septal defect (VSD) and a case of Ebstein's anomaly. The two infants with VSD were born to women with schizophrenia and the mother of the infant with Ebstein's anomaly had bipolar disorder and was treated with lithium during pregnancy. Neonatal outcomes are shown in Table 3. Babies born to women with schizophrenia or bipolar disorder were less likely to have an Apgar score of ≥8 at 1 minute or at 5 minutes compared to the control group. The mean birth weight of infants born to women in the study group was only slightly less than that of infants of women in the control group, and excluding smokers reduced the difference even further. The rate of preterm birth was significantly increased in the study group compared to the controls and a greater percentage of their infants than of controls required admission to special care/neonatal intensive care (NISC) nursery. Compared to infants of women who did not smoke (30.9%) or use illicit drugs (11.3%) during pregnancy, the infants of women who smoked (61.5%) or used illicit drugs (38.5%) were significantly more likely to require admission to NISC. There was only one difference on the indices of neonatal outcomes between the women with schizophrenia and bipolar disorder. Babies born at term (≥ 37 weeks) to the women with schizophrenia were significantly smaller than those born to women in the bipolar group (3256 ± 470 gm vs. 3463 ± 491 gm; p = .04) and closer investigation
Table 2 Summary of logistic regression equation predicting pre-eclampsia. Predictor
B
Wald χ2
p
OR (CI)
Smoking Alcohol use Drug use Diagnosis⁎
−0.36 0.10 −0.02 1.66
2.85 0.04 0.00 26.26
.09 .84 .96 b.001
0.70 (0.46–1.06) 1.10 (0.41–2.94) 1.00 (0.54–1.81) 5.28 (2.79–9.98)
⁎ Schizophrenia or bipolar disorder.
3.5. Predicting pre-term birth
4. Discussion 4.1. General findings This study examined the obstetric and neonatal outcomes of women with schizophrenia and bipolar disorder compared with those of women without these diagnoses treated in the same maternity setting. Notably, while the delivery outcomes for the study group were not statistically different from controls, important differences in antenatal characteristics, obstetric and neonatal outcomes were identified. Firstly, women in the clinical sample were older than controls. They attended their first antenatal appointment later in the pregnancy, and were much more likely to have used alcohol or illicit drugs and smoked during the pregnancy. As would be expected, a large number in the clinical sample were treated with antipsychotic medication. Both obstetric and neonatal outcomes were worse for women in the study sample compared with the control group. Women in the clinical sample had more complications of pregnancy, and higher rates of preeclampsia and gestational diabetes compared to the control group. Women in the clinical group had a higher risk of pre-term birth, and their infants were less likely to have an Apgar score of 8–10 at both 1 and 5 minutes, and more likely to be admitted to NISC. The admission to NISC figures may be artificially increased by the illicit drug use in this group, requiring the baby to be admitted to SCN for observation of signs of drug withdrawal. Preterm birth is likely to be explained by higher rates of smoking in the clinical sample. In contrast to the findings of earlier studies, we did not find a greater rate of intervention at the time of delivery. This finding may reflect the treatment setting, a specialist maternity hospital with a focus on the management of ‘high risk’ pregnancies, the frequency of attendance by women for antenatal care, and the low need for psychiatric inpatient admission during pregnancy. Previous studies have demonstrated a greater rate of low birth weight infants and of small or growth retarded babies in mothers with SMI (Bennedsen et al., 2001; Nilsson et al., 2002; Jablensky et al., 2005; MacCabe et al., 2007; Lee and Lin, 2010; Bodén et al., 2012). Like Nguyen and colleagues (Nguyen et al., 2012), we did not find a greater risk of these complications. Our study confirmed the finding of increased risk of preterm birth seen in data linkage studies (Bennedsen et al., 2001; Nilsson et al., 2002; Jablensky et al., 2005; MacCabe et al., 2007; Lee and Lin, 2010) but not in the more recent study of Nguyen et al. (2012). However, our findings of higher rates of gestational diabetes and pre-eclampsia are consistent with those of Nguyen et al. (2012) and
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Table 3 Neonatal outcomes: comparing study and control groups.
