12 - Chapter 7 Prescribing in pregnancy and breastfeedi 01 - Drug choice in pregnancy Drug choice in pregnancy The Maudsley® Prescribing Guidelines in Psychiatry, Fifteenth Edition. David M. Taylor, Thomas R. E. Barnes and Allan H. Young. © 2025 David M. Taylor. Published 2025 by John Wiley & Sons Ltd. Chapter 7 Drug choice in pregnancy A ‘normal’ outcome to pregnancy can never be guaranteed. The spontaneous abortion rate in confirmed early pregnancy is 10–20%, and the risk of major malformation in the newborn is 2–3% (approximately 1 in 40 pregnancies).1 Lifestyle factors, such as smoking cigarettes, poor diet and drinking alcohol during pregnancy, can have adverse consequences for the fetus. Pre-­pregnancy obesity increases the risk of neural tube defects and is associated with risk factors for the mother. Psychiatric illness during pregnancy is an independent risk factor for congenital malformations, stillbirths and neonatal deaths2 and perinatal mental disorders are associated with a broad range of negative child outcomes, many of which can persist into late adolescence.3 Severe mental illness is also associated with increased risk of obstetric near misses (life-­threatening obstetric complications).4 The safety of psychotropics in pregnancy cannot be clearly established because robust, prospective trials are unethical and long-­term observational studies are challenging to ­undertake. Data are derived from database studies (many of which fail to control for confounders such as the impact of maternal mental illness, use of illicit drugs and alcohol, smoking, obesity and other medications), limited prospective data from teratology information centres and published case reports. For many drugs, the perceived association or otherwise with adverse outcomes changes over time, as more information is gathered and analysed. The patient’s view of risks and benefits has paramount importance and needs to be informed by up-­to-­date evidence. Clinicians should be aware of the importance of prescribing medication to women with a severe mental illness. Perinatal suicides are notable for being associated with lack of active treatment, specifically the lack of treatment with psychotropic medication.5 The American College of Obstetricians and Gynecologists (ACOG) warns against withholding or discontinuing medications for mental health ­conditions because of pregnancy or lactation status alone.6 Box 7.1 provides a brief summary of the relevant issues and evidence available in early 2024. Prescribing in pregnancy and breastfeeding 714 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 7 Box 7.1  General principles of prescribing in pregnancy In all women of child-bearing potential ■ ■Always discuss the possibility of pregnancy – half of all pregnancies are unplanned7 ■ ■Avoid using drugs that are contraindicated during pregnancy (notably valproate, topiramate and carbamazepine). If use of these drugs is unavoidable then women should be made fully aware of their teratogenic properties even if not planning pregnancy. In addition, the prescriber should confirm the presence of an effective and stable long-­term contraceptive plan If mental illness is newly diagnosed in a pregnant woman ■ ■Consider non-­pharmacological interventions ■ ■Try to avoid all drugs in the first trimester (when major organs are being formed) unless benefits clearly outweigh risks (i.e. if non-­drug treatments are not effective/appropriate) ■ ■Use an established drug and use the lowest effective dose ■ ■Review current medication regimen to ensure there is a clear indication for each drug and that ineffective drugs are stopped If a woman taking psychotopic drugs is planning a pregnancy ■ ■Consideration should be given to discontinuing treatment if the woman is well and at low risk of relapse, after a careful review of her history ■ ■Discontinuation of treatment for women with severe mental illness (SMI) and at a high risk of relapse is generally unwise but consideration should be given to switching to a low-­risk drug. However, be aware that switching drugs may increase the risk of relapse. Any changes must be made with caution and considered in the context of the woman’s illness history and previous response to treatment ■ ■Drug-­induced hyperprolactinaemia may prevent pregnancy. Consider switching to an alternative drug if hyperprolactinaemia occurs and a pregnancy is planned ■ ■For women with SMI, pre-­conception advice from a perinatal psychiatrist should be sought to ensure that women are aware of their risk of relapse in the perinatal period and are able to discuss a prospective perinatal care plan If a woman taking psychotropic medication discovers that she is pregnant ■ ■Abrupt discontinuation of treatment post-­conception is unwise for women with SMI and at a high risk of relapse. Relapse may ultimately be more harmful to the mother and child than continued, effective drug therapy ■ ■Consider continuing with current (effective) medication rather than switching, to minimise the risk of relapse and the number of drugs to which the fetus is exposed ■ ■Valproate (if prescribed as a mood stabiliser) must be stopped immediately ■ ■Early pregnancy can be associated with noticeable changes in mood, therefore it may be necessary to review the medication plan at this stage to ensure symptoms are well controlled If the patient smokes (smoking is more common in pregnant women with psychiatric illness8) ■ ■Smoking has been associated with the greatest proportion of excess risk of poor pregnancy outcomes9 ■ ■Always encourage switching to nicotine replacement therapy. Referral to smoking cessation ­services is mandated by NICE in the UK ■ ■Vaping is probably safer than tobacco smoking but is not without risk. Nicotine replacement is probably safer than vaping10 ■ ■Stopping smoking can increase plasma levels of certain drugs (e.g. clozapine) 02 - Psychosis during pregnancy and postpartum Psychosis during pregnancy and postpartum Prescribing in pregnancy and breastfeeding CHAPTER 7 Psychosis during pregnancy and postpartum Pregnancy does not protect against psychotic relapse and psychosis during pregnancy predicts postpartum psychosis.13 The incidence of postpartum psychosis is 0.1–0.25% in the general population (around 1–2 psychiatric hospitalisations per 1000 births). Women with bipolar disorder have an increased risk of postpartum psychosis with around one in five experiencing a psychotic relapse postpartum.14 There is a high risk of relapse in women with a family history of postpartum psychosis or a personal history of postpartum psychosis.15 The risk of postpartum psychosis for women with a previous episode of illness, a diagnosis of bipolar disorder type 1 or schizoaffective disorder, and genetic loading for postpartum psychosis, bipolar 1 or schizoaffective disorder, can be as high as 50%. The mental health of the mother in the perinatal period influences fetal well-­being, obstetric outcome and child development. The risks of not treating psychosis include harm to the mother and harm to the fetus or neonate (ranging from neglect to infanticide). First-­generation antipsychotics ■ ■Some specific malformations have been reported with individual agents. However, first-­generation antipsychotics (FGAs) are unlikely to be major teratogens.16 ■ ■Most initial data originated from studies that included primarily women with hyperemesis gravidarum (a condition associated with an increased risk of congenital malformations) treated with low doses of phenothiazines. The modest increase in risk identified in some of these studies, along with the absence of clear clustering of congenital abnormalities, suggested that the condition being treated may be responsible rather than drug treatment. ■ ■In a large American study including over a million women, no meaningful increase in the risk of major malformations or cardiac malformations was seen in 733 women prescribed an FGA.17 A 2023 study of nearly 6.5 million women (6371 prescribed an FGA) in the USA and Nordic countries found that antipsychotics were not major In all pregnant women ■ ■Ensure that parents are as involved as possible in all decisions ■ ■Prescribe as few drugs as possible (both simultaneously and in sequence) and use the lowest effective dose ■ ■Be prepared to adjust doses as pregnancy progresses and drug handling is altered. Dose increases are frequently required in the third trimester11 when blood volume expands by around 30%. Plasma level monitoring may be helpful, where available. Hepatic enzyme activity also changes markedly during pregnancy. CYP2D6 activity is increased by almost 50% by the end of pregnancy while the activity of CYP1A2 is reduced by up to 70%12 ■ ■For patients with SMI, discuss with the patient a referral to specialist perinatal services ■ ■Ensure adequate fetal screening by liaison with obstetric services ■ ■Be aware of potential problems with individual drugs around the time of delivery ■ ■Inform the obstetric team of psychotropic use and possible complications and where appropriate liaise with the neonatology team ■ ■Monitor the neonate for withdrawal effects after birth ■ ■Document all decisions (including the plan for medication) 716 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 7 teratogens. In the same study, the authors reported an observed increased risk of ­cardiac malformations with (the rarely used) chlorprothixene, which the authors ­suggest should be viewed as a safety signal for further study.18 ■ ■There may be an association between haloperidol and limb defects (based on a small number of cases) but, if real, the risk is likely to be extremely low and it has not been replicated in larger studies. ■ ■An increased risk of gestational diabetes19 and possibly preterm birth20 has been reported. A prospective study that included 284 women who took an FGA during pregnancy concluded that preterm birth and low birth weight were more common with FGAs than second-­generation antipsychotics (SGAs) (or no antipsychotic exposure).21 In addition to this, 20% of neonates exposed to an FGA in the last week of gestation experienced early somnolence and jitteriness. ■ ■A higher risk of postpartum bleeding in vaginal delivery and a higher placenta to birth weight ratio has been reported.22 ■ ■Neonatal dyskinesia has been reported with FGAs.23 ■ ■Neonatal jaundice has been reported with phenothiazines.24 ■ ■An increased risk (greater in late pregnancy exposure) of neonatal withdrawal symptoms, neurological disorders and persistent pulmonary hypertension has been reported. The absolute risk is low, and the effects appear to be predominantly mild and transient.25 Prolonged neonatal hospital stay after birth has been reported.22 Second-­generation antipsychotics ■ ■Some specific malformations have been reported with individual agents. However, SGAs are unlikely to be major teratogens.16 ■ ■In a large American study, no meaningful increase in the risk of major malformations or cardiac malformations was seen in 9258 women prescribed an SGA. In this same study a small increase in absolute risk of malformations was seen with risperidone. The authors suggested that this particular finding should be interpreted with caution and be seen as a possible safety signal that requires further investigation.17 In a separate study of 214 women taking an SGA, the absolute risk of major malformation was estimated to be 1.4% (1.1% in the control group).17 Another American study which analysed data from the National Birth Defects Prevention Study reported an association between SGA use in early pregnancy and conotruncal heart defects, tetralogy of Fallot, anorectal atresia/stenosis and gastroschisis. The study included over 22,000 cases and over 11,000 controls. Notably (and this may explain the findings