Psychopharmacology and Pregnancy: Treatment Efficacy, Risks, and Guidelines 2014

9. Schizophrenia, Psychopharmacology, and Pregnancy

Kathryn M. Abel1, Katie Au2 and Louise M. Howard 

(1)

Centre for Women’s Mental Health, The University of Manchester, 3rd Floor East, Jean McFarlane Building, Oxford Rd, Manchester, M13 9PL, UK

(2)

South London and Maudsley NHS Foundation Trust, London, UK

(3)

Section of Women’s Mental Health, Institute of Psychiatry, King’s College London, London, SE5 8AF, UK

Louise M. Howard

Email: louise.howard@kcl.ac.uk

9.1 Schizophrenia: An Overview

9.2 Natural History of Schizophrenia in the Perinatal Period

9.3 Summary of the Evidence for Treatment Improving the Condition in the Perinatal Period

9.4 Risk of Not Treating Schizophrenia in Pregnancy (for Mother, Pregnancy, and Fetus)

9.5 Maternal–Fetal Exposure to Psychotropic Medications as a Contemporary Problem

9.6 Antipsychotics

9.6.1 Congenital Malformations

9.6.2 Pregnancy and Maternal Outcomes

9.6.3 Neonatal Risks

9.6.4 Developmental and Longer Term Outcomes

9.7 Management Recommendations

References

Abstract

Most women with schizophrenia have children at some point in their lives despite reduced fertility compared with the general population. They often stop psychotropic medication due to concerns about harming their infant and it is not clear to what extent they are at risk of relapse in pregnancy, though there is good evidence that the postpartum period is a time of increased risk. Their pregnancies are at increased risk of adverse outcomes including pre-eclampsia, poor fetal growth, preterm birth, low birth weight, still births, and neonatal and post-neonatal deaths. Lifestyle risk factors, such as smoking and nutritional deficiencies, are likely to explain many of these outcomes. Current evidence suggests that most antipsychotics are unlikely to be major teratogens, and it is unclear to what extent other adverse outcomes, including developmental outcomes, are related to medication or confounders. Pregnancy in women with a diagnosis of schizophrenia should be considered high risk and managed accordingly. A focus on reducing modifiable risk factors, such as obesity and smoking, ideally before conception, as well as optimising antenatal care using the lowest effective medication doses with appropriate monitoring through pregnancy, is key to improving the long-term outcomes in these vulnerable families.

Keywords

antipsychoticschizophreniapsychosis

9.1 Schizophrenia: An Overview

Schizophrenia is a major psychiatric disorder characterised by distortions of thought, perception, affect, and behaviour. Symptoms of schizophrenia are conventionally divided into positive symptoms such as delusions, hallucinations, and formal thought disorder, and negative symptoms such as loss of volition, blunting of affect, and poverty of thought and speech. Cognitive difficulties are also an important feature, especially in more severe illness. It is a relatively uncommon disorder, with a lifetime risk of 7.2 per 1,000 and is significantly more common in men than in women (1.4:1) (McGrath et al. 2004). Symptoms usually start in adolescence or young adulthood, but can occur at any age. For the majority, the first acute episode resolves with pharmacological treatment (Emsley et al. 2007), but the course of schizophrenia varies widely with some individuals making a complete recovery, others having a chronic course with severe, persistent disorder and disability, and for others an episodic course, with complete or partial resolution of symptoms between acute episodes with substantial disability (Emsley et al. 2007). Each relapse significantly increases the risk of chronicity, as well as worsening of personal, social, and occupational functioning (Wiersma et al. 1998; Wiersma et al. 2000). Risk of relapse is linked to non-adherence with antipsychotic treatment, substance misuse, carers’ critical comments. and poor premorbid adjustment (Alvarez-Jimenez et al. 2012). There is a high prevalence of comorbid problems including substance and alcohol misuse, depressive and anxiety disorders, obesity, smoking, and physical health problems such as hypertension, cardiovascular disease, and diabetes (Buckley et al. 2009; Wildgust and Beary 2010).