Apgar score 8–10 at 1 min (%) Apgar score b4 at 1 min (%) Apgar score 8–10 at 5 min (%) Mean infant weight, grams (SD) - Excluding smokers Mean gestation at birth, weeks (SD) Pre-term births (b37 weeks) (%) NISC admission (%)
Study (n = 112)
Control (n = 19,755)
χ2/t-test
p
69.6 5.4 86.6 3172 (680) 3262 (711) 38.4 (2.7) 17.9 27.7
79.8 5.7 92.5 3247 (719) 3275 (699) 38.5 (3.0) 10.9 12.5
7.08 0.02 5.43 1.10 0.15 0.46 5.52 23.38
.008 .88 .02 .27 .88 .64 .02 b.001
Note: NISC = neonatal intensive special care.
appear to indicate a change in the profile of obstetric risks seen for women with schizophrenia and bipolar disorder. In our study, a clinical diagnosis of schizophrenia or bipolar disorder conferred a five times increased risk of pre-eclampsia, a major obstetric problem which can lead to substantial maternal and perinatal complications. The latter include pre-term delivery and hypoxia–neurologic injury (Sibai et al., 2005). In addition, pre-eclampsia has been linked to an increased risk of later schizophrenia (Dalman et al., 1999). Although we did not have data from the control group for comparison, two-thirds of the women in the clinical sample were overweight or obese (BMI N 25) at their first antenatal visit with the largest group (38.4%) BMI N 30 or obese. This is much higher than the estimate for obesity in major cities of 18.4% obtained from the Ausdiab study, for example (Cameron et al., 2003). Obesity is known to be a strong risk factor for pre-eclampsia with one study estimating that every unit increase in pre-pregnancy BMI resulted in an 8% increased risk of pre-eclampsia (Frederick et al., 2006). Obstetric and neonatal complications in women with SMI may cumulate to impact negatively the neurodevelopmental trajectory of their child. In addition, mothers with mental illness are more likely to have difficulties in early emotional interaction with the infant and in promoting attachment organization. Infants may be exposed to stressful interactions and inconsistent care (Wan et al., 2008). These factors may all add to the risks posed by genetic loading for SMI to increase the likelihood of poor developmental outcomes. It is essential to determine whether the adverse obstetric and neonatal outcomes of women with schizophrenia and bipolar disorder relate to maternal risk factors such as lifestyle exposures including smoking, and alcohol and illicit drug use and socioeconomic disadvantage (Sacker et al., 1996; Jablensky et al., 2005) rather than being intrinsic to the clinical diagnosis as, if this is the case, interventions which aim to reduce both short and long-term adverse neurodevelopmental outcomes should be trialled. We found clear differences between women with a diagnosis of schizophrenia or bipolar disorder and the control group with respect to lifestyle exposures known to affect neonatal outcomes, and one of these lifestyle exposures, smoking, more than doubled the risk of delivering a pre-term infant. A recent review highlighted the increased risk of gestational metabolic complications and babies large for gestational age in women treated with second generation antipsychotics (Gentile, 2010). This raises the possibility that use of antipsychotic medications is an explanation for the elevated rate of gestational diabetes and preeclampsia found in this study, as prescribing patterns have changed over the last two decades and now typical or first generation medications
Table 4 Summary of logistic regression equation predicting pre-term (b37 weeks) birth. Predictor
B
Wald χ2
p
OR (CI)
Smoking Alcohol use Drug use Diagnosis⁎
0.85 0.01 0.28 0.16
121.72 0.00 5.15 0.34
b.001 .94 .02 .56
2.35 (2.02–2.73) 1.01 (0.63–1.61) 1.32 (1.04–1.68) 1.17 (0.69–2.00)
⁎ Schizophrenia or bipolar disorder.