in relation to SGAs), women exposed to SGAs were more likely to report pre-­pregnancy obesity, illicit drug use, smoking and alcohol use and use of other psychiatric medications during pregnancy.26 A 2023 study of nearly 6.5 million women (21,751 prescribed an SGA) in the USA and Nordic countries reported that antipsychotics were not major teratogens. In the same study there was an observed increased risk of oral clefts with olanzapine and gastroschisis and brain anomalies with all SGAs, which the authors suggested should be viewed only as safety signals for further study.18 ■ ■A prospective study of 561 women who took an SGA during pregnancy concluded that SGA exposure was associated with increased birth weight, a modestly increased risk of cardiac septal defects (possibly due to screening bias or co-­exposure to ­selective Prescribing in pregnancy and breastfeeding CHAPTER 7 serotonin reuptake inhibitors [SSRIs]) and, as with FGAs, withdrawal effects in 15% of neonates.20 ■ ■Available data do not suggest that lurasidone is a major teratogen.27 ■ ■Olanzapine has been associated with lower birth weight and increased risk of intensive care admission,28 a large head circumference29 and macrosomia30 (the last of these is consistent with the reported increase in the risk of gestational diabetes24,29,31,32). ■ ■Neonatal seizures may be more likely to occur with clozapine31 than with other SGAs. There is a single case report of maternal overdose resulting in fetal death24 and there are theoretical concerns about the risk of agranulocytosis in the fetus/ neonate.24 Overall, pharmacovigilance data do not indicate that clozapine is less safe in pregnancy than other antipsychotics.33 Clozapine is included by the UK National Institute for Health and Care Excellence (NICE) in medications that may be prescribed in pregnancy. Lower mean adaptive behaviour scores have been reported in infants exposed to clozapine in utero compared with risperidone, quetiapine or olanzapine. A higher rate of disturbed sleep and lability were reported in clozapine-­ exposed infants in the same study.34 On the balance of evidence available, clozapine should usually be continued during pregnancy. Clozapine plasma level monitoring may be beneficial,35 especially if there are changes in smoking habits. ■ ■An increased risk of gestational diabetes has been reported for SGAs19 and possibly preterm birth,20 low birth weight36 and postpartum bleeding in vaginal delivery. The risk of gestational diabetes may be greatest with clozapine, olanzapine and quetiapine,37 and aripiprazole may not be associated with an increased risk.38 In a population-­ based study of over a million women, an increased risk of caesarean section, large for gestational age and preterm birth were reported in women prescribed an SGA compared with no antipsychotic. The risk of caesarean section and large for gestational age was higher with SGAs than with FGAs.39 Maternal mental illness and lifestyle may also be important factors in the risk for gestational diabetes.40,41 A lower risk with SGAs compared with FGAs has also been reported19 and other studies did not report increased risk of metabolic complications.36 ■ ■An increased risk (greater in late pregnancy exposure) of neonatal withdrawal ­symptoms, neurological disorders and persistent pulmonary hypertension has been reported. The absolute risk is low, and the effects appear to be predominantly mild and transient.37 ■ ■Quetiapine has a relative low rate of placental passage.42,43 One study of antipsychotic use in Finland showed a higher risk of increased postpartum bleeding in vaginal delivery, prolonged neonatal hospitalisation stay and a higher placenta to birth weight ratio with antipsychotics use. Quetiapine was the most commonly used antipsychotic in this study.22 ■ ■The manufacturers of cariprazine have advised against its use in pregnancy because of an increased risk of malformations noted in animal studies. It should probably be avoided. Antipsychotic use and longer-term neurodevelopment The effect of antipsychotics on longer-term neurodevelopment is unclear.44 A small prospective case–control study reported that babies who were exposed to SGAs in utero had delayed cognitive, motor and social–emotional development at 2 and 6 months old but 718 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 7 not at 12 months.45 The clinical significance of this finding is unclear. No significant adverse effect on IQ or neurodevelopmental functioning was shown in a small study of school-­aged children following exposure to antipsychotics during pregnancy.46 A cohort study of 667,517 children did not show an association between maternal antipsychotic prescription and poorer standardised test performance in language and mathematics in schoolchildren.47 Two large cohort studies have reported increased risk of attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) associated with maternal mental illness but not with prenatal antipsychotic exposure.20,48 A smaller study reported no increased risk of psychiatric disorders in children born to women who continued antipsychotics in pregnancy.49 A 2022 birth cohort study found antipsychotics to not be causally associated with neurodevelopmental disorders although there was a safety ­signal for aripiprazole, which requires further study.50 Recommendations for psychosis in pregnancy are outlined in Box 7.2. Box 7.2  Recommendations – psychosis in pregnancy ■ ■Overall, the data do not allow an assessment of relative risks associated with different agents and certainly do not confirm absolutely the safety of any particular drug. However, the high risk of adverse outcomes for the mother and child associated with untreated maternal illness should be noted ■ ■Patients with a history of psychosis who are maintained on antipsychotic medication should be advised to discuss a planned pregnancy as early as possible ■ ■Women should be supported to minimise the risks in pregnancy from smoking and alcohol and drug misuse. Women should be referred to appropriate services such as smoking cessation clinics and addictions services ■ ■Drug-­induced hyperprolactinaemia may prevent pregnancy. Consider switching to an alternative drug if hyperprolactinaemia occurs and a pregnancy is planned ■ ■If a pregnant woman is stable on an antipsychotic and likely to relapse without medication, advise her to continue the antipsychotic.51 Switching medication is generally not advised owing to the risk of relapse ■ ■When initiating an antipsychotic consider using the antipsychotic that has previously worked best for the woman, after discussion of benefits and risks.43 This may minimise fetal exposure by avoiding the need for higher doses and/or multiple drugs should relapse occur ■ ■Be clear of the indication for each drug, use the lowest effective dose and prescribe as few drugs as possible both simultaneously and in sequence. Do not continue medication that is not effective ■ ■Advise pregnant women taking antipsychotic medication about diet and monitor for excessive weight gain ■ ■Women taking an antipsychotic during pregnancy should be monitored for gestational diabetes. In the UK, NICE recommends women are offered an oral glucose tolerance test ■ ■In the UK, NICE recommends avoiding depot preparations in a woman who is planning a pregnancy, pregnant or considering breastfeeding, unless she is responding well to a depot and has a previous history of non-­adherence with oral medication51 ■ ■The Australian Centre of Perinatal Excellence (COPE) recommends a 13-­ or 18–20-­week ultrasound for women taking antipsychotics in the first trimester52 ■ ■Antipsychotic discontinuation symptoms can occur in the neonate (e.g. crying, agitation, increased suckling). This is thought to be a class effect.53 When antipsychotics are taken in pregnancy it is recommended that the woman gives birth in a unit that has access to paediatric intensive care facilities.21 Some centres used mixed (breast/bottle) feeding to minimise withdrawal symptoms ■ ■Document all decisions 03 - Depression during pregnancy and postpartum545 Depression during pregnancy and postpartum54–56 Prescribing in pregnancy and breastfeeding CHAPTER 7 Depression during pregnancy and postpartum54–56 Approximately 10% of pregnant women develop or have a pre-­existing depressive illness. Around a third of cases of postpartum depression begin before birth and there is a significant increase in new psychiatric episodes in the first 3 months after delivery. At least 80% of these are mood disorders, particularly severe depression. Women who have had a previous episode of depressive illness (postpartum or not) are at higher risk of further episodes during pregnancy and postpartum. The risk is highest in women with bipolar illness who are also at risk of mania or mixed affective episodes. There is some evidence that depression increases the risk of spontaneous abortion (miscarriage),57 having a low birth weight or small for gestational age baby, or of preterm delivery, although effects are small.3,58,59 The mental health of the mother influences fetal well-­being, obstetric outcome and child development. The risks of not treating depression include harm to the mother through poor self-­care, lack of obstetric care or self-­harm and harm to the fetus or neonate (ranging from neglect to infanticide). Antidepressants Relapse rates are higher in those with a history of depression who discontinue medication compared with those who continue. One study found that 68% of women who were well on antidepressant treatment and stopped during pregnancy relapsed, compared with 26% who continued antidepressants.54 Risk is likely to be highest for women with a history of severe and/or recurrent depression.60 The rate of antidepressant withdrawal will also influence the risk of depressive relapse. Available data do not suggest an association between prenatal antidepressant use and neurodevelopmental disorders (after controlling for maternal illness and other confounders).61 There is also some evidence that successful antidepressant use can be beneficial for child behavioural outcomes. A Danish study found that adverse outcomes were relatively more likely in depressed women not taking antidepressants.62 However, antidepressant exposure in pregnancy may be an important marker of the need for early screening and intervention. Tricyclic antidepressants ■ ■Fetal exposure to tricyclics (via the umbilicus and amniotic fluid) is high.63,64 ■ ■Tricyclic antidepressants (TCAs) have been widely used throughout pregnancy without apparent detriment to the fetus.65–67 ■ ■A weak association between clomipramine use and cardiovascular defects cannot be excluded68 and the European summary of product characteristics (SPC) for Anafranil states: ‘Neonates whose mothers had taken tricyclic antidepressants until delivery have developed dyspnoea, lethargy, colic, irritability, hypotension or hypertension, tremor or spasms, during the first few hours or days. Studies in animals have shown reproductive toxicity. Anafranil (i.e. branded clomipramine) is not recommended during pregnancy and in women of child-­bearing potential not using contraception.’ The labels for other TCAs also contain a caution about withdrawal effects in neonates. One case of neonatal QT prolongation and torsades de pointes has been reported following maternal clomipramine use69 and one case of Timothy syndrome 720 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 7 (a disorder characterised by severe QT prolongation) in a newborn whose mother took amitriptyline in early pregnancy.70 ■ ■TCA use during pregnancy is associated with an increased risk of preterm delivery.65,66,71 ■ ■Use of TCAs in the third trimester is well known to produce neonatal withdrawal effects, such as agitation, irritability, seizures, respiratory distress and endocrine and metabolic disturbances.65 These are usually mild and self-­limiting. ■ ■Little is known of the early developmental effects of prenatal exposure to tricyclics, although one small study detected no adverse consequences.72 Limited data suggest in utero exposure to tricyclics has no effects on later development.72,73 The authors of a study that reported an association between maternal antidepressant use and an increased risk of affective disorders in offspring74 suggested the observed associations may be attributable to underlying parental psychopathology. There are no convincing data suggesting an association between prenatal antidepressant use and neurodevelopmental disorders61 or ASD diagnoses or traits.75 Selective serotonin reuptake inhibitors (SSRIs) ■ ■SSRIs appear not to be major teratogens.65,67,76–78 An association between prenatal SSRI use and congenital heart defects has been reported, with some studies reporting a higher risk with fluoxetine and paroxetine.79 However, other studies have found no association between any SSRI and an increased risk of cardiac septal defects80–82 nor any other heart defects83–87 and it is suggested that mood disorders alone may be the cause of any increased risk of congenital heart defects.78 ■ ■One database study reported that fetal alcohol disorders were 10 times more common in those exposed to SSRIs in utero than in controls,88 and that alcohol use during pregnancy (which may be used as self-­medication for depression) is associated with an increased risk of cardiac defects in the fetus.68 ■ ■Sertraline appears to result in the least placental exposure.89 ■ ■There may be a small increased risk of preterm birth and low birth weight and lower Apgar scores and admission to neonatal intensive care units with SSRIs.78 Maternal depression itself increases these risks.90,91 Poor neonatal adaptation (including withdrawal symptoms) has been reported and risk may be increased with prematurity92 and increasing dose, and may be higher with other SSRIs than sertraline.93 ■ ■SSRIs may increase the risk for persistent pulmonary hypertension of the newborn. The absolute risk appears to be small and more modest than previously estimated.94 The risk may exist only in late pregnancy exposure95 and may be lower with sertraline.96 ■ ■Gestational hypertension, pre-­eclampsia, placental abnormalities and postpartum haemorrhage have been reported with SSRI use. The risks appear to be small and it should be noted that maternal depression itself increases the risk of these outcomes.78 The UK Medicines and Healthcare products Regulatory Agency (MHRA) advises that healthcare professionals need to be aware of the small increased risk of postpartum haemorrhage with SSRI/serotonin–noradrenaline reuptake inhibitor (SNRI) antidepressant use during the month before delivery. ■ ■Data relating to neurodevelopmental outcome of fetal exposure to SSRIs are less than conclusive.72,73,97–100 Depression itself may have more obvious adverse effects on development.72,101 Some studies have reported a small increased risk of ASD.102–104 Prescribing in pregnancy and breastfeeding CHAPTER 7 However, larger studies have either failed to show this association after accounting for maternal illness and other demographic confounders75,105–107 or have found it to be no longer statistically significant.108,109 A large cohort study in 2022 reported that antidepressant use in pregnancy itself does not appear to increase the risk of neurodevelopmental disorders in children.61 There is no reliable evidence indicating an increased risk of ADHD.91 Poorer cognitive and gross motor development110 and problems with speech and language,111–113 behaviour114,115 and fine motor control have been reported116 but it is not clear whether or not this is a result of confounding. Authors of two separate studies, one reporting an association between antidepressant exposure in pregnancy and increased risk in the offspring of affective disorders74 and the other describing higher rates of emotional disorders and antidepressant medication prescriptions,117 have suggested the observed associations may be attributable to underlying parental psychopathology rather than direct exposure in utero. A 2023 study reported changes in brain morphology associated with SSRI exposure during pregnancy, some of which persisted into adolescence. The study did not assess clinical outcomes in the children and as such the significance of these findings is unclear.118 Other antidepressants ■ ■Despite a previous reported association between venlafaxine and increased risk of specific birth defects111 including cardiac defects, anencephaly and cleft palate,119 a 2022 meta-­analysis concluded that available data do not indicate any SNRIs to be major teratogens.120 An earlier observational study of 281 venlafaxine-­exposed pregnancies did not find conclusive evidence that venlafaxine increased the risk of adverse pregnancy or fetal outcomes.121 However, venlafaxine has been associated with neonatal withdrawal and poor neonatal adaptation syndrome,122 babies being born small for gestational age123 and postpartum haemorrhage.124 The UK MHRA advises that healthcare professionals need to be aware of the small increased risk of postpartum haemorrhage with SSRI/SNRI antidepressant use during the month before delivery. SNRIs may be associated with an increased risk for persistent pulmonary hypertension of the newborn. The absolute risk appears to be low.96 ■ ■A large cohort study using propensity scores and several sensitivity analyses found duloxetine use in pregnancy may be associated with a small increase in the risk of postpartum hemorrhage,124 and a case of suspected withdrawal syndrome in the newborn requiring hospitalisation has been reported.125 However, no specific risks were identified with duloxetine in a study that prospectively followed 233 women through pregnancy and delivery.126 A population-­based observational study from Sweden and Denmark did not show an increased risk of major or minor congenital malformations or stillbirth with duloxetine.127 ■ ■Trazodone, bupropion (amfebutamone) and mirtazapine have few data supporting their safety.122,128,129 A 2023 observational study did not find a significant difference in the risk of major congenital anomalies after first-­trimester exposure to trazodone compared with SSRI exposure.130 Available data suggest that both bupropion and mirtazapine are not associated with malformations but, like SSRIs, may be linked to  an increased rate of spontaneous abortion;131–133 however this might be attri­ butable to underlying psychiatric disease. A 2022 Danish study did not observe an 04 - Bipolar illness during pregnancy and postpart Bipolar illness during pregnancy and postpartum 722 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 7 association between mirtazapine use and major congenital malformations, spontaneous abortion, stillbirth or neonatal death.134 ■ ■First-­trimester exposure to bupropion may be associated with a slightly elevated risk of ventricular septal defects.135 Bupropion exposure in utero has been associated with an increased risk of ADHD in young children.136,137 Rather limited data suggest the absence of teratogenic potential with moclobemide138 and reboxetine.139 ■ ■Monamine oxidase inhibitors should be avoided in pregnancy because of a suspected increased risk of congenital malformations and because of the risk of hypertensive crisis.140 ■ ■There is no evidence to suggest that electroconvulsive therapy (ECT) causes harm to either the mother or fetus during pregnancy141 although general anaesthesia is of course not without risks. NICE recommends ECT for pregnant women with severe depression, severe mixed affective states or mania, or catatonia, whose physical health or that of the fetus is at serious risk. Box 7.3 summarises recommendations for treating depression in pregnancy. Bipolar illness during pregnancy and postpartum The risk of relapse during pregnancy if mood-­stabilising medication is discontinued is high143 and the risk of relapse after delivery is hugely increased. The mental health of the mother influences fetal well-­being, obstetric outcome and child development. The risks of not stabilising mood include harm to the mother through poor self-­care, lack of obstetric care, the need for hospital admission and harm to the fetus or neonate (ranging from neglect to infanticide). Box 7.3  Recommendations – depression in pregnancy ■ ■Patients who are already receiving antidepressants and are at high risk of relapse are best maintained on the same antidepressant (assuming it is effective and well tolerated) during and after pregnancy ■ ■Those who develop a moderate to severe or severe depressive illness during pregnancy should be treated with antidepressant drugs. If initiating an antidepressant during pregnancy or for a woman considering pregnancy, previous response to treatment must be taken into account. The antidepressant which has previously proved to be effective should be considered. For previously untreated patients, sertraline may be considered. ACOG recommends selective serotonin reuptake inhibitors (SSRIs) first line (with serotonin–noradrenaline reuptake inhibitors [SNRIs] a reasonable alternative) and if there is no pharmacotherapy history, sertraline or escitalopram is a reasonable first-­line medication. COPE recommends SSRIs first line ■ ■For moderate to severe perinatal depression with onset in the third trimester, ACOG recommends consideration of brexanolone ■ ■Screen for alcohol use and be vigilant for the development of hypertension and pre-­eclampsia ■ ■Women who take SSRIs or SNRIs late in pregnancy may be at increased risk of postpartum haemorrhage ■ ■When taken in late pregnancy, SSRIs may increase the risk of persistent pulmonary hypertension of the newborn. The absolute risk is very low ■ ■The neonate may experience poor neonatal adaptation syndrome or discontinuation symptoms ■ ■NICE in the UK142 advises additional monitoring of the newborn of women who have taken an SRRI or SNRI antidepressant during pregnancy Prescribing in pregnancy and breastfeeding CHAPTER 7 Mood ­stabilisers (non-­antipsychotics) ■ ■Lithium completely equilibrates across the placenta.144 Lithium exposure during pregnancy has been associated with an increased risk of congenital anomalies.145 The risk is higher in the first trimester146 and may be greater at higher doses.145 Although the overall risk of major malformations in infants exposed in utero has probably been overestimated in the past, lithium should be avoided in pregnancy if possible. However, if lithium is the best drug for the woman and the drug most likely to keep her well, she should be advised of the increased risk but supported to stay on lithium. If discontinuation is planned, slow discontinuation before conception is the preferred course of action31,147 because abrupt discontinuation worsens the risk of relapse. The relapse rate postpartum may be as high as 70% in women who discontinued lithium before conception.148 ■ ■Lithium use during pregnancy has a well-­known association with the cardiac malformation Ebstein’s anomaly. However, more recent data suggest that the magnitude of the effect is much smaller than previously estimated.149,150 Furthermore, a large surveillance study of 5.6 million births found an association of Ebstein’s anomaly with maternal mental health problems generally rather than specifically with lithium.151 The period of maximum risk to the fetus is 2–6 weeks after conception,152 before many women know that they are pregnant. The risk of atrial and ventricular septal defects may also be increased.28 If lithium