Pharmacological intervention, specifically antipsychotic medications, remains the primary treatment at least for the positive symptoms of schizophrenia. Antipsychotic drugs are effective for the treatment of acute episodes, for relapse prevention, for the emergency treatment of acute behavioural disturbance, and for symptom reduction. A recent systematic review and meta-analysis (Leucht et al. 2012) (65 trials, n = 6,493 patients) reported that antipsychotic drugs compared with placebo significantly reduced relapse rates at 1 year (drugs 27 % vs. placebo 64 %; risk ratio [RR] 0.40, 95 % CI 0.33–0.49; number needed to treat to benefit [NNTB] 3, 95 % CI 2–3) and re-admission rates (10 % vs. 26 %; RR 0.38, 95 % CI 0.27–0.55; NNTB 5, 4–9), with some evidence of better quality of life and fewer aggressive acts. More patients given antipsychotic drugs than placebo gained weight (10 % vs. 6 %; RR 2.07, 95 % CI 2.31–3.25), had movement disorders (16 % vs. 9 %; 1.55, 1.25–1.93), and experienced sedation (13 % vs. 9 %; 1.50, 1.22–1.84). Depot preparations reduced relapse (RR 0.31, 95 % CI 0.21–0.41) more than oral drugs (0.46, 0.37–0.57; p = 0.03). A systematic review and meta-analysis by the same group (Leucht et al. 2009) comparing “second-generation” versus “first-generation” antipsychotic drugs for schizophrenia (150 RCTs; n = 21,533 participants) reported better overall efficacy for four of these drugs, with small to medium effect sizes (amisulpride −0.31 [95 % CI −0.44 to −0.19, p < 0.0001], clozapine −0.52 [−0.75 to −0.29, p < 0.0001], olanzapine −0.28 [−0.38 to −0.18, p < 0.0001], and risperidone −0.13 [−0.22 to −0.05, p = 0.002]). The other second-generation drugs were not more efficacious than the first-generation drugs, even for negative symptoms. Second-generation antipsychotic (SGA) drugs were associated with fewer extrapyramidal side effects than haloperidol (even at low doses) and other than aripiprazole and ziprasidone SGA drugs were associated with more weight gain, in various degrees, than haloperidol.

Recognition of the poor effectiveness of antipsychotics for negative and cognitive symptoms has led to research into psychological and psychosocial interventions for schizophrenia offered as adjunctive therapy. There is some evidence for effectiveness of cognitive behavioural therapy (CBT), particularly for the affective problems associated with the illness (Pharoah et al. 2010; Jones et al. 2011), cognitive remediation therapy for cognition and function (Wykes et al. 2011), and family interventions which reduce hospitalisation rates and global symptom severity (Pharoah et al. 2010).

9.2 Natural History of Schizophrenia in the Perinatal Period

Women with schizophrenia have lower fertility rates compared with women in the general population, though recent studies suggest fertility has increased since the advent of antipsychotics that are not associated with persistent hyperprolactinaemia (Howard et al. 2002; Vigod et al. 2012). The nature of schizophrenia can also affect a women’s ability to make and sustain relationships (Howard 2005) which will also affect general fertility rates. However, most women with schizophrenia have children (Howard et al. 2001), value motherhood highly, and often describe motherhood as central to their existence (Dolman et al. 2013). Nevertheless, pregnancies of women with schizophrenia are more likely to be unplanned and unwanted (Miller and Finnerty 1996) than women in the general population for whom around 50 % of pregnancies are unplanned.

There are few studies published investigating the impact of pregnancy on schizophrenia. One of the few prospective studies is now three decades old but reported that two-thirds of pregnant women with a history of psychosis were not in contact with psychiatric services during pregnancy, despite the presence of active mental disturbance (McNeil et al. 1984). There is little evidence about how pregnancy itself affects symptoms of schizophrenia. It is likely that women who are usually maintained on medication to stabilise their condition may stop treatment when they discover they are pregnant because of fears about potential teratogenicity; this is probably why the prevalence of prescriptions of antipsychotics in women with schizophrenia may be lower for the second and third trimesters of pregnancy compared with the first (Toh et al. 2013). What is not clear is the extent to which relapse occurs in pregnant women who continue with medication compared with those who do not.

Pregnant women with schizophrenia are at increased risk of obstetric complications, including pre-eclampsia, poor fetal growth, preterm birth, low birth weight, low Apgar score, congenital defects, still births, and subsequent neonatal deaths and sudden infant death syndrome (Dalman et al. 1999; Bennedsen et al. 2001b; Howard et al. 2003; Howard 2005; Jablensky et al. 2005; Webb et al. 2005; Webb et al. 2006; Matevosyan 2011). Many risk factors for obstetric complications are also more frequent in women with schizophrenia, such as smoking (Howard et al. 2003; Goodwin et al. 2007), alcohol and substance misuse (Menezes et al. 1996), financial difficulties (Howard et al. 2001), domestic violence (Trevillion et al. 2012), nutritional deficiencies (McColl et al. 2013), obesity and diabetes (Howard and Croker 2012), and decreased access to antenatal care (Howard 2005). Smoking is the leading preventable cause of fetal morbidity and mortality in high income countries and is associated with an increased risk of pre-eclampsia, miscarriage, congenital malformations, low birth weight, prematurity, stillbirths, sudden infant death syndrome, and physical and mental disorders in childhood (Royal College of Physicians 2010). Women with mental disorders are more likely to be smoking at conception, at antenatal booking, and up until delivery (Shah and Howard 2006; Goodwin et al. 2007) and to find it more difficult to stop smoking (Webb et al. 2010) even if they accept referral to smoking cessation services (Howard et al. 2013). Women with severe mental disorders are particularly likely to smoke heavily and be more addicted to nicotine (Aubin et al. 2012) and when pregnant are less likely to be asked about smoking than women from the general population (Howard et al. 2003).