are infrequently used. Changes in prescribing may also account for the lack of replication of previous findings regarding growth restriction and low birth weight babies. Further findings which may be linked to maternal medication use include the lower rate of Apgar scores of 8–10 and the higher rate of admission to NISC. Data regarding the reason for NISC admission underscore the role of smoking and illicit drug use in adverse neonatal outcomes. 4.2. Limitations A major strength of the study is that both the clinical and control groups received antenatal care in the same setting. However, the findings need to be considered within the context of several limitations of the study. First, we could not match the study group to the control group on any socio-demographic characteristics such as race or socioeconomic status nor on potential confounding variables such as parity, body mass index (BMI), hypertension or history of pre-eclampsia. Second, lack of information about some important variables, such as medication use among the controls and duration of illness in the study group, precluded investigation of some possible causative factors. It would also have been useful to understand the contribution of maternal nutritional status to the birth outcomes, however this information was not available. The role of these factors needs to be elucidated in future studies. A final limitation is that because of multiple comparisons, some of the significant findings, especially those bordering on p b .05 may not survive allowance for multiple comparisons. 5. Conclusions The findings of this study have implications for both maternity and mental health care of women with schizophrenia and bipolar disorder who wish to have children. The data point to maternal risk factors and lifestyle exposures, including prescribed medications, as being potent contributors to adverse outcomes. Important areas for consideration include choosing the best medication regimen that reduces the risk of relapse but pays attention to the potential risks of medication use and side-effects. Second, the importance of smoking reduction/cessation with or without the use of nicotine replacement therapy cannot be underestimated. Despite significant barriers to smoking cessation amongst women with mental illness, pregnancy is a time when all women are more likely to be motivated to stop smoking (Howard et al., 2013). Similarly, minimization of alcohol and illicit drug use is important. Pre-pregnancy care is a well-established approach in the management of pregnancies complicated by pre-existing diabetes (Ray et al., 2001; McCance, 2011). This approach focuses on optimizing a woman's average blood glucose level before becoming pregnant and thus minimizing the risks posed by her diabetes during pregnancy. A similar approach could be taken with women with pre-existing mental illness. Here, care would focus on addressing lifestyle and treatment related factors which appear to have significant effects on pregnancy outcome as well as stabilization of maternal mental state. This could then be followed by early attendance at antenatal care and careful monitoring for both mental health and obstetric health throughout the pregnancy
F. Judd et al. / Schizophrenia Research 157 (2014) 305–309
and the postnatal period. Strategies for reducing stress and supporting regular antenatal care and preparation for parenthood are important. This approach offers a means to improve the rate of adverse obstetric and neonatal outcomes in women with SMI. If this approach is adopted, further studies can be undertaken to determine, both the short and long-term impact, as well as barriers and facilitators to this type of care. Role of funding source The project was funded by internal department funds. Contributors The study was designed by F. Judd and P. Sheehan. The data collection and case audits were conducted A. Komiti and P. Sheehan. Statistical analysis was conducted by A. Komiti. The first copy of the manuscript was drafted by F. Judd and all other co-authors provided feedback and contributed to the subsequent revisions. All authors have approved the final manuscript. Conflict of interest The authors declare that there was no existing conflict of interest regarding the subject of this study Acknowledgments The authors are grateful to Drs. L. Laios, O Wong, D. Handrinos, K. Mercuri and T. Nguyen who provided clinical care to the women in the study and to Ms L. Rigg who provided data extracts from the GE system. The Centre for Women's Mental Health is supported by the Pratt Foundation.
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Contents lists available at ScienceDirect
Schizophrenia Research journal homepage: www.elsevier.com/locate/schres
Adverse obstetric and neonatal outcomes in women with severe mental illness: To what extent can they be prevented? Fiona Judd a,b,⁎, Angela Komiti a,b, Penny Sheehan c, Louise Newman d, David Castle a,e, Ian Everall a,f,g a
Department of Psychiatry, The University of Melbourne, Melbourne, Australia The Centre for Women's Mental Health, Royal Women's Hospital, Melbourne, Australia Pregnancy Research Centre, Royal Women's Hospital, Melbourne, Australia d Centre for Developmental Psychiatry & Psychology, Monash University, Melbourne, Australia e St Vincent's Hospital, Melbourne, Australia f Florey Institute of Neuroscience and Mental Health, Melbourne, Australia g North West Mental Health, Melbourne, Australia b c
a r t i c l e
i n f o
Article history: Received 10 September 2013 Received in revised form 29 April 2014 Accepted 17 May 2014 Available online 13 June 2014 Keywords: Schizophrenia Bipolar disorder Pregnancy Pre-eclampsia Pre-term birth
a b s t r a c t Background: Women with schizophrenia and bipolar disorder are at a higher risk of obstetric and neonatal complications. The aim of this study was to better understand the factors that may influence these adverse outcomes. Method: We examined obstetric and neonatal outcomes of pregnant women with schizophrenia and bipolar disorder and factors possibly influencing these outcomes. A retrospective review of the medical history of 112 women with a DSM-IV diagnosis of schizophrenia or bipolar disorder was undertaken. Data for controls were extracted from the hospital's electronic birth record data. Results: Women with schizophrenia and bipolar disorder presented later for their first antenatal visit and had higher rates of smoking and illicit drug use than the control group. They also had higher rates of pre-eclampsia and gestational diabetes. Their infants were less likely to have Apgar scores 8–10 at both 1 and 5 minutes and were more likely to be admitted to special care/neonatal intensive care nursery than the infants of controls. The rate of pre-term birth was significantly increased in the women with schizophrenia and bipolar disorder. Pre-term birth and admission to special care/neonatal intensive care were predicted by smoking and illicit drug use. Conclusion: These data point to potentially modifiable factors as significant contributors to the high rate of adverse obstetric and neonatal outcomes in women with mental illness. Comprehensive management of women with mental illness prior to, during pregnancy and in the postnatal period may have long-term benefits for their offspring. © 2014 Elsevier B.V. All rights reserved.