is continued during pregnancy, high-­ resolution ultrasound and echocardiography should be performed in liaison with fetal medicine obstetric services. ■ ■In the third trimester, the use of lithium may be problematic because of changing pharmacokinetics. An increasing dose of lithium is required to maintain the lithium level during pregnancy as total body water increases, but the requirements return abruptly to pre-­pregnancy levels immediately after delivery.153 Women taking lithium should deliver in hospital where fluid balance can be monitored and maintained. ■ ■Lithium use in pregnancy has been associated with an increased risk of spontaneous preterm birth and large for gestational age neonates.154 However, a large cohort study reported that lithium was not associated with placenta-­mediated complications or preterm birth.155 Lithium use may increase the risk of neonatal readmission within 4  weeks postpartum,146 although a later study failed to replicate this finding.156 Neonatal goitre, hypotonia, lethargy, cardiac arrhythmia, respiratory symptoms157 and low Apgar scores158 have been reported. ■ ■Lithium probably does not affect neonatal brain development.159 ■ ■Most data relating to carbamazepine, valproate and lamotrigine come from studies in epilepsy, a condition associated with increased neonatal malformation. These data may not be precisely relevant to use in mental illness. Both carbamazepine and valproate have a clear causal link with increased risk of a variety of fetal abnormalities, particularly neural tube defects including spina bifida.160 Both drugs should be avoided, and an antipsychotic prescribed instead. Valproate confers a higher risk (around 10% for major malformations) than carbamazapine161–163 and should not be used in women of child-­bearing age except where all other treatment has failed and when there is a long-­term effective contraception plan. There is no evidence that folate protects against anticonvulsant-­induced neural tube defects if given during pregnancy,164 but it may do so if given prior to conception (the neural tube is ­essentially 724 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 7 formed by 8 weeks of pregnancy165 before many women realise they are pregnant). However, folate supplementation may be beneficial with regard to early neurodevelopment and so should always be offered.164 Valproate monotherapy has also been associated with an increased relative risk of atrial septal defects, cleft palate, hypospadias, polydactyly and craniosynostosis, although absolute risks are low.166 Valproate is also associated with a reduced head circumference in the neonate.167 ■ ■There appears to be a clear causal association between valproate use in pregnancy and motor and neurodevelopmental problems in exposed children. A review of studies by the European Medicines Agency showed that up to 40% of pre-­school children exposed to valproate in utero experienced some form of developmental delay, including delayed walking and talking, memory problems, difficulty with speech and language and a lower intellectual ability. Poorer outcomes have been shown in language functioning, attention, memory, executive functioning and adaptive behaviour compared with carbamazepine and lamotrigine exposure. Lower IQs and an increased diagnosis rate of ASD are also reported.168,169 Processing, working memory and learning deficits appear to be dose-­related.170 Decreased school performance has been associated with valproate use compared with children unexposed to anticonvulsants and with children exposed to lamotrigine.171 ■ ■Valproate use may increase risk of pre-­eclampsia.172 ■ ■Where continued use of carbamazepine is deemed essential, low-­dose (but effective) monotherapy is strongly recommended as the teratogenic effect is probably dose ­related.173,174 Use of carbamazepine in the third trimester may necessitate maternal vitamin K. ■ ■There is growing evidence that lamotrigine is safer in pregnancy than carbamazepine or valproate across a range of outcomes.164,168,175–177 The risk of major malformations appears to be in the range reported for children not exposed to anticonvulsants.178 Clearance of lamotrigine seems to increase radically during pregnancy179,180 and then reduces postpartum181 so frequent lamotrigine levels are necessary. ■ ■Behaviour problems have been reported by parents of children exposed to lamotrigine in pregnancy.182 Lamotrigine may be associated with an increased risk of autism.183 However, available data suggest the effect of lamotrigine on neurodevelopment appears to not be significant.184 ■ ■Lower Apgar scores at birth have been reported with carbamazepine, valproate and topiramate. If an association exists, the absolute risk is low.185 ■ ■Major malformations,186 specifically orofacial clefts, have been reported with topiramate.187 The risk of oral clefts may be higher in women with epilepsy who use higher doses of the drug.188 A large population study reported an increased risk of neurodevelopmental disorders, small for gestational age and congenital malformations189 with prenatal topiramate exposure. Topiramate should not be used in pregnant women, and women of child-­bearing age should take precautions to avoid getting pregnant.190 ■ ■The data for oxcarbazepine are not clear. A 2022 meta-­analysis reported a small but not statistically significant increased risk of malformations in children exposed to oxcarbazepine.191 Three studies in the same analysis reported an association with fetal/perinatal deaths. Because of some notable limitations in the studies incuded in this analysis, it is difficult to draw firm conclusions. ■ ■Similarly, data for pregabalin are not clear.192 However, based on a Nordic study193 that showed a small increased risk of major malformations (compared with Prescribing in pregnancy and breastfeeding CHAPTER 7 ­lamotrigine and duloxetine) the UK MHRA194 and the manufacturers of pregabalin advise that women taking pregabalin be made aware of this risk and advised to use effective contraception. ■ ■A large cohort study reported that anticonvulsant mood stabilisers were not associated with placenta-­mediated complications or preterm birth.170 Recommendations for the treatment of bipolar disorder in pregnancy are outlined in Box 7.4. Box 7.4  Recommendations – bipolar disorder in pregnancy ■ ■For women who have had a long period without relapse, the possibility of switching to a safer drug (antipsychotic) or withdrawing treatment completely before conception and for at least the first trimester should be considered ■ ■For women with a severe mental illness, discuss referral to perinatal services for pre-­conception advice ■ ■The risk of relapse both pre-­ and postpartum is very high if medication is discontinued abruptly ■ ■No mood stabiliser is clearly safe. In the UK, NICE recommends the use of mood-­stabilising antipsychotics as a preferable alternative to continuation with a mood ­stabiliser ■ ■Women with severe illness or who are known to relapse quickly after discontinuation of a mood-­stabilising agent should be advised to continue their medication, following discussion of the risks. (This advice does not apply to valproate.) NICE recommends that if a woman taking lithium becomes pregnant, consider stopping lithium gradually over 4 weeks if she is well. Explain to her that there is a risk of relapse, particularly in the postnatal period, if she has bipolar disorder. If a woman taking lithium becomes pregnant and is not well or is at high risk of relapse, consider switching gradually to an antipsychotic or stopping lithium and restarting it in the second trimester (if the woman is not planning to breastfeed and her symptoms have responded better to lithium than to other drugs in the past) or continuing with lithium if she is at high risk of relapse and an antipsychotic is unlikely to be effective. If lithium is considered essential in a woman planning pregnancy, the woman should be informed of the risk of fetal heart malformations when lithium is taken in the first trimester and the risk of toxicity in the baby if lithium is continued during breastfeeding. In the UK, NICE recommends checking the plasma lithium levels every 4 weeks, then weekly from the 36th week, and to adjust the dose to keep plasma lithium levels in the woman’s therapeutic range, ensuring the woman maintains an adequate fluid balance. The woman should give birth in hospital and be monitored by the obstetric team when labour starts, including checking plasma lithium levels and fluid balance because of the risk of dehydration and lithium toxicity. Lithium should be stopped during labour and plasma lithium levels checked 12 hours after the mother’s last dose. ACOG recommends that pregnant patients taking lithium in the first trimester receive a detailed ultrasound examination in the second trimester to evaluate the fetal anatomy with a particular focus on cardiac anatomy. COPE recommends a 13-­ or 18–20-­week ultrasound for women taking lithium or anticonvulsants in the first trimester ■ ■Women prescribed lithium should undergo appropriate monitoring of the fetus in liaison with fetal medicine obstetric services to screen for Ebstein’s anomaly ■ ■NICE, ACOG and COPE strongly advise against the use of valproate in pregnancy. Valproate should be discontinued before a woman becomes pregnant. Women taking valproate who are planning a pregnancy should be strongly advised to gradually stop the drug because of the high risk of fetal malformations and adverse neurodevelopmental outcomes after any exposure in pregnancy. COPE recommends once the decision to conceive is made to stop valproate over 2–4 weeks, while adding in high-­dose folic acid (5mg/day), which should continue for the first trimester.52 In the UK, valproate may not be initiated in patients under 55 or continued in women of child-­bearing potential unless two specialists agree and document that there is no other effective or tolerated treatment195 05 - Anxiety and insomnia during pregnancy and pos Anxiety and insomnia during pregnancy and postpartum 726 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 7 Anxiety and insomnia during pregnancy and postpartum Anxiety disorders and insomnia are commonly seen in pregnancy.196 Preferred treatments are cognitive behavioural therapy (CBT) and sleep-­hygiene measures, respectively. Sedatives ■ ■First-­trimester exposure to benzodiazepines has been associated with specific malformations197 such as oral clefts in newborns,198 although other studies198–202 have failed to confirm this association. Benzodiazepine use in pregnancy may be a marker for cardiac and total malformation risk.203 ■ ■Benzodiazepine use in pregnancy has been associated with caesarean delivery, spontaneous abortion, neonatal intensive care admission, neonatal ventilatory support, low birth weight, preterm delivery, small head circumference and small for gestational age babies.199,204–208 Third-­trimester use is commonly associated with neonatal difficulties (floppy baby syndrome).209 A Taiwanese population-­based study which accounted for confounding factors such as indication reported that benzodiazepine or Z drug use in early pregnancy was not associated with a substantial increase in the risk of stillbirth and preterm birth but there was an increased risk of small for gestational age. Exposure during late pregnancy was found to be associated with a substantially elevated risk of stillbirth and preterm birth.210 ■ ■Note that, in the UK, NICE advises that benzodiazepines are not offered to women in pregnancy and the postnatal period except for the short-­term treatment of severe anxiety and agitation. It also suggests gradually stopping benzodiazepines in women who are planning a pregnancy, pregnant or