Similarly, other health and social care needs of women with a diagnosis of schizophrenia may not be detected by professionals, but are likely to affect health during pregnancy (Howard and Hunt 2008; Wan et al. 2008a; Webb et al. 2010). However, even after adjusting for risk factors such as smoking and socio-economic status, maternal schizophrenia appears to predict poorer obstetric and perinatal outcomes (Matevosyan 2011). In addition, women who are chronically unwell may develop psychotic denial of pregnancy, particularly if there has been previous loss of custody of a child (Miller 1990). This can lead to refusal of antenatal care or failure to recognise labour, with consequent unassisted delivery (Jenkins et al. 2011). It is therefore of paramount importance that women with a diagnosis of schizophrenia should be provided with optimal psychiatric, as well as antenatal, care.

In the postpartum, there is an increased risk of relapse of psychosis—a Danish population-based register study found a relative risk of 5 for hospital admissions in women with a diagnosis of schizophrenia within the first month following delivery (Munk-Olsen et al. 2006). This represents a far lower risk than that for postpartum women with bipolar disorder (see Chap. 8). This increased risk of relapse persists throughout the first year postpartum, probably because of a number of factors associated with new motherhood, including sleep deprivation and the stress of looking after an infant, potentially with social services supervision (Howard et al. 2004a). Other risk factors include affective symptoms, recent active symptoms, hospitalisation during pregnancy, and severe illness history, including long admissions (McNeil 1987; Kumar et al. 1995; Harlow et al. 2007). In addition to risk of relapse of psychosis, mothers with a diagnosis of schizophrenia may also be more likely to be depressed postnatally than controls (Howard et al. 2004b).

In general, infanticide and suicide are rare. They are also rare in women with a diagnosis of schizophrenia (Flynn et al. 2007). The UK Confidential Enquiry into Maternal Death has consistently reported low rates of suicide during pregnancy for all women, but an increased risk of suicide in the first year postpartum for women with psychosis, although this is more common in women with severe affective disorders than schizophrenia (Cantwell et al. 2011). A study of the homicide of infants in England and Wales between 1996 and 2001 showed that 24 % (17 out of 112) had symptoms of mental illness at the time of the offence, mostly depression, and only four perpetrators were women with a lifetime diagnosis of schizophrenia (Flynn et al. 2007).

9.3 Summary of the Evidence for Treatment Improving the Condition in the Perinatal Period

There has been little research into interventions for schizophrenia in the perinatal period and no high-quality studies of antipsychotic medication in pregnancy (Webb et al. 2004). There is weak evidence from a small before and after study of 20 women with schizophrenia treated with antipsychotics that non-drug-related support, such as liaison with maternity care staff and consent for partner to carry out child care, contributed to improvements in mental state (Nishizawa et al. 2007). We, therefore, rely on other sources of evidence for practice guidelines when considering how to care for women with a diagnosis of schizophrenia in the perinatal period.

9.4 Risk of Not Treating Schizophrenia in Pregnancy (for Mother, Pregnancy, and Fetus)

As discussed above, it is unclear to what extent prophylactic antipsychotic medication will reduce risk of relapse of schizophrenia during pregnancy. Data for relapse rates in schizophrenia in non-pregnant populations suggest that rehospitalisation rates and relapse rates are significantly increased following discontinuation of antipsychotic medication in women and men, and risk associated with discontinuation of antipsychotics may be especially increased in the first years after illness onset (Robinson et al. 1999; Morken et al. 2008). Acute and untreated psychosis is well recognised to be associated with psychological distress and behavioural disturbance that may put the mother and fetus at risk and affect the ability of a mother to care for her infant should acute relapse persist postpartum. Acute psychosis is associated with significant activation of the hypothalamic–pituitary–adrenal axis (Abel et al. 1996). These and other physiological changes associated with acute illness could also affect fetal development through changes in feto-placental integrity and fetal central nervous system development (Cohen and Rosenbaum 1998). Acute illness may also increase the risk of suicide and/or infanticide, although the risk is less in mothers with schizophrenia than in mothers with affective disorders (Flynn et al. 2007). Importantly, reinstatement of treatment for an acute episode following discontinuation often requires higher doses of medication compared with maintenance treatment, exposing the fetus to higher doses of drug.

Social withdrawal, delusional thinking, and inappropriate behaviour can impair daily living (Howard 2005), mother–infant interaction, and consistent caregiving behaviour (Wan et al. 2007; Wan et al. 2008ab). However, there is some evidence that reducing the symptoms of severe mental illness in the mother can improve mother–child relations (Kahng et al. 2008), so if women are treated during pregnancy and the postpartum period, they may avoid the high levels of social services intervention, supervision, and custody loss reported in many studies of mothers with schizophrenia (Howard et al. 2004ab).