1. Introduction Pregnancy and birth complications may result in a range of injuries extending from fetal and neonatal death to developmental compromise including later emotional, cognitive and behavioral problems in the child (Verdoux and Bourgeois, 1993; Schetter and Tanner, 2012; Unterscheider et al., 2014). Data linkage studies have shown that women with schizophrenia (Bennedsen et al., 2001; Nilsson et al., 2002; Jablensky et al., 2005) and bipolar disorder are at increased risk of a range of obstetric and neonatal complications (MacCabe et al., 2007; Lee and Lin, 2010; Bodén et al., 2012). Women with
⁎ Corresponding author at: The Centre for Women's Mental Health, The Royal Women's Hospital, Locked Bag 300, Grattan St & Flemington Rd, Parkville, VIC 3052, Australia. Tel.: +61 3 8345 2077; fax: +61 3 8345 2070. E-mail address: fi[email protected] (F. Judd).
http://dx.doi.org/10.1016/j.schres.2014.05.030 0920-9964/© 2014 Elsevier B.V. All rights reserved.
schizophrenia have an increased risk of pre-term birth, low birth weight and small for gestational age babies (Bennedsen et al., 2001; Nilsson et al., 2002; Jablensky et al., 2005), greater risk of placental abruption (Jablensky et al., 2005) and of infants with cardiovascular congenital abnormalities (Jablensky et al., 2005), stillbirth and infant death (Nilsson et al., 2002). Women with schizophrenia have also been shown to be at greater risk of interventions such as cesarean section, vaginal assisted delivery, and pharmacological stimulation of labor (Bennedsen et al., 2001). Women with bipolar disorder have an increased risk of preterm birth (MacCabe et al., 2007; Lee and Lin, 2010) and small or growth retarded babies (MacCabe et al., 2007; Lee and Lin, 2010; Bodén et al., 2012) as well as increased risk of placenta previa and antepartum hemorrhage (Jablensky et al., 2005). Studies have also shown that pregnancy outcomes are worse for women with schizophrenia than those with bipolar disorder (Verdoux and Bourgeois, 1993; Jablensky et al., 2005). The cause(s) of these complications and the potential to prevent them is unclear. Possible causative factors include an abnormality in
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fetal development due to a genetic predisposition, the effects of maternal mental illness and stress, co-morbid problems such as sociodemographic disadvantage, poor nutrition and associated lifestyle factors, poor attendance at antenatal care, or the effects of prescribed drugs (Sacker et al., 1996; Jablensky et al., 2005; McColl et al., 2013). It is likely that multiple factors influence risk and mediate poor outcomes. Data sets vary in the range and detail of information available to explore causal hypotheses and the effects of potential confounding factors. In particular, information about the quality and quantity of both obstetric and mental health care provided to women during their pregnancy is usually scant. Recently, Nguyen et al. (2012) compared obstetric and neonatal outcomes of a sample of women with severe mental illness (SMI) with general population data. Consistent with previous studies, women with SMI had a lower rate of spontaneous vaginal delivery and a higher rate overall of complications of pregnancy. In contrast with some earlier studies, women with SMI had a greater risk of gestational diabetes mellitus and pre-eclampsia. In addition, the birth weights of infants of women with SMI were similar to those in the control group, and risk of preterm birth was not significantly greater compared with controls. A changed profile of obstetric and neonatal outcomes suggests that factors other than or in addition to genetic predisposition, may account for the higher rates of complications seen in women with SMI. If this is so, these complications may be preventable, with the potential to reduce later emotional, cognitive and behavioral problems in the children of women with SMI. The current study was undertaken to further explore the nature of obstetric and neonatal outcomes of pregnant women with schizophrenia and bipolar disorder, as well as determine factors possibly influencing these outcomes. 2. Methods 2.1. Setting The Royal Women's Hospital (RWH) in Melbourne, is Australia's largest specialist women's hospital, providing care to women with ‘high risk’ pregnancies as well as to all women living in a local catchment area. Care is delivered by four multidisciplinary teams (Teamcare) comprising midwives, obstetricians, a social worker, dietician, physiotherapist, physician and psychiatrist. The hospital has a multidisciplinary consultation-liaison mental health team. Women with mental health problems are seen in Teamcare rather than in a stand-alone or specialist clinic. All women identified in the antenatal period as having a mental health problem by maternity staff are referred to the team psychiatrist who then provides direct care to the woman and/or is involved in ongoing liaison with the woman's usual mental health care provider. The study received ethical approval by the institutional review board. 2.2. Subjects Women who delivered a baby at the hospital were included in the study if a diagnosis of schizophrenia or bipolar disorder was made following clinical interview with the maternity team psychiatrist between August 2008 and September 2012. Diagnoses were made using DSM-IV criteria. Data were collected by retrospective file audit. A comparison sample was obtained from the hospital's electronic birth record data for the period 2009–2012. The Centricity Perinatal data recording system (GE) was first introduced at RWH in October 2009 and contains information regarding antenatal course as well as labor and delivery. Our control sample comprised all women seen for antenatal care who delivered at the hospital from 2009 to September 2012, but excluding those with schizophrenia or bipolar disorder. Hereafter, the women with schizophrenia and bipolar disorder and the comparison sample will be referred to as the study group and control group, respectively.