considering breastfeeding.51 ACOG recommends that benzodiazepines be avoided or prescribed sparingly as a treatment for perinatal anxiety. ■ ■Promethazine has been used in hyperemesis gravidarum and appears not to be teratogenic, although data are limited. ■ ■If valproate is the only drug that works for a particular woman, and this is seen as the only option for her during pregnancy, then the patient should be given a clear briefing of the risks and give written consent confirming that she understands the risk of malformations and developmental delays. Having said this, it is difficult to imagine any situation where the benefits of valproate outweigh the huge risks presented by using valproate in pregnancy ■ ■NICE advises that carbamazepine not be offered to treat a mental health problem in women who are planning a pregnancy, pregnant or considering breastfeeding. NICE advises discussing the possibility of stopping carbamazepine if a woman is planning a pregnancy or becomes pregnant. If carbamazepine is used, prophylactic vitamin K should be administered to the mother and ­neonate after delivery. ACOG recommends against discontinuing mood stabilisers (except for valproate) during pregnancy due to the risk of recurrence or exacerbation of mood symptoms ■ ■NICE advises if a woman is taking lamotrigine to check lamotrigine levels frequently during ­pregnancy and into the postnatal period because they vary substantially at these times ■ ■In acute mania in pregnancy use an antipsychotic and, if ineffective, consider electroconvulsive therapy ■ ■In bipolar depression during pregnancy use cognitive behavioural therapy for moderate ­depression and a selective serotonin reuptake inhibitor for more severe depression. Lamotrigine is also an option 06 - Attention deficit hyperactivity disorder (ADH Attention deficit hyperactivity disorder (ADHD) in pregnancy 07 - References References Prescribing in pregnancy and breastfeeding CHAPTER 7 ■ ■Hypnotic benzodiazepine receptor agonists (Z drugs) are probably not associated with an increased risk of congenital malformations,211,212 but an increased risk of premature birth, low birth weight and small for gestational age has been reported.211 ■ ■Zolpidem may be associated with an increased likelihood of caesarean section.213 ■ ■Available data do not appear to show an association between in utero benzodiazepine and/or Z drug exposure and neurodevelopmental disorders.214–216 Attention deficit hyperactivity disorder (ADHD) in pregnancy Methylphenidate and amfetamines are probably not major teratogens.217,218 A small increased risk of cardiac malformations has been reported with methylphenidate but is not seen with amfetamines.219 There may be a small increased risk of spontaneous abortion with methylphenidate and a small increased risk of premature birth and low birth weight with amfetamines.218 Modafinil may be associated with an increased risk of congenital malformations (including congenital heart defects, hypospadias and orofacial clefts).220,221 In the UK, the MHRA advises that modafinil should not be used during pregnancy.220 Women of child-­bearing age must understand the risk of taking modafinil in pregnancy and should be advised to use effective contraception during treatment with modafinil and for 2 months after discontinuing treatment.220 Available data do not show an increased risk of neurodevelopmental disorders in children exposed to ADHD medications in utero.222,223 References McElhatton PR. Pregnancy: (2) general principles of drug use in pregnancy. Pharm J 2003; 270:232–234. Schneid-­Kofman N, et al. Psychiatric illness and adverse pregnancy outcome. Int J Gynaecol Obstet 2008; 101:53–56. Stein A, et al. Effects of perinatal mental disorders on the fetus and child. Lancet 2014; 384:1800–1819. Easter A, et  al. Obstetric near misses among women with serious mental illness: data linkage cohort study. Br J Psychiatry 2021; 219: 494–500. Khalifeh H, et al. Suicide in perinatal and non-­perinatal women in contact with psychiatric services: 15 year findings from a UK national inquiry. Lancet Psychiatry 2016; 3:233–242. Treatment and management of mental health conditions during pregnancy and postpartum: ACOG Clinical Practice Guideline No. 5. Obstet Gynecol 2023; 141:1262–1288. De La Rochebrochard E, et al. Children born after unplanned pregnancies and cognitive development at 3 years: social differentials in the United Kingdom Millennium Cohort. Am J Epidemiol 2013; 178:910–920. Goodwin RD, et  al. Mental disorders and nicotine dependence among pregnant women in the United States. Obstet Gynecol 2007; 109:875–883. Vigod SN, et al. Maternal schizophrenia and adverse birth outcomes: what mediates the risk? Soc Psychiatry Psychiatr Epidemiol 2020; 55:561–570. Vilcassim MJR, et al. Electronic cigarette use during pregnancy: is it harmful? Toxics 2023; 11:278. Sit DK, et  al. Changes in antidepressant metabolism and dosing across pregnancy and early postpartum. J Clin Psychiatry 2008; 69:652–658. Ter Horst PG, et al. Pharmacological aspects of neonatal antidepressant withdrawal. Obstet Gynecol Surv 2008; 63:267–279. Harlow BL, et al. Incidence of hospitalization for postpartum psychotic and bipolar episodes in women with and without prior prepregnancy or prenatal psychiatric hospitalizations. Arch Gen Psychiatry 2007; 64:42–48. Wesseloo R, et al. Risk of postpartum relapse in bipolar disorder and postpartum psychosis: a systematic review and meta-­analysis. Am J Psychiatry 2016; 173:117–127. Jones I, et  al. Bipolar disorder, affective psychosis, and schizophrenia in pregnancy and the post-­partum period. Lancet 2014; 384:1789–1799. Wang Z, et al. Prenatal exposure to antipsychotic agents and the risk of congenital malformations in children: a systematic review and meta-­ analysis. Br J Clin Pharmacol 2021; 87:4101–4123. Huybrechts KF, et al. Antipsychotic use in pregnancy and the risk for congenital malformations. JAMA Psychiatry 2016; 73:938–946. Huybrechts KF, et al. Association of in utero antipsychotic medication exposure with risk of congenital malformations in Nordic countries and the US. JAMA Psychiatry 2023; 80:156–166. 728 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 7 19. Kulkarni J, et al. The use of first and second-­generation antipsychotic drugs and the potential to develop gestational diabetes mellitus among perinatal patients with psychosis. Schizophr Res 2023; 254:22–26. 20. Wang Z, et al. Association between prenatal exposure to antipsychotics and attention-­deficit/hyperactivity disorder, autism spectrum disorder, preterm birth, and small for gestational age. JAMA Intern Med 2021; 181:1332–1340. 21. Habermann F, et al. Atypical antipsychotic drugs and pregnancy outcome: a prospective, cohort study. J Clin Psychopharmacol 2013; 33:453–462. 22. Kananen A, et al. Quetiapine and other antipsychotic medications during pregnancy: a 15-­year follow-­up of a university hospital birth register. Nord J Psychiatry 2023; 77:651–660. 23. Collins KO, et al. Maternal haloperidol therapy associated with dyskinesia in a newborn. Am J Health Syst Pharm 2003; 60:2253–2255. 24. Gentile S. Antipsychotic therapy during early and late pregnancy. A systematic review. Schizophr Bull 2010; 36:518–544. 25. Heinonen E, et al. Neonatal morbidity after fetal exposure to antipsychotics: a national register-­based study. BMJ Open 2022; 12:e061328. 26. Anderson KN, et al. Atypical antipsychotic use during pregnancy and birth defect risk: National Birth Defects Prevention Study, 1997–2011. Schizophr Res 2020; 215:81–88. 27. Cohen LS, et al. Reproductive safety of lurasidone and quetiapine: update from the National Pregnancy Registry for Psychiatric Medications. J Women’s Health (Larchmt) 2023; 32:452–462. 28. Reis M, et al. Maternal use of antipsychotics in early pregnancy and delivery outcome. J Clin Psychopharmacol 2008; 28:279–288. 29. Boden R, et al. Antipsychotics during pregnancy: relation to fetal and maternal metabolic effects. Arch Gen Psychiatry 2012; 69:715–721. 30. Newham JJ, et al. Birth weight of infants after maternal exposure to typical and atypical antipsychotics: prospective comparison study. Br J Psychiatry 2008; 192:333–337. 31. Ernst CL, et  al. The reproductive safety profile of mood stabilizers, atypical antipsychotics, and broad-­spectrum psychotropics. J Clin Psychiatry 2002; 63 Suppl 4:42–55. 32. McKenna K, et al. Pregnancy outcome of women using atypical antipsychotic drugs: a prospective comparative study. J Clin Psychiatry 2005; 66:444–449. 33. Beex-­Oosterhuis MM, et al. Safety of clozapine use during pregnancy: analysis of international pharmacovigilance data. Pharmacoepidemiol Drug Saf 2020; 29:725–735. 34. Shao P, et al. Effects of clozapine and other atypical antipsychotics on infants development who were exposed to as fetus: a post-­hoc analysis. PLoS One 2015; 10:e0123373. 35. Nguyen T, et al. Obstetric and neonatal outcomes of clozapine exposure in pregnancy: a consecutive case series. Arch Women’s Ment Health 2020; 23:441–445. 36. Lin HY, et  al. Antipsychotic use in early pregnancy and the risk of maternal and neonatal complications. Mayo Clin Proc 2022; 97:2086–2096. 37. Heinonen E, et al. Antipsychotic use during pregnancy and risk for gestational diabetes: a national register-­based cohort study in Sweden. CNS Drugs 2022; 36:529–539. 38. Galbally M, et al. Aripiprazole and pregnancy: a retrospective, multicentre study. J Affect Disord 2018; 238:593–596. 39. Ellfolk M, et al. Second-­generation antipsychotics and pregnancy complications. Eur J Clin Pharmacol 2020; 76:107–115. 40. Galbally M, et al. The association between gestational diabetes mellitus, antipsychotics and severe mental illness in pregnancy: a multicentre study. Aust N Z J Obstet Gynaecol 2020; 60:63–69. 41. Uguz F. Antipsychotic use during pregnancy and the risk of gestational diabetes mellitus: a systematic review. J Clin Psychopharmacol 2019; 39:162–167. 42. Schoretsanitis G, et al. Excretion of antipsychotics into the amniotic fluid, umbilical cord blood, and breast milk: a systematic critical review and combined analysis. Ther Drug Monit 2020; 42:245–254. 43. McAllister-­Williams RH, et al. British Association for Psychopharmacology consensus guidance on the use of psychotropic medication preconception, in pregnancy and postpartum 2017. J Psychopharmacol 2017; 31:519–552. 44. Gentile S, et al. Neurodevelopmental outcomes in infants exposed in utero to antipsychotics: a systematic review of published data. CNS Spectr 2017; 22:273–281. 45. Peng M, et al. Effects of prenatal exposure to atypical antipsychotics on postnatal development and growth of infants: a case-­controlled, prospective study. Psychopharmacology (Berl) 2013; 228:577–584. 46. Schrijver L, et al. Neurodevelopment in school-­aged children after intrauterine exposure to antipsychotics. Acta Psychiatr Scand 2023; 147:43–53. 47. Liu X, et al. Association of maternal antipsychotic prescription during pregnancy with standardized test scores of schoolchildren in Denmark. JAMA Intern Med 2022; 182:1035–1043. 48. Hálfdánarson Ó, et al. Antipsychotic use in pregnancy and risk of attention/deficit-­hyperactivity disorder and autism spectrum disorder: a Nordic cohort study. Evid Based Ment Health 2022; 25:54–62. 49. Momen NC, et al. In utero exposure to antipsychotic medication and psychiatric outcomes in the offspring. Neuropsychopharmacology 2022; 47:759–766. 50. Straub L, et al. Association of antipsychotic drug exposure in pregnancy with risk of neurodevelopmental disorders: a national birth cohort study. JAMA Intern Med 2022; 182:522–533. 51. National Institute for Health and Care Excellence. Antenatal and postnatal mental health: clinical management and service guidance. Clinical Guidance [CG192]. 