9.5 Maternal–Fetal Exposure to Psychotropic Medications as a Contemporary Problem

Pregnant women and fetuses are more likely than ever to be exposed to antipsychotic medications and perhaps to the newer second-generation agents in particular. Drugs such as clozapine, olanzapine, risperidone, and quetiapine are increasingly used in women of reproductive age for a range of psychiatric and behavioural disorders other than schizophrenia (Buchanan et al. 2010). Reproductive safety data remain surprisingly incomplete and guideline recommendations lend limited support to clinical risk–benefit analyses (Howard 2005; McKenna et al. 2005; NICE 2007) (Abel 2013). This is a problem not least because the gold standard randomised controlled trial is considered unethical for assessing psychotropic medication use during pregnancy while available observational studies are generally underpowered with biased samples and therefore remain unfit for this purpose in a rapidly changing prescribing landscape (Abel 2013).

In a UK population approaching 66 million, 3–4,000 births per year are likely to be exposed to antipsychotics or other psychotropic medications. This chapter provides a critical summary of current knowledge about the potential risks of fetal antipsychotic drug exposure and proposes how future observational studies might fill crucial gaps in the evidence to deliver workable new clinical guidance in an evidence-poor arena.

Most incident cases of severe mental illness (schizophrenia, related disorders, and bipolar disorder) in women occur during the reproductive years and most are treated with continuous psychotropic pharmacotherapy. In the last few decades, some key changes in care, including deinstitutionalisation and the use of newer agents with fewer effects on fertility, mean that women treated with antipsychotics are increasingly likely to become pregnant, while the broadening use of newer “atypical” antipsychotics for other more common mental disorders among women of childbearing age is also expanding. Psychotropic medications are therefore increasingly likely to be prescribed to mothers during pregnancy (Newport et al. 2007). It is surprising then that the reproductive safety data for these agents remain so incomplete, and guideline recommendations lend limited support to women, their partners, and their treating clinicians in difficult clinical risk–benefit analyses (NICE 2007). Recent reports conclude that prospective studies are needed which can access unbiased and reliable (i.e. large enough) samples of ill mothers exposed to psychotropic medication that they can take account of key characteristics (e.g. maternal psychiatric diagnosis, smoking, pre-pregnancy weight, and polypharmacy) in the estimation of risk.

9.6 Antipsychotics

Antipsychotic drugs will be considered under the two classes commonly referred to as first (FGA) and second-generation antipsychotic (SGA) drugs. It is generally believed that studies are limited for SGAs, but that there is a wealth of information for FGAs. In fact, most of the information on adverse drug effects has been slowly accumulated through spontaneous reports or through reports accumulated by pharmaceutical companies of adverse effects. By their very nature, these data are biased, unrepresentative, and unreliable. For both antipsychotic drug classes, studies examining the key outcomes that we shall consider (congenital malformations, pregnancy and maternal outcomes, and developmental outcomes) remain limited in number and size and, as a result, yield inconsistent findings overall (Table 9.1).

Table 9.1

Risks of adverse outcomes following antipsychotic (AP) exposure in pregnancy

Study

Outcome

Prenatal exposure

n

Findings

Boden et al (2012)

GDM

Prematurity

SGA

All APs 1st trimester

507 exposed

2× increased risk

60 % increased risk

>2 fold increased risk (but likely confounded)

Reis and Kallen (2008)

Newham et al. (2008)

Severe CMs

GDM

LSCS

Prematurity

SGA

LGA

Prematurity

SGA

LGA

All APs 1st trimester

All APs 1st trimester

576 exposed

70 exposed

50 % increased risk

2× increased risk

No increased risk

70 % increased risk

50 % increased risk

No increased risk

No increased risk

No increased risk

Increased risk for atypicals

but v small numbers (n = 5)

Newport et al (2007)

McKenna et al (2005)

LBW

Hypoxia

CMs

Spontaneous

Abortion

Prematurity

Pregnancy complications

LBW

Atypical APs

Atypical APs

41 exposed

151 exposed

No significant increase risk

No significant increase

Lin et al (2010)

Prematurity

LBW

SGA/LGA

Prematurity

All APs 1st trimester

Compared to women with SCZ on NO APs

242 exposed SCZ only

two fold increase typical

antipsychotics only

No increased risk

No increased risk

No increased risk

LBW low birth weight, SGA or LGA small or large for gestational age, GDM gestational diabetes mellitus, CMs congenital malformations, APs antipsychotics, SCZ schizophrenia