2.3. Data analysis Prior to analysis, the data were examined for the assumptions of normality required for parametric tests. No violations of assumptions were found. Independent sample t-tests were used to compare groups on continuous measures and Pearson chi-square tests were employed for categorical data. Two separate logistic regression analyses were conducted. The first was to test predictors of the antenatal complication of pre-eclampsia and the second to test for predictors of the neonatal complication of pre-term birth. Four predictors (smoking, alcohol use, illicit drug use and having a diagnosis of either schizophrenia or bipolar disorder) were used for both logistic regression analyses. Direct logistic regression method was used whereby all four predictors were entered simultaneously into each equation. Significant predictors were identified by examining the resultant Wald test statistics, odds ratios (OR) and 95% confidence intervals (CI). A multiple regression analysis was then performed to identify whether the same set of predictors used in the logistic regression, predicted birth weight in the combined study and control group. Differences for all analyses were considered statistically significant at p b .05. For the chi-square tests, Fisher's exact test was reported when cell numbers were less than expected. All statistical analyses were performed using the statistical software package IBM SPSS for Windows release 21.0. 3. Results 3.1. Antenatal care Sixty-three women with schizophrenia and 49 women with bipolar disorder were seen during the period of interest. The pregnancies resulted in 110 singleton births and two twin births. One twin in one of the sets was stillborn. The control sample identified comprised 19,755 women. As can be seen in Table 1, the women in the study group were, on average, older and presented for their first antenatal visit significantly later in their gestation (18.8 weeks) compared to the control group (15.1 weeks). Women in the study group attended a mean of 8.8 (±3.6) antenatal visits. This same information regarding the control population was unavailable for comparison. Smoking, alcohol use and illicit drug use were all significantly higher among the study group compared to the controls. The same comparison was then undertaken between the women with schizophrenia and bipolar disorder. There were few differences between the two groups except that antenatal therapeutic drug exposure was significantly different between the two disorders. Although antipsychotic medications were the most commonly prescribed drug for both groups, the women with schizophrenia were significantly more likely to take these medications than the bipolar group (65% vs. 43%, p = .02). Women with schizophrenia attended their first antenatal visit a little later than did those with bipolar disorder (19.7 ± 8.4 weeks vs. 17.6 ± 7.0) and alcohol use, smoking and illicit drug use in pregnancy was higher in the group with schizophrenia than those with bipolar disorder, but these differences did not reach statistical significance. Just under 10% of women with schizophrenia or bipolar disorder, were admitted to an acute psychiatric unit during their pregnancy (12.7% with schizophrenia and 6.1% with bipolar disorder). Following the birth of their baby, 20.6% of women with schizophrenia and 10.2% with bipolar disorder were admitted with their infant to a mother baby psychiatric unit. Statutory child welfare services were significantly (p b .001) more likely to be involved with women with schizophrenia (34.9%) than those with bipolar disorder (8.2%). 3.2. Obstetric outcomes The study group had significantly more obstetric complications than controls. Women with schizophrenia and bipolar disorder had
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Table 1 Antenatal care: Comparing study and control groups.