2014 (last updated February 2020, last accessed March 2024); https://www.nice.org.uk/guidance/cg192. 52. Centre of Perinatal Excellence (COPE). National Perinatal Mental Health Guideline. 2023; https://www.cope.org.au/health-­professionals/ review-­of-­new-­perinatal-­mental-­health-­guidelines/. 53. European Medicines Agency. Antipsychotics – risk of extrapyramidal effects and withdrawal symptoms in newborns after exposure during pregnancy. Pharmacovigilance Working Party, July 2011 plenary meeting. Issue 1107. 2011; http://www.ema.europa.eu/docs/en_GB/ document_library/Report/2011/07/WC500109581.pdf. Prescribing in pregnancy and breastfeeding CHAPTER 7 54. Cohen LS, et al. Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment. JAMA 2006; 295:499–507. 55. Munk-­Olsen T, et al. New parents and mental disorders: a population-­based register study. JAMA 2006; 296:2582–2589. 56. Mahon PB, et  al. Genome-­wide linkage and follow-­up association study of postpartum mood symptoms. Am J Psychiatry 2009; 166:1229–1237. 57. Smith S, et al. Association between antidepressant use during pregnancy and miscarriage: a systematic review and meta-­analysis. BMJ Open 2024; 14:e074600. 58. Engelstad HJ, et al. Perinatal outcomes of pregnancies complicated by maternal depression with or without selective serotonin reuptake inhibitor therapy. Neonatology 2014; 105:149–154. 59. Yonkers KA, et al. The management of depression during pregnancy: a report from the American Psychiatric Association and the American College of Obstetricians and Gynecologists. Gen Hosp Psychiatry 2009; 31:403–413. 60. Yonkers KA, et  al. Does antidepressant use attenuate the risk of a major depressive episode in pregnancy? Epidemiology 2011; 22:848–854. 61. Suarez EA, et al. Association of antidepressant use during pregnancy with risk of neurodevelopmental disorders in children. JAMA Intern Med 2022; 182:1149–1160. 62. Grzeskowiak LE, et al. Antidepressant use in late gestation and risk of postpartum haemorrhage: a retrospective cohort study. BJOG 2016; 123:1929–1936. 63. Loughhead AM, et al. Placental passage of tricyclic antidepressants. Biol Psychiatry 2006; 59:287–290. 64. Loughhead AM, et al. Antidepressants in amniotic fluid: another route of fetal exposure. Am J Psychiatry 2006; 163:145–147. 65. Davis RL, et al. Risks of congenital malformations and perinatal events among infants exposed to antidepressant medications during pregnancy. Pharmacoepidemiol Drug Saf 2007; 16:1086–1094. 66. Kallen B. Neonate characteristics after maternal use of antidepressants in late pregnancy. Arch Pediatr Adolesc Med 2004; 158:312–316. 67. Ban L, et al. Maternal depression, antidepressant prescriptions, and congenital anomaly risk in offspring: a population-­based cohort study. BJOG 2014; 121:1471–1481. 68. Gentile S. Tricyclic antidepressants in pregnancy and puerperium. Expert Opin Drug Saf 2014; 13:207–225. 69. Fukushima N, et  al. A neonatal prolonged QT syndrome due to maternal use of oral tricyclic antidepressants. Eur J Pediatr 2016; 175:1129–1132. 70. Corona-­Rivera JR, et al. Unusual retrospective prenatal findings in a male newborn with Timothy syndrome type 1. Eur J Med Genet 2015; 58:332–335. 71. Maschi S, et al. Neonatal outcome following pregnancy exposure to antidepressants: a prospective controlled cohort study. BJOG 2008; 115:283–289. 72. Nulman I, et al. Child development following exposure to tricyclic antidepressants or fluoxetine throughout fetal life: a prospective, controlled study. Am J Psychiatry 2002; 159:1889–1895. 73. Nulman I, et al. Neurodevelopment of children exposed in utero to antidepressant drugs. N Engl J Med 1997; 336:258–262. 74. Rommel AS, et al. Long-­term prenatal effects of antidepressant use on the risk of affective disorders in the offspring: a register-­based cohort study. Neuropsychopharmacology 2021; 46:1518–1525. 75. Brennan PA, et al. Prenatal antidepressant exposures and autism spectrum disorder or traits: a retrospective, multi-­cohort study. Res Child Adolesc Psychopathol 2023; 51:513–527. 76. Ramos E, et  al. Duration of antidepressant use during pregnancy and risk of major congenital malformations. Br J Psychiatry 2008; 192:344–350. 77. Gentile S. Selective serotonin reuptake inhibitor exposure during early pregnancy and the risk of birth defects. Acta Psychiatr Scand 2011; 123:266–275. 78. Lebin LG, et al. Selective serotonin reuptake inhibitors (SSRIs) in pregnancy: an updated review on risks to mother, fetus, and child. Curr Psychiatry Rep 2022; 24:687–695. 79. Reefhuis J, et al. Specific SSRIs and birth defects: Bayesian analysis to interpret new data in the context of previous reports. BMJ 2015; 351:h3190. 80. Alwan S, et  al. Use of selective serotonin-­reuptake inhibitors in pregnancy and the risk of birth defects. N Engl J Med 2007; 356:2684–2692. 81. Margulis AV, et al. Use of selective serotonin reuptake inhibitors in pregnancy and cardiac malformations: a propensity-­score matched cohort in CPRD. Pharmacoepidemiol Drug Saf 2013; 22:942–951. 82. Riggin L, et al. The fetal safety of fluoxetine: a systematic review and meta-­analysis. J Obstet Gynaecol Can 2013; 35:362–369. 83. Anderson KN, et al. Maternal use of specific antidepressant medications during early pregnancy and the risk of selected birth defects. JAMA Psychiatry 2020; 77:1246–1255. 84. Furu K, et al. Selective serotonin reuptake inhibitors and venlafaxine in early pregnancy and risk of birth defects: population based cohort study and sibling design. BMJ 2015; 350:h1798. 85. Petersen I, et al. Selective serotonin reuptake inhibitors and congenital heart anomalies: comparative cohort studies of women treated before and during pregnancy and their children. J Clin Psychiatry 2016; 77:e36–e42. 86. Wang S, et al. Selective serotonin reuptake inhibitors (SSRIs) and the risk of congenital heart defects: a meta-­analysis of prospective cohort studies. J Am Heart Assoc 2015; 4:e001681. 87. Ansah DA, et al. A prospective study evaluating the effects of SSRI exposure on cardiac size and function in newborns. Neonatology 2019; 115:320–327. 88. Malm H, et al. Selective serotonin reuptake inhibitors and risk for major congenital anomalies. Obstet Gynecol 2011; 118:111–120. 89. Hendrick V, et al. Placental passage of antidepressant medications. Am J Psychiatry 2003; 160:993–996. 730 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 7 90. Vlenterie R, et al. Associations between maternal depression, antidepressant use during pregnancy, and adverse pregnancy outcomes: an individual participant data meta-­analysis. Obstet Gynecol 2021; 138:633–646. 91. Desaunay P, et al. Benefits and risks of antidepressant drugs during pregnancy: a systematic review of meta-­analyses. Paediatr Drugs 2023; 25:247–265. 92. Yang A, et al. Neonatal discontinuation syndrome in serotonergic antidepressant-­exposed neonates. J Clin Psychiatry 2017; 78:605–611. 93. Cornet MC, et al. Maternal treatment with selective serotonin reuptake inhibitors during pregnancy and delayed neonatal adaptation: a population-­based cohort study. Arch Dis Child Fetal Neonatal Ed 2024; 109:294–300. 94. Huybrechts KF, et al. Antidepressant use late in pregnancy and risk of persistent pulmonary hypertension of the newborn. JAMA 2015; 313:2142–2151. 95. Byatt N, et al. Exposure to selective serotonin reuptake inhibitors in late pregnancy increases the risk of persistent pulmonary hypertension of the newborn, but the absolute risk is low. Evid Based Nurs 2015; 18:15–16. 96. Masarwa R, et al. Prenatal exposure to selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors and risk for persistent pulmonary hypertension of the newborn: a systematic review, meta-­analysis, and network meta-­analysis. Am J Obstet Gynecol 2019; 220:57.e1–57.e13. 97. Gentile S. SSRIs in pregnancy and lactation: emphasis on neurodevelopmental outcome. CNS Drugs 2005; 19:623–633. 98. Casper RC, et al. Follow-­up of children of depressed mothers exposed or not exposed to antidepressant drugs during pregnancy. J Pediatr 2003; 142:402–408. 99. Hermansen TK, et al. Prenatal SSRI exposure: effects on later child development. Child Neuropsychol 2015; 21:543–569. 100. Kaplan YC, et al. Maternal SSRI discontinuation, use, psychiatric disorder and the risk of autism in children: a meta-­analysis of cohort studies. Br J Clin Pharmacol 2017; 83:2798–2806. 101. Ames JL, et al. Maternal psychiatric conditions, treatment with selective serotonin reuptake inhibitors, and neurodevelopmental disorders. Biol Psychiatry 2021; 90:253–262. 102. Boukhris T, et al. Antidepressant use in pregnancy and the risk of attention deficit with or without hyperactivity disorder in children. Paediatr Perinat Epidemiol 2017; 31:363–373. 103. Croen LA, et  al. Antidepressant use during pregnancy and childhood autism spectrum disorders. Arch Gen Psychiatry 2011; 68:1104–1112. 104. Healy D, et al. Links between serotonin reuptake inhibition during pregnancy and neurodevelopmental delay/spectrum disorders: a systematic review of epidemiological and physiological evidence. Int J Risk Saf Med 2016; 28:125–141. 105. Brown HK, et al. Association between serotonergic antidepressant use during pregnancy and autism spectrum disorder in children. JAMA 2017; 317:1544–1552. 106. Sujan AC, et al. Associations of maternal antidepressant use during the first trimester of pregnancy with preterm birth, small for gestational age, autism spectrum disorder, and attention-­deficit/hyperactivity disorder in offspring. JAMA 2017; 317:1553–1562. 107. Castro VM, et al. Absence of evidence for increase in risk for autism or attention-­deficit hyperactivity disorder following antidepressant exposure during pregnancy: a replication study. Transl Psychiatry 2016; 6:e708. 108. Clements CC, et al. Prenatal antidepressant exposure is associated with risk for attention-­deficit hyperactivity disorder but not autism spectrum disorder in a large health system. Mol Psychiatry 2015; 20:727–734. 109. Brown HK, et al. The association between antenatal exposure to selective serotonin reuptake inhibitors and autism: a systematic review and meta-­analysis. J Clin Psychiatry 2017; 78:e48–e58. 110. Van der Veere CN, et al. Intra-­uterine exposure to selective serotonin reuptake inhibitors (SSRIs), maternal psychopathology, and neurodevelopment at age 2.5years – results from the prospective cohort SMOK study. Early Hum Dev 2020; 147:105075. 111. Brown AS, et al. Association of selective serotonin reuptake inhibitor exposure during pregnancy with speech, scholastic, and motor disorders in offspring. JAMA Psychiatry 2016; 73:1163–1170. 112. Skurtveit S, et al. Prenatal exposure to antidepressants and language competence at age three: results from a large population-­based pregnancy cohort in Norway. BJOG 2014; 121:1621–1631. 113. Handal M, et al. Prenatal exposure to folic acid and antidepressants and language development: a population-­based cohort study. J Clin Psychopharmacol 2016; 36:333–339. 114. Hanley GE, et al. Prenatal exposure to serotonin reuptake inhibitor antidepressants and childhood behavior. Pediatr Res 2015; 78:174–180. 115. Johnson KC, et al. Preschool outcomes following prenatal serotonin reuptake inhibitor exposure: differences in language and behavior, but not cognitive function. J Clin Psychiatry 2016; 77:e176–e182. 116. Partridge MC, et al. Fine motor differences and prenatal serotonin reuptake inhibitors exposure. J Pediatr 2016; 175:144–149.e141. 117. Bliddal M, et al. Prenatal antidepressant exposure and emotional disorders until age 22: a Danish register study. Child Adolesc Psychiatry Ment Health 2023; 17:73. 118. Koc D, et al. Prenatal antidepressant exposure and offspring brain morphologic trajectory. JAMA Psychiatry 2023; 80:1208–1217. 