9.6.1 Congenital Malformations

9.6.1.1 First-Generation Antipsychotics

In 1960, Sobel reported that women with a psychotic illness were twice as likely as women in the general population to have a pregnancy resulting in congenital malformation or death, irrespective of chlorpromazine use in pregnancy (Sobel 1961). Currently, it is uncertain whether or not antipsychotics as a group lead to increases in congenital anomalies above the general population rate of 2–4 % (http://www.statisticsgov.uk) ONS Congenital Anomaly Statistics, England and Wales (Series MB3, No.23, 2008; EUROCAT classification of congenital malformations http://www.eurocat-network.eu/content/EUROCAT-Guard-1.3-Chapeter-3.3-Jan2012.pdf). Older studies have not found an association between birth defects and maternal nonorganic psychosis (McNeil et al. 1992) or maternal postpartum psychosis (Paffenbarger et al. 1961). Theoretically, offspring of mothers with major mental illness should indeed develop more neural tube defects because of higher rates of maternal obesity and reduced serum folate levels related to poor diet (McColl et al. 2013). In a relatively small population sample from Western Australia, Jablensky and colleagues reported no increased risk of overall birth defects associated with maternal schizophrenia; they did however report an increase in cardiovascular defects and other defects such as minor physical anomalies (Jablensky et al. 2005). The most robust attempts to answer this question come from Scandinavian population-based samples. Bennedsen reported a small increase in the risk of birth defects in children of mothers with schizophrenia using Danish register data (Bennedsen et al. 2001b). Webb et al. observed a markedly elevated risk of fatal birth defects with maternal schizophrenia (RR 2.34), but not with paternal schizophrenia (Webb et al. 2008). While increased rates of birth defects in the children of women with psychosis may imply a role for maternal genetic factors, environmental effects exclusive to mother such as smoking or drug exposure become more likely. None of the studies discussed above have been able to take maternal exposure to medication into account, but the size and lipophilicity of psychotropic and especially antipsychotic medications increase the likelihood that they will cross the placenta (Pinkofsky 1995) and this bioavailability makes them potential candidates as teratogens.

Meta-analysis of older, mainly prospective cohort studies, reports small but significant excess of congenital malformations in infants exposed to phenothiazine (n = 2,591) compared with unexposed infants of well mothers (n = 71,746) (OR 1.21, 1.01–1.45) (Altshuler et al. 1996). Over the decades, changing antenatal and obstetric care means that the rate of some key outcomes in the background population has also changed so that estimates from more recent cohorts are likely to be more reliable.

Using a 10 year cohort of births (1995–2005) from Swedish national registers, Reis and Kallen report that maternal antipsychotic use overall was associated with a moderate excess of congenital malformation compared to well population controls, but the increase was only marginally significant (OR 1.45, 0.99–1.41) (Reis and Kallen 2008). Here, the excess was largely accounted for by cardiovascular anomalies (atrial or ventricular septal defects). Results adjusted for concomitant antiepileptic use, but not for antidepressant use, were also associated with small increases in cardiovascular anomaly (Reis and Kallen 2010). A review to July 2008 (Gentile 2010) also concludes that risk of limb anomalies cannot be excluded with typical antipsychotics (i.e. haloperidol) exposure.

9.6.1.2 Second-Generation Antipsychotics

Although primarily used to treat schizophrenia and psychotic disorders, newer “second-generation” antipsychotics (SGAs) now treat a spectrum of disorders, including major depression, bipolar disorder, repeated self-harm, PTSD, and other anxiety disorders (McKenna et al. 2005). Far less data have accumulated for newer agents: olanzapine, risperidone, quetiapine, aripiprazole, amisulpride, and clozapine. Again, most data on reproductive safety for these compounds are limited to manufacturers’ case series and spontaneous reports. Among reports of olanzapine-exposed pregnancies from the manufacturer, no increase in risk of major malformations is reported. In 523 clozapine-exposed pregnancies, 22 “unspecified malformations” were reported (4.2 %) while in 151 quetiapine-exposed pregnancies, 8 infants had congenital anomalies (5.2 %). Eight malformations were reported in infants born to 250 women taking risperidone (3.2 %); however, pregnancy outcomes were unknown in many of these cases reported to the manufacturer (McKenna et al. 2005). Taken together, these reports do not suggest an increase in major malformation above that seen in the general population, nor do they indicate any specific pattern of abnormalities among second-generation drug-exposed infants. This information does not suggest particular concerns for SGA use in early pregnancy, but again conclusions can only be provisional.

9.6.1.3 Individual Antipsychotics

Most women exposed to first-generation antipsychotics (FGAs) have been prescribed these medications for hyperemesis gravidarum rather than for mental illness. This represents a potentially important (if not contemporary) control group which might allow distinction between effects of maternal illness from maternal medication. However, for hyperemesis, FGAs tended to be used in much lower doses, and intermittently, limited the benefit of using this as a comparison group. Restricting cases from relatively unbiased population samples, over 200 cases have been reported for olanzapine, haloperidol, or fluphenazine; 100–200 cases for risperidone or flupenthixol and less than 100 for all other antipsychotics, including chlorpromazine, clozapine, sulpiride, trifluoperazine, and quetiapine (Barnes 2011). Taken together these, albeit limited data, and the considerable number of years that many compounds have been available, do not suggest antipsychotic drugs are major teratogens. However, a recent review (Gentile 2010) concluded that risk of limb anomalies associated with early in utero exposure to haloperidol and penfluridol cannot be excluded, and no conclusions can be drawn about the teratogenicity of fluphenazine, thioridazine, and promethazine. To date, there are very few reported first trimester exposures to aripiprazole and one child was born with major congenital anomalies. Little or no published information is currently available for sertindole, amisulpride, and zotepine.