Mean age (SD) Alcohol use (%) Smoking—b20 weeks (%) Illicit drug use (%) Mean gestation at 1st AN appt. (SD)
Study (n = 112)
Control (n = 19,755)
χ2/t-test
p
31.7 (6.1) 20.6 38.3 17.9 18.8 (7.8)
30.4 (5.3) 0.6 6.6 2.6 15.1 (6.6)
−2.3 625 171 95.5 −5.0
.02 b.001 b.001 b.001 b.001
Note: AN = antenatal.
significantly higher risk of pre-eclampsia (11.0% vs. 2.6%, p b .001) and gestational diabetes (12.7% vs. 6.4%, p = .007); the incidence of gestational diabetes (14.5% v 10.4%) and pre-eclampsia (11.4% vs. 10.6%) was not significantly different between the schizophrenia and bipolar disorder groups. Outcomes for labor and delivery were similar for both the study and control groups.
reveals a significant difference in babies born under the 25th centile. Even when smokers were excluded, the difference in birth weights (for term infants) between the two groups remained significant (3299 ± 521 gm vs. 3591 ± 482 gm; p = .04).
3.3. Predictors of pre-eclampsia
The results of the logistic regression analysis (Table 4) indicated that smoking and illicit drug use in pregnancy were the only independent significant predictors of preterm (b 37 weeks) birth in this cohort. Smoking doubled the risk of delivering a pre-term infant and illicit drug use increased the risk by almost one and half times.
Logistic regression analysis was used to determine whether smoking, alcohol use, illicit drug use and having a diagnosis of schizophrenia or bipolar disorder predicted the pregnancy complication of pre-eclampsia. Having a diagnosis of schizophrenia or bipolar disorder was the only significant predictor (p b .001), conferring a five-fold increased risk of having pre-eclampsia. A summary of the logistic regression is presented in Table 2. 3.4. Neonatal outcomes Data regarding the rates of congenital abnormality were not available for the control group. In the study group, one infant was still-born and six infants (5.4%) were born with congenital abnormalities, including echogenic intracardiac focus (EIF) in papillary muscle, two cases of clicky hip, two cases of ventricular septal defect (VSD) and a case of Ebstein's anomaly. The two infants with VSD were born to women with schizophrenia and the mother of the infant with Ebstein's anomaly had bipolar disorder and was treated with lithium during pregnancy. Neonatal outcomes are shown in Table 3. Babies born to women with schizophrenia or bipolar disorder were less likely to have an Apgar score of ≥8 at 1 minute or at 5 minutes compared to the control group. The mean birth weight of infants born to women in the study group was only slightly less than that of infants of women in the control group, and excluding smokers reduced the difference even further. The rate of preterm birth was significantly increased in the study group compared to the controls and a greater percentage of their infants than of controls required admission to special care/neonatal intensive care (NISC) nursery. Compared to infants of women who did not smoke (30.9%) or use illicit drugs (11.3%) during pregnancy, the infants of women who smoked (61.5%) or used illicit drugs (38.5%) were significantly more likely to require admission to NISC. There was only one difference on the indices of neonatal outcomes between the women with schizophrenia and bipolar disorder. Babies born at term (≥ 37 weeks) to the women with schizophrenia were significantly smaller than those born to women in the bipolar group (3256 ± 470 gm vs. 3463 ± 491 gm; p = .04) and closer investigation
Table 2 Summary of logistic regression equation predicting pre-eclampsia. Predictor
B
Wald χ2
p
OR (CI)
Smoking Alcohol use Drug use Diagnosis⁎
−0.36 0.10 −0.02 1.66
2.85 0.04 0.00 26.26
.09 .84 .96 b.001
0.70 (0.46–1.06) 1.10 (0.41–2.94) 1.00 (0.54–1.81) 5.28 (2.79–9.98)
⁎ Schizophrenia or bipolar disorder.