119. Polen KN, et al. Association between reported venlafaxine use in early pregnancy and birth defects, national birth defects prevention study, 1997–2007. Birth Defects Res A Clin Mol Teratol 2013; 97:28–35. 120. Lou ZQ, et al. Exposure to selective noradrenalin reuptake inhibitors during the first trimester of pregnancy and risk of congenital malformations: a meta-­analysis of cohort studies. Psychiatry Res 2022; 316:114756. 121. Richardson JL, et  al. Pregnancy outcomes following maternal venlafaxine use: a prospective observational comparative cohort study. Reprod Toxicol 2019; 84:108–113. 122. Gentile S. The safety of newer antidepressants in pregnancy and breastfeeding. Drug Saf 2005; 28:137–152. 123. Ramos E, et al. Association between antidepressant use during pregnancy and infants born small for gestational age. Can J Psychiatry 2010; 55:643–652. Prescribing in pregnancy and breastfeeding CHAPTER 7 124. Huybrechts KF, et al. Maternal and fetal outcomes following exposure to duloxetine in pregnancy: cohort study. BMJ 2020; 368:m237. 125. Abdy NA, et al. Duloxetine withdrawal syndrome in a newborn. Clin Pediatr (Phila) 2013; 52:976–977. 126. Hoog SL, et al. Duloxetine and pregnancy outcomes: safety surveillance findings. Int J Med Sci 2013; 10:413–419. 127. Ankarfeldt MZ, et al. Exposure to duloxetine during pregnancy and risk of congenital malformations and stillbirth: a nationwide cohort study in Denmark and Sweden. PLoS Med 2021; 18:e1003851. 128. Einarson A, et al. A multicentre prospective controlled study to determine the safety of trazodone and nefazodone use during pregnancy. Can J Psychiatry 2003; 48:106–110. 129. Rohde A, et al. Mirtazapine (Remergil) for treatment resistant hyperemesis gravidarum: rescue of a twin pregnancy. Arch Gynecol Obstet 2003; 268:219–221. 130. Dao K, et al. Reproductive safety of trazodone after maternal exposure in early pregnancy: a comparative ENTIS cohort study. J Clin Psychopharmacol 2023; 43:12–19. 131. Djulus J, et al. Exposure to mirtazapine during pregnancy: a prospective, comparative study of birth outcomes. J Clin Psychiatry 2006; 67:1280–1284. 132. Cole JA, et al. Bupropion in pregnancy and the prevalence of congenital malformations. Pharmacoepidemiol Drug Saf 2007; 16:474–484. 133. Smit M, et al. Mirtazapine in pregnancy and lactation – a systematic review. Eur Neuropsychopharmacol 2016; 26:126–135. 134. Ostenfeld A, et  al. Mirtazapine exposure in pregnancy and fetal safety: a nationwide cohort study. Acta Psychiatr Scand 2022; 145:557–567. 135. Louik C, et  al. First-­trimester exposure to bupropion and risk of cardiac malformations. Pharmacoepidemiol Drug Saf 2014; 23:1066–1075. 136. Figueroa R. Use of antidepressants during pregnancy and risk of attention-­deficit/hyperactivity disorder in the offspring. J Dev Behav Pediatr 2010; 31:641–648. 137. Forsberg L, et al. School performance at age 16 in children exposed to antiepileptic drugs in utero – a population-­based study. Epilepsia 2010; 52:364–369. 138. Rybakowski JK. Moclobemide in pregnancy. Pharmacopsychiatry 2001; 34:82–83. 139. Pharmacia Ltd. Erdronax: use on pregnancy, renally and hepatically impaired patients. Personal communication, 2003. 140. Hendrick V, et al. Management of major depression during pregnancy. Am J Psychiatry 2002; 159:1667–1673. 141. Miller LJ. Use of electroconvulsive therapy during pregnancy. Hosp Community Psychiatry 1994; 45:444–450. 142. National Institute for Care and Health Excellence. Intrapartum care. NICE Guideline [NG235]. 2023 (last checked March 2024); https:// www.nice.org.uk/guidance/ng235/chapter/Recommendations#care-­of-­the-­newborn-­baby. 143. Taylor CL, et al. Predictors of severe relapse in pregnant women with psychotic or bipolar disorders. J Psychiatr Res 2018; 104:100–107. 144. Newport DJ, et al. Lithium placental passage and obstetrical outcome: implications for clinical management during late pregnancy. Am J Psychiatry 2005; 162:2162–2170. 145. Fornaro M, et al. Lithium exposure during pregnancy and the postpartum period: a systematic review and meta-­analysis of safety and efficacy outcomes. Am J Psychiatry 2020; 177:76–92. 146. Munk-­Olsen T, et al. Maternal and infant outcomes associated with lithium use in pregnancy: an international collaborative meta-­analysis of six cohort studies. Lancet Psychiatry 2018; 5:644–652. 147. Dodd S, et al. The pharmacology of bipolar disorder during pregnancy and breastfeeding. Exp Opin Drug Saf 2004; 3:221–229. 148. Viguera AC, et al. Risk of recurrence of bipolar disorder in pregnant and nonpregnant women after discontinuing lithium maintenance. Am J Psychiatry 2000; 157:179–184. 149. Diav-­Citrin O, et al. Pregnancy outcome following in utero exposure to lithium: a prospective, comparative, observational study. Am J Psychiatry 2014; 171:785–794. 150. McKnight RF, et al. Lithium toxicity profile: a systematic review and meta-­analysis. Lancet 2012; 379:721–728. 151. Boyle B, et al. The changing epidemiology of Ebstein’s anomaly and its relationship with maternal mental health conditions: a European registry-­based study. Cardiol Young 2017; 27:677–685. 152. Yonkers KA, et al. Lithium during pregnancy: drug effects and therapeutic implications. CNS Drugs 1998; 4:269. 153. Blake LD, et al. Lithium toxicity and the parturient: case report and literature review. Int J Obstet Anesth 2008; 17:164–169. 154. Hastie R, et al. Maternal lithium use and the risk of adverse pregnancy and neonatal outcomes: a Swedish population-­based cohort study. BMC Med 2021; 19:291. 155. Cohen JM, et  al. Anticonvulsant mood stabilizer and lithium use and risk of adverse pregnancy outcomes. J Clin Psychiatry 2019; 80:18m12572. 156. Schonewille NN, et al. Neonatal admission after lithium use in pregnant women with bipolar disorders: a retrospective cohort study. Int J Bipolar Disord 2023; 11:24. 157. Torfs M, et al. Early postnatal outcome and care after in utero exposure to lithium: a single center analysis of a Belgian tertiary university hospital. Int J Environ Res Public Health 2022; 19:10111. 158. Sagué-­Vilavella M, et al. Obstetric outcomes regarding the use of lithium in pregnant women with bipolar disorders: a prospective cohort study. Arch Womens Ment Health 2022; 25:729–737. 159. Poels EMP, et al. Brain development after intrauterine exposure to lithium: a magnetic resonance imaging study in school-­age children. Bipolar Disord 2023; 25:181–190. 160. James L, et al. Informing patients of the teratogenic potential of mood stabilising drugs: a case note review of the practice of psychiatrists. J Psychopharmacol 2007; 21:815–819. 161. Wide K, et al. Major malformations in infants exposed to antiepileptic drugs in utero, with emphasis on carbamazepine and valproic acid: a nation-­wide, population-­based register study. Acta Paediatr 2004; 93:174–176. 732 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 7 162. Wyszynski DF, et  al. Increased rate of major malformations in offspring exposed to valproate during pregnancy. Neurology 2005; 64:961–965. 163. Weston J, et al. Monotherapy treatment of epilepsy in pregnancy: congenital malformation outcomes in the child. Cochrane Database Syst Rev 2016; 11:CD010224. 164. Campbell E, et al. Malformation risks of antiepileptic drug monotherapies in pregnancy: updated results from the UK and Ireland Epilepsy and Pregnancy Registers. J Neurol Neurosurg Psychiatry 2014; 85:1029–1034. 165. Bestwick JP, et al. Prevention of neural tube defects: a cross-­sectional study of the uptake of folic acid supplementation in nearly half a million women. PLoS One 2014; 9:e89354. 166. Jentink J, et al. Valproic acid monotherapy in pregnancy and major congenital malformations. N Engl J Med 2010; 362:2185–2193. 167. Tomson T, et al. Teratogenic effects of antiepileptic drugs. Lancet Neurol 2012; 11:803–813. 168. Bromley R, et al. Treatment for epilepsy in pregnancy: neurodevelopmental outcomes in the child. Cochrane Database Syst Rev 2014; 10:CD010236. 169. Bromley RL, et al. Fetal antiepileptic drug exposure and cognitive outcomes. Seizure 2017; 44:225–231. 170. Cohen MJ, et al. Fetal antiepileptic drug exposure and learning and memory functioning at 6 years of age: the NEAD prospective observational study. Epilepsy Behav 2019; 92:154–164. 171. Elkjær LS, et al. Association between prenatal valproate exposure and performance on standardized language and mathematics tests in school-­aged children. JAMA Neurol 2018; 75:663–671. 172. Danielsson KC, et al. Hypertensive pregnancy complications in women with epilepsy and antiepileptic drugs: a population-­based cohort study of first pregnancies in Norway. BMJ Open 2018; 8:e020998. 173. Vajda FJ, et al. Critical relationship between sodium valproate dose and human teratogenicity: results of the Australian register of anti-­ epileptic drugs in pregnancy. J Clin Neurosci 2004; 11:854–858. 174. Vajda FJ, et al. Maternal valproate dosage and foetal malformations. Acta Neurol Scand 2005; 112:137–143. 175. Tomson T, et al. Dose-­dependent risk of malformations with antiepileptic drugs: an analysis of data from the EURAP epilepsy and pregnancy registry. Lancet Neurol 2011; 10:609–617. 176. Molgaard-­Nielsen D, et al. Newer-­generation antiepileptic drugs and the risk of major birth defects. JAMA 2011; 305:1996–2002. 177. Vajda FJE, et al. Antiepileptic drugs and foetal malformation: analysis of 20 years of data in a pregnancy register. Seizure 2019; 65:6–11. 178. Tomson T, et al. Comparative risk of major congenital malformations with eight different antiepileptic drugs: a prospective cohort study of the EURAP registry. Lancet Neurol 2018; 17:530–538. 179. De Haan GJ, et al. Gestation-­induced changes in lamotrigine pharmacokinetics: a monotherapy study. Neurology 2004; 63:571–573. 180. Karanam A, et al. Lamotrigine clearance increases by 5 weeks gestational age: relationship to estradiol concentrations and gestational age. Ann Neurol 2018; 84:556–563. 181. Clark CT, et al. Lamotrigine dosing for pregnant patients with bipolar disorder. Am J Psychiatry 2013; 170:1240–1247. 182. Huber-­Mollema Y, et al. Neurocognition after prenatal levetiracetam, lamotrigine, carbamazepine or valproate exposure. J Neurol 2020; 267:1724–1736. 183. Veroniki AA, et al. Comparative safety of antiepileptic drugs for neurological development in children exposed during pregnancy and breast feeding: a systematic review and network meta-­analysis. BMJ Open 2017; 7:e017248. 184. Knight R, et al. Neurodevelopmental outcomes in children exposed to newer antiseizure medications: a systematic review. Epilepsia 2021; 62:1765–1779. 185. Christensen J, et al. Apgar-­score in children prenatally exposed to antiepileptic drugs: a population-­based cohort study. BMJ Open 2015; 5:e007425. 186. Cohen JM, et al. Comparative safety of antiseizure medication monotherapy for major malformations. Ann Neurol 2023; 93:551–562. 187. Bromley RL, et  al. Cognition in school-­age children exposed to levetiracetam, topiramate, or sodium valproate. Neurology 2016; 87:1943–1953. 188. Hernandez-­Diaz S, et  al. Topiramate use early in pregnancy and the risk of oral clefts: a pregnancy cohort study. Neurology 2018; 90:e342–e351. 189. Bjørk MH, et al. Association of prenatal exposure to antiseizure medication with risk of autism and intellectual disability. JAMA Neurol 2022; 79:672–681. 190. European Medicines Agency. Topiramate. New measures to avoid topiramate exposure in pregnancy. 2023; https://www.ema.europa.eu/en/ medicines/human/referrals/topiramate. 191. Athar F, et al. Adverse fetal and neonatal outcomes following in-­utero exposure to oxcarbazepine: a systematic review and meta-­analysis. Br J Clin Pharmacol 2022; 88:3600–3609. 192. Richardson JL, et al. A critical appraisal of controlled studies investigating malformation risks following pregabalin use in early pregnancy. Br J Clin Pharmacol 2023; 89:630–640. 