9.6.2 Pregnancy and Maternal Outcomes

The term “obstetric complications” (OCs) refers to a very large set of, in the main, rare obstetric events, ranging from the enigmatic “delivered by an untrained person” (Sacker et al. 1995) to a more clearly defined notion of prematurity or premature labour (Dalman et al. 1999). Even the latter variable can be unclear: some studies do not distinguish between delivery before 37 weeks and 33 weeks, despite rather different risk distributions associated with the two. Some have attempted to get around the problem of rarity of exposure to OCs by grouping together disparate complications. One of the most popular groupings has been “hypoxic–ischaemic-related” events (Zornberg et al. 2000; Cannon et al. 2002). Despite a lack of evidence, categories such as these assume common casual mechanisms for the various OCs within the group. For example “hypoxia” may include events leading to chronic fetal hypoxia (e.g. maternal anaemia, pre-eclampsia, maternal smoking), which may be quite different from those leading to acute fetal hypoxia (e.g. apnoea at birth related to poor Apgar scores, strangulation by prolapse of cord, meconium inhalation, prematurity), and may have quite different sequelae in terms of brain development and risk of subsequent neurodevelopmental outcome. This problem affects both studies which measure OCs as well as those which adjust for OCs as potential confounders of other associations. Furthermore, apart from the risk of obscuring differences, pooling OCs fails to provide sufficient additional information compared to analysis of single complications (Bennedsen et al. 2001a).

Taking such considerations into account, population samples from Australia and Scandinavia have reported varying results for the risk of OCs in women with severe maternal mental illness. An earlier study in Denmark reported an adjusted excess risk of 1.57 for low birth weight and 1.34 for small for gestational age (Bennedsen et al. 1999). In Western Australia, women with a diagnosis of schizophrenia or major affective disorder had raised risk of placental abnormalities and antepartum haemorrhage (Jablensky et al. 2005). Using a similar methodology in a later study, Bennedsen et al. reported no excess OCs for Danish women with schizophrenia (Bennedsen et al. 2001b). Ellman et al. explored whether any adverse outcomes were related to a shared genetic liability in the mother to OC risk and schizophrenia by studying first-degree relatives of mothers with a schizophrenia diagnosis; they found no excess OCs in first-degree relatives compared to controls with no family history of schizophrenia (Ellman et al. 2007). None of these studies was able to assess OC risks associated with exposure to medication. Only more recent linked databases from Sweden have specifically attempted to address this question; of note, findings in these recent reports tend to support the earlier studies and the crude risks are of similar magnitude.

9.6.2.1 First-Generation Antipsychotics

Reis and Kallen (2008) examined births between 1995 and 2005 from the Swedish Medical Births register. Excess risk of premature delivery (OR 1.73, 1.31–2.29), low birth weight (OR 1.67, 1.21–2.29), and a trend for increased risk of small for gestational age (OR 1.46, 0.99–2.15) was reported for pregnancies exposed to any antipsychotic (n = 576) compared to well, unexposed population controls. Boden et al. (2012) examined a slightly different Swedish dataset: the Prescribed Drug Registry. Over a 4-year period (2005–2009), they found that infants exposed to antipsychotics (n = 507) overall had higher risk of small for gestational age (OR 2.11, 1.29–3.47) and gestational diabetes (OR 2.78, 1.64–4.70). Risk was further divided into being born small for gestational age for birth length (OR 2.29, 1.41–3.73) and small for gestational age for head circumference (OR 2.19, 1.33–3.62). However, none of these risks remained significant after adjusting for maternal factors, such as smoking.

In a similar era cohort, Lin et al. report on Taiwanese schizophrenia mothers (n = 242) prescribed any antipsychotic who had given birth between 2001 and 2003 (Lin et al. 2010). They only found excess risk of prematurity (OR 2.46, 1.50–4.11), and only in mothers receiving FGAs, but no excess risk of low birth weight, small, or large for gestational age with early pregnancy antipsychotic exposure overall. No other outcomes were assessed.

A far smaller study in the UK (Newham et al. 2008) reports that infants exposed to FGAs (n = 45) and SGAs (n = 25) compared to unexposed controls had no significant risk of small for gestational age. Significantly more small-for-gestational-age infants were exposed to typical drugs than the reference group; this difference disappeared after exclusion of mothers exposed to other “weight-altering” drugs. Finally, a review of studies to July 2008 (Gentile 2010) concluded that risk of perinatal complications (ranging from withdrawal symptoms to instability of body temperature) is associated with late in utero exposure to haloperidol and phenothiazine, such as chlorpromazine.