3.5. Predicting pre-term birth
4. Discussion 4.1. General findings This study examined the obstetric and neonatal outcomes of women with schizophrenia and bipolar disorder compared with those of women without these diagnoses treated in the same maternity setting. Notably, while the delivery outcomes for the study group were not statistically different from controls, important differences in antenatal characteristics, obstetric and neonatal outcomes were identified. Firstly, women in the clinical sample were older than controls. They attended their first antenatal appointment later in the pregnancy, and were much more likely to have used alcohol or illicit drugs and smoked during the pregnancy. As would be expected, a large number in the clinical sample were treated with antipsychotic medication. Both obstetric and neonatal outcomes were worse for women in the study sample compared with the control group. Women in the clinical sample had more complications of pregnancy, and higher rates of preeclampsia and gestational diabetes compared to the control group. Women in the clinical group had a higher risk of pre-term birth, and their infants were less likely to have an Apgar score of 8–10 at both 1 and 5 minutes, and more likely to be admitted to NISC. The admission to NISC figures may be artificially increased by the illicit drug use in this group, requiring the baby to be admitted to SCN for observation of signs of drug withdrawal. Preterm birth is likely to be explained by higher rates of smoking in the clinical sample. In contrast to the findings of earlier studies, we did not find a greater rate of intervention at the time of delivery. This finding may reflect the treatment setting, a specialist maternity hospital with a focus on the management of ‘high risk’ pregnancies, the frequency of attendance by women for antenatal care, and the low need for psychiatric inpatient admission during pregnancy. Previous studies have demonstrated a greater rate of low birth weight infants and of small or growth retarded babies in mothers with SMI (Bennedsen et al., 2001; Nilsson et al., 2002; Jablensky et al., 2005; MacCabe et al., 2007; Lee and Lin, 2010; Bodén et al., 2012). Like Nguyen and colleagues (Nguyen et al., 2012), we did not find a greater risk of these complications. Our study confirmed the finding of increased risk of preterm birth seen in data linkage studies (Bennedsen et al., 2001; Nilsson et al., 2002; Jablensky et al., 2005; MacCabe et al., 2007; Lee and Lin, 2010) but not in the more recent study of Nguyen et al. (2012). However, our findings of higher rates of gestational diabetes and pre-eclampsia are consistent with those of Nguyen et al. (2012) and
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Table 3 Neonatal outcomes: comparing study and control groups.
Apgar score 8–10 at 1 min (%) Apgar score b4 at 1 min (%) Apgar score 8–10 at 5 min (%) Mean infant weight, grams (SD) - Excluding smokers Mean gestation at birth, weeks (SD) Pre-term births (b37 weeks) (%) NISC admission (%)
Study (n = 112)
Control (n = 19,755)
χ2/t-test
p
69.6 5.4 86.6 3172 (680) 3262 (711) 38.4 (2.7) 17.9 27.7
79.8 5.7 92.5 3247 (719) 3275 (699) 38.5 (3.0) 10.9 12.5
7.08 0.02 5.43 1.10 0.15 0.46 5.52 23.38
.008 .88 .02 .27 .88 .64 .02 b.001
Note: NISC = neonatal intensive special care.
appear to indicate a change in the profile of obstetric risks seen for women with schizophrenia and bipolar disorder. In our study, a clinical diagnosis of schizophrenia or bipolar disorder conferred a five times increased risk of pre-eclampsia, a major obstetric problem which can lead to substantial maternal and perinatal complications. The latter include pre-term delivery and hypoxia–neurologic injury (Sibai et al., 2005). In addition, pre-eclampsia has been linked to an increased risk of later schizophrenia (Dalman et al., 1999). Although we did not have data from the control group for comparison, two-thirds of the women in the clinical sample were overweight or obese (BMI N 25) at their first antenatal visit with the largest group (38.4%) BMI N 30 or obese. This is much higher than the estimate for obesity in major cities of 18.4% obtained from the Ausdiab study, for example (Cameron et al., 2003). Obesity is known to be a strong risk factor for pre-eclampsia with one study estimating that every unit increase in pre-pregnancy BMI resulted in an 8% increased risk of pre-eclampsia (Frederick et al., 2006). Obstetric and neonatal complications in women with SMI may cumulate to impact negatively the neurodevelopmental trajectory of their child. In addition, mothers with mental illness are more likely to have difficulties in early emotional interaction with the infant and in promoting attachment organization. Infants may be exposed to stressful interactions and inconsistent care (Wan et al., 2008). These factors may all add to the risks posed by genetic loading for SMI to increase the likelihood of poor developmental outcomes. It is essential to determine whether the adverse obstetric and neonatal outcomes of women with schizophrenia and bipolar disorder relate to maternal risk factors such as lifestyle exposures including smoking, and alcohol and illicit drug use and socioeconomic disadvantage (Sacker et al., 1996; Jablensky et al., 2005) rather than being intrinsic to the clinical diagnosis as, if this is the case, interventions which aim to reduce both short and long-term adverse neurodevelopmental outcomes should be trialled. We found clear differences between women with a diagnosis of schizophrenia or bipolar disorder and the control group with respect to lifestyle exposures known to affect neonatal outcomes, and one of these lifestyle exposures, smoking, more than doubled the risk of delivering a pre-term infant. A recent review highlighted the increased risk of gestational metabolic complications and babies large for gestational age in women treated with second generation antipsychotics (Gentile, 2010). This raises the possibility that use of antipsychotic medications is an explanation for the elevated rate of gestational diabetes and preeclampsia found in this study, as prescribing patterns have changed over the last two decades and now typical or first generation medications
Table 4 Summary of logistic regression equation predicting pre-term (b37 weeks) birth. Predictor
B
Wald χ2
p
OR (CI)
Smoking Alcohol use Drug use Diagnosis⁎
0.85 0.01 0.28 0.16
121.72 0.00 5.15 0.34
b.001 .94 .02 .56
2.35 (2.02–2.73) 1.01 (0.63–1.61) 1.32 (1.04–1.68) 1.17 (0.69–2.00)
⁎ Schizophrenia or bipolar disorder.