193. Dudukina E, et al. Prenatal exposure to pregabalin, birth outcomes and neurodevelopment – a population-­based cohort study in four Nordic countries. Drug Saf 2023; 46:661–675. 194. Medicines and Healthcare products Regulatory Agency. Pregabalin and risks in pregnancy. 2022; https://www.gov.uk/government/ publications/pregabalin-­and-­risks-­in-­pregnancy. 195. Medicines and Healthcare products Regulatory Agency. Valproate: review of safety data and expert advice on management of risks. 2023; https://www.gov.uk/government/publications/valproate-­review-­of-­safety-­data-­and-­expert-­advice-­on-­management-­of-­risks. 196. Ross LE, et  al. Anxiety disorders during pregnancy and the postpartum period: a systematic review. J Clin Psychiatry 2006; 67:1285–1298. 197. Noh Y, et al. First-­trimester exposure to benzodiazepines and risk of congenital malformations in offspring: a population-­based cohort study in South Korea. PLoS Med 2022; 19:e1003945. Prescribing in pregnancy and breastfeeding CHAPTER 7 198. Dolovich LR, et al. Benzodiazepine use in pregnancy and major malformations or oral cleft: meta-­analysis of cohort and case-­control studies. BMJ 1998; 317:839–843. 199. Wikner BN, et al. Use of benzodiazepines and benzodiazepine receptor agonists during pregnancy: neonatal outcome and congenital malformations. Pharmacoepidemiol Drug Saf 2007; 16:1203–1210. 200. Reis M, et al. Combined use of selective serotonin reuptake inhibitors and sedatives/hypnotics during pregnancy: risk of relatively severe congenital malformations or cardiac defects. A register study. BMJ Open 2013; 3(2):e002166. 201. Tinker SC, et al. Use of benzodiazepine medications during pregnancy and potential risk for birth defects, National Birth Defects Prevention Study, 1997–2011. Birth Defects Res 2019; 111:613–620. 202. Grigoriadis S, et al. Benzodiazepine use during pregnancy alone or in combination with an antidepressant and congenital malformations: systematic review and meta-­analysis. J Clin Psychiatry 2019; 80:18r12412. 203. Andrade C. Gestational exposure to benzodiazepines, 2: the risk of congenital malformations examined through the prism of compatibility intervals. J Clin Psychiatry 2019; 80:19f13081. 204. Calderon-­Margalit R, et al. Risk of preterm delivery and other adverse perinatal outcomes in relation to maternal use of psychotropic medications during pregnancy. Am J Obstet Gynecol 2009; 201:579–578. 205. Okun ML, et al. A review of sleep-­promoting medications used in pregnancy. Am J Obstet Gynecol 2015; 212:428–441. 206. Yonkers KA, et al. Maternal antidepressant use and pregnancy outcomes. JAMA 2017; 318:665–666. 207. Freeman MP, et al. Obstetrical and neonatal outcomes after benzodiazepine exposure during pregnancy: results from a prospective registry of women with psychiatric disorders. Gen Hosp Psychiatry 2018; 53:73–79. 208. Sheehy O, et al. Association between incident exposure to benzodiazepines in early pregnancy and risk of spontaneous abortion. JAMA Psychiatry 2019; 76:948–957. 209. McElhatton PR. The effects of benzodiazepine use during pregnancy and lactation. Reprod Toxicol 1994; 8:461–475. 210. Meng LC, et al. Association between maternal benzodiazepine or Z-­hypnotic use in early pregnancy and the risk of stillbirth, preterm birth, and small for gestational age: a nationwide, population-­based cohort study in Taiwan. Lancet Psychiatry 2023; 10:499–508. 211. Grigoriadis S, et al. Hypnotic benzodiazepine receptor agonist exposure during pregnancy and the risk of congenital malformations and other adverse pregnancy outcomes: a systematic review and meta-­analysis. Acta Psychiatr Scand 2022; 146:312–324. 212. Wikner BN, et al. Are hypnotic benzodiazepine receptor agonists teratogenic in humans? J Clin Psychopharmacol 2011; 31:356–359. 213. Wang LH, et al. Increased risk of adverse pregnancy outcomes in women receiving zolpidem during pregnancy. Clin Pharmacol Ther 2010; 88:369–374. 214. Chen VC, et al. Association of prenatal exposure to benzodiazepines with development of autism spectrum and attention-­deficit/hyperactivity disorders. JAMA Network Open 2022; 5:e2243282. 215. Sundbakk LM, et al. Association of prenatal exposure to benzodiazepines and Z-­hypnotics with risk of attention-­deficit/hyperactivity disorder in childhood. JAMA Network Open 2022; 5:e2246889. 216. Chan AYL, et al. Maternal benzodiazepines and Z-­drugs use during pregnancy and adverse birth and neurodevelopmental outcomes in offspring: a population-­based cohort study. Psychother Psychosom 2023; 92:113–123. 217. Pottegard A, et al. First-­trimester exposure to methylphenidate: a population-­based cohort study. J Clin Psychiatry 2014; 75:e88–e93. 218. Ornoy A, et al. Neurotropic drugs in pregnancy and lactation from the point of view of the clinical teratologist. Curr Neuropharmacol 2021; 19:1792–1793. 219. Huybrechts KF, et al. Association between methylphenidate and amphetamine use in pregnancy and risk of congenital malformations: a cohort study from the International Pregnancy Safety Study Consortium. JAMA Psychiatry 2018; 75:167–175. 220. Gov.UK. Modafinil (Provigil): increased risk of congenital malformations if used during pregnancy. 2020; https://www.gov.uk/drug-­safety-­ update/modafinil-­provigil-­increased-­risk-­of-­congenital-­malformations-­if-­used-­during-­pregnancy?utm_source=e-­shot&utm_medium= email&utm_campaign=DSU_November2020split1. 221. Damkier P, et al. First-­trimester pregnancy exposure to modafinil and risk of congenital malformations. JAMA 2020; 323:374–376. 222. Bang Madsen K, et al. In utero exposure to ADHD medication and long-­term offspring outcomes. Mol Psychiatry 2023; 28:1739–1746. 223. Suarez EA, et al. Prescription stimulant use during pregnancy and risk of neurodevelopmental disorders in children. JAMA Psychiatry 2024; 81:477–488. 08 - Drug choice in breastfeeding Drug choice in breastfeeding 09 - Infant exposure Infant exposure 10 - General principles of prescribing psychotropi General principles of prescribing psychotropics in breastfeeding 734 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 7 Drug choice in breastfeeding The long-­term benefits of breastfeeding on a child’s physical health and cognitive development are well known. Women are generally encouraged to breastfeed for at least 6 months. One factor that may influence a mother’s decision to breastfeed is the safety of a drug taken while breastfeeding. With some notable exceptions, most psychotropic drugs should be continued in breastfeeding women because of the benefits of breastfeeding and the lack of evidence of harm for most drugs. However, current evidence suggests that for a few drugs the woman should be advised not to breastfeed if such medications are the best and only option for her care. Data on the safety of psychotropic medication in breastfeeding are largely derived from small studies or case reports and case series. Reported infant and neonatal outcomes in most cases are limited to short-­term acute adverse effects. Long-­term safety cannot therefore be guaranteed for the psychotropics mentioned here. The information presented must be interpreted with caution with respect to the limits of the data from which it is derived and the need for such information to be regularly updated. There are two distinct clinical scenarios. In the first, the mother will have been taking the psychotropic drug(s) during pregnancy and often up until birth. In these people, the same psychotropic(s) should be continued during breastfeeding to mitigate withdrawal symptoms in the neonate (but see exceptions later). In the second, the mother is newly prescribed a psychotropic after the child has been born but wishes to breastfeed. Decisions in this scenario are rather more complex and the reader is referred to the tables in this section. Infant exposure All psychotropics are excreted in breast milk to varying degrees. The most direct measure of infant exposure is, of course, infant plasma levels but these data are rarely available. Instead, many publications report only drug concentrations in breast milk and in maternal plasma. Maternal plasma levels of antipsychotics may be a useful estimate of infant exposure.1 Breast milk drug concentrations can be used to estimate the daily infant dose (by assuming a milk intake of 150mL/kg/day). The infant weight-­adjusted dose when expressed as a proportion of the maternal weight-­adjusted dose is known as the relative infant dose (RID). The RID should be used as a guide only, as values are estimates and these estimates vary widely in the literature for individual drugs. Drugs with an RID below 10% are usually regarded as safe in breastfeeding. Where measured, infant plasma levels below 10% of average maternal plasma levels have also been proposed as being safe in breastfeeding.2 General principles of prescribing psychotropics in breastfeeding ■ ■The safety of individual drugs in breastfeeding should be taken into account when prescribing psychotropic medication for women considering pregnancy. ■ ■Discussions about the safety of drugs in breastfeeding should be held as early as ­possible – ideally before conception or early in pregnancy. Decisions about the use of drugs in pregnancy should include the discussion about breastfeeding. Switching drugs at the end of pregnancy or in the days after birth is not advisable because of the high risk of relapse. 11 - Antidepressants in breastfeeding Antidepressants in breastfeeding Prescribing in pregnancy and breastfeeding CHAPTER 7 ■ ■Where a mother has taken a particular psychotropic during pregnancy and until delivery, continuation with the drug while breastfeeding will usually be appropriate (but see notable exceptions later), as this may minimise withdrawal symptoms in the infant. ■ ■In each case the benefits of breastfeeding to the mother and infant must be weighed against the risk of drug exposure in the infant. Consider the infant’s general health and gestational age at birth.3 ■ ■It is usually inappropriate to stop breastfeeding unless the currently prescribed drug is absolutely contraindicated in breastfeeding. As treatment of maternal mental illness is the priority, in such cases treatment should not be withheld but the mother should be advised to bottle feed with formula milk. ■ ■When initiating a drug postpartum it is: ■ ■important to consider the mother’s previous response to treatment ■ ■best to avoid a psychotropic with high reported infant plasma levels or a high RID ■ ■important to consider the half-­lives of the drugs: drugs with a long half-­life can accumulate in breast milk and the infant. ■ ■Neonates and infants do not have the same capacity for drug clearance as adults. Premature infants and infants with renal, hepatic, cardiac or neurological impairment are at a greater risk from exposure to drugs. ■ ■Infants should be monitored for any specific adverse effects of the drugs as well as for abnormalities in feeding patterns and growth and development. ■ ■Infant plasma levels should be monitored if adverse effects are noted or toxicity is suspected. ■ ■Women receiving sedating medication should be strongly advised to not breastfeed in bed as they may fall asleep and roll onto the baby, with a potential risk of hypoxia to the baby. ■ ■Sedation may affect women’s ability to interact with their children. Women receiving sedating drugs should be monitored for this effect. ■ ■Wherever possible: ■ ■use the lowest effective dose ■ ■avoid polypharmacy ■ ■continue the regimen prescribed during pregnancy. Table  7.1 outlines recommendations for treatment with psychotropics in breastfeeding. Antidepressants in breastfeeding Table 7.2 provides information on individual drugs in breastfeeding based on available published data in