9.6.2.2 Second-Generation Antipsychotics

McKenna et al. (2005) conclude that women exposed to SGAs have significantly higher rates of low birth weight infants than controls (10 % vs. 2 %), whereas two subsequent studies reported excess of large-for-gestational-age infants: Newham et al. (2008) report increase in infant birth weight and large for gestational age based on only five cases exposed to either clozapine or olanzapine, but excluding cases with gestational diabetes; Bodén et al. (2012) report increased risk of gestational diabetes (OR 2.39, 1.12–5.13) and small for gestational age (OR for 2.42, 1.24–4.70) after early exposure to olanzapine and clozapine as a group. They examine risk of anabolic fetal growth with olanzapine and clozapine as a group, but do not find a significant effect. This latest study has the largest number of cases of women exposed to olanzapine or clozapine (n = 169) to date. No studies have been able to look separately at clozapine or other agents, such as olanzapine, quetiapine, or risperidone. This is important because not only are these drugs becoming the most prescribed antipsychotics in the UK (http://www.ic.nhs.uk/statistics-and-data-collections/primary-care/prescriptons/precription-cost-analysis-england-2010), but also because recent examination of placental passage (umbilical cord: maternal plasma concentration) of antipsychotics shows olanzapine had highest passage (mean 72.1 %, SD = 42.0 %) and, also, higher rates of either low birth weight and/or perinatal complications than other antipsychotics (Newport et al. 2007).

Finally, it is worth noting that to date, no studies have examined drug adherence, or time to, or risk of, relapse in mothers with a diagnosis of schizophrenia or related disorder who discontinue antipsychotic medication in pregnancy in powerful enough datasets. Furthermore, outcomes increasingly noted as relevant by service users, such as quality of life, are missing from most older, larger population register datasets.

9.6.3 Neonatal Risks

There is a remarkable absence of systematic studies of neonatal reaction following pregnancy exposure to antipsychotics. Several cases of neonatal extrapyramidal syndrome have been reported following exposure to first-generation antipsychotics (Gentile 2010), but there are no other consistent patterns of adverse effects in the literature.

9.6.4 Developmental and Longer Term Outcomes

9.6.4.1 Neurocognitive and Intellectual Disability

Over 40 years ago, Barbara Fish published her seminal paper on developmental delay and neurological deviation in so-called “high-risk” children of women with schizophrenia (Fish 1977). Since then, many have reported delays in neurological and motor development, generalised cognitive deficits and learning difficulties, as well as poorer performance than controls on specific neurocognitive tasks in these children. For excellent reviews, see (Goodman 1984; Asarnow 1988; Cornblatt and Obuchowski 1997; Niemi et al. 2003; Wan et al. 2008a). However, effects of fetal antipsychotic exposure on cognitive, psychopathological, or developmental outcomes have not been taken into consideration. This is particularly important because much of the so-called “high-risk” literature does show evidence of poorer cognitive, social, and clinical outcomes (Wan et al. 2008a). For example, Niemi et al. (2003) report on 145 children of mothers with psychosis and found them significantly more likely to have a severe academic problem (15 %) than controls (8 %). Impairments are more consistently reported in specific cognitive domains, such as verbal ability, executive functioning, and processing speed (Wan et al. 2008a).

In the older studies, when mothers could have been exposed to typical antipsychotics, deficits reported in infancy and early childhood may have poor predictive value and have disappeared later in childhood (Sameroff et al. 1987). Meanwhile, two reviews of the older literature fail to find differences in behavioural functioning or IQ up to 5 years (Thiels 1987; Altshuler et al. 1996). One contemporary study by Morgan et al., including mothers likely to have been exposed to atypical agents, found children of mothers with schizophrenia, bipolar disorder, and unipolar depression up to three times more likely to have intellectual disability as comparison children (Morgan et al. 2009). Morgan suggested that multivariate analysis indicated both genetic and environmental risks acted independently.

Much evidence implies substantial familiality across outcomes/disorders, i.e. greater rates of intellectual disability in families with schizophrenia (Heston 1966; Modrzewska 1980; Alaghband-Rad et al. 1998), and vice versa (Gustavson et al. 1986), as well as increased rates of multiply affected families in people with co-occurring intellectual disability and schizophrenia compared to those with schizophrenia only or intellectual disability only (Penrose 1938; Doody et al. 1998). Similarly, neurocognitive impairment in unaffected schizophrenia relatives (Gur et al. 2007) suggests a genetic component to neurocognitive outcomes. However, environmental risks factors, including obstetric complications, are also strongly implicated in the aetiology of both neurocognitive impairments and intellectual disability (Leonard and Wen 2002), including autism (Glasson et al. 2004; Abel et al. 2013).

9.6.4.2 Psychiatric Outcomes

In the general population, it is likely that multiple genes of small effect contribute to risk of developing serious mental illness, including schizophrenia, and that a range of environmental risk factors interact with this genetic susceptibility (Abel 2004). Children of women with schizophrenia have an eight- to tenfold higher risk of developing the disorder compared to the general population (Gottesman et al. 1987), with the risk in a monozygotic co-twin increased to about 50-fold (Gottesman and Erlenmeyer-Kimling 2001). A recent Danish register study reported that the cumulative incidence by age 52 of schizophrenia in children where one parent had a psychiatric inpatient or outpatient admission for schizophrenia was 7.0 % (Gottesman et al. 2010). If both parents had schizophrenia admissions, the cumulative incidence of schizophrenia in children was 27.3 %, rising to 39.2 % for schizophrenia and related disorders (schizotypal and delusional disorder) and 67.5 % for any psychiatric diagnosis. These population data for schizophrenia consider presence of illness by recording primarily inpatient admissions only. While this is likely to represent a good approximation of risk for schizophrenia (nearly all sufferers are admitted at some point), it provides a poorer representation of risk for less severe, more common psychiatric outcomes.