are infrequently used. Changes in prescribing may also account for the lack of replication of previous findings regarding growth restriction and low birth weight babies. Further findings which may be linked to maternal medication use include the lower rate of Apgar scores of 8–10 and the higher rate of admission to NISC. Data regarding the reason for NISC admission underscore the role of smoking and illicit drug use in adverse neonatal outcomes. 4.2. Limitations A major strength of the study is that both the clinical and control groups received antenatal care in the same setting. However, the findings need to be considered within the context of several limitations of the study. First, we could not match the study group to the control group on any socio-demographic characteristics such as race or socioeconomic status nor on potential confounding variables such as parity, body mass index (BMI), hypertension or history of pre-eclampsia. Second, lack of information about some important variables, such as medication use among the controls and duration of illness in the study group, precluded investigation of some possible causative factors. It would also have been useful to understand the contribution of maternal nutritional status to the birth outcomes, however this information was not available. The role of these factors needs to be elucidated in future studies. A final limitation is that because of multiple comparisons, some of the significant findings, especially those bordering on p b .05 may not survive allowance for multiple comparisons. 5. Conclusions The findings of this study have implications for both maternity and mental health care of women with schizophrenia and bipolar disorder who wish to have children. The data point to maternal risk factors and lifestyle exposures, including prescribed medications, as being potent contributors to adverse outcomes. Important areas for consideration include choosing the best medication regimen that reduces the risk of relapse but pays attention to the potential risks of medication use and side-effects. Second, the importance of smoking reduction/cessation with or without the use of nicotine replacement therapy cannot be underestimated. Despite significant barriers to smoking cessation amongst women with mental illness, pregnancy is a time when all women are more likely to be motivated to stop smoking (Howard et al., 2013). Similarly, minimization of alcohol and illicit drug use is important. Pre-pregnancy care is a well-established approach in the management of pregnancies complicated by pre-existing diabetes (Ray et al., 2001; McCance, 2011). This approach focuses on optimizing a woman's average blood glucose level before becoming pregnant and thus minimizing the risks posed by her diabetes during pregnancy. A similar approach could be taken with women with pre-existing mental illness. Here, care would focus on addressing lifestyle and treatment related factors which appear to have significant effects on pregnancy outcome as well as stabilization of maternal mental state. This could then be followed by early attendance at antenatal care and careful monitoring for both mental health and obstetric health throughout the pregnancy
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and the postnatal period. Strategies for reducing stress and supporting regular antenatal care and preparation for parenthood are important. This approach offers a means to improve the rate of adverse obstetric and neonatal outcomes in women with SMI. If this approach is adopted, further studies can be undertaken to determine, both the short and long-term impact, as well as barriers and facilitators to this type of care. Role of funding source The project was funded by internal department funds. Contributors The study was designed by F. Judd and P. Sheehan. The data collection and case audits were conducted A. Komiti and P. Sheehan. Statistical analysis was conducted by A. Komiti. The first copy of the manuscript was drafted by F. Judd and all other co-authors provided feedback and contributed to the subsequent revisions. All authors have approved the final manuscript. Conflict of interest The authors declare that there was no existing conflict of interest regarding the subject of this study Acknowledgments The authors are grateful to Drs. L. Laios, O Wong, D. Handrinos, K. Mercuri and T. Nguyen who provided clinical care to the women in the study and to Ms L. Rigg who provided data extracts from the GE system. The Centre for Women's Mental Health is supported by the Pratt Foundation.
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