None of the literature discussed in this section accounts for fetal psychotropic exposure, and much cannot account for unmeasured family influences and confounders. In the Rochester high-risk sample of children of women with schizophrenia, low socio-economic status, and maternal illness chronicity were more important predictors of early outcomes of children to age 4 years than maternal diagnosis per se (Sameroff et al. 1987). This suggests that fetal antipsychotic exposure becomes less likely as a powerful explanatory variable in the generation of risk the more distal and the more complex the behavioural outcomes become. However, unlikely it may be that a drug causes intellectual disability, interactions which prove “risky-for-neurodevelopment” occurring between genetic predisposition and drug exposure are not only conceivable, but also increasingly plausible.

The very limited availability of data on potential longer term neurobehavioural sequelae of fetal exposure to antipsychotics is not difficult to understand. Long-term follow-up is expensive and challenging. It is hard to account for many postnatal risk factors also likely to be associated with being born to a mother with symptoms severe enough to warrant psychotropic agents during pregnancy (Abel and Morgan 2011). However, given the evidence suggesting a range of poorer adverse outcomes for these families, more translational research is needed to delineate modifiable risk factors so that appropriate interventions can be developed and implemented for both mother and child across the developmental life course, commencing in the antenatal period.

9.7 Management Recommendations

The pregnancies of women with a diagnosis of schizophrenia are high risk. As such, identifiable risk factors ideally should be addressed as far as possible before conception. But many of these women are likely to be sexually active and less likely to use contraception or be able to negotiate condom use than well women in the community (Abel and Rees 2010). Reproductive health planning should therefore be a part of the routine care for all women with serious mental illness of reproductive age (Abel et al. 2011). Interventions for the illness and for co-morbid problems such as smoking, obesity, and nutritional deficiencies need tailoring for individual patients; this means time for trials off medications and, as women are at greatest risk (compared to men) of developing metabolic syndrome and morbid obesity with second-generation antipsychotics (Goff et al. 2005), mental health teams need to consider the possibility of pregnancy when planning treatments for young women of reproductive potential. Intensive support is also needed to prepare for smoking cessation, diet and exercise management programmes, etc. These are best delivered before pregnancy with family planning advice. Preconception counselling, at a time when women are not acutely ill and have capacity to make decisions, should also include a discussion of the risks and benefits of taking medication compared with not taking medication so that women with their families can make informed collaborative decisions.

Lack of reproductive and pregnancy planning means that most women with schizophrenia are likely to become pregnant while taking medications. This means that maternity and mental health professionals need to be aware of the increased risk of adverse obstetric and psychosocial outcomes so that they can ensure delivery of optimal care. For example, women with a diagnosis of schizophrenia are more likely than healthy women to have a partner with a psychiatric illness or to have no partner and few or no social supports (Abel et al. 2005). Helping women to engage with antenatal care may be an important way to offer support and guidance and may improve antenatal clinic attendance. Optimal care also needs to identify and address risk factors such as domestic violence and smoking, and comprehensive care is likely to need coordination by a named health professional and modification of maternal care pathways (NICE 2010).

Many women with a diagnosis of schizophrenia and related (non-affective) psychoses are likely to relapse if medication is stopped; women with severe illnesses and recent long hospitalisations will be at particularly high risk. The consequences of an acute episode of illness—child protection proceedings for the unborn child, behavioural disturbance, and/or self-neglect that may put the woman and the fetus at risk, and adverse obstetric and fetal outcomes—are potentially devastating. Women who are likely to relapse will need antipsychotic medication throughout their pregnancies and into the postpartum period, and decisions around medication will often focus on which medication to take and what monitoring is needed, e.g. increased monitoring of glucose metabolism during pregnancy (SIGN 2012). Switching and/or withdrawal of medication may itself lead to relapse, particularly if an untried medication is started because of its putative lower risk. We would therefore recommend that where possible changes in medication are avoided if the woman is already on medication that keeps her well. Of note, clozapine will usually have been prescribed for treatment resistant illness and should be continued, as stopping may lead to a severe psychotic relapse.

In addition to medication, management should address other risk factors for adverse outcomes such as smoking and substance misuse, and providing psychosocial interventions that will reduce stressors and enhance support for the whole family. This should include consistent support through the perinatal period, monitoring for early relapse indicators which can be quickly treated, and interventions that will help the woman prepare for motherhood, as well as active involvement of other members of the family to help with child care in the postnatal period. Careful multidisciplinary planning with women and relevant others offers women with a diagnosis of schizophrenia the opportunity to minimise harms and to maximise the very many benefits and joys associated with new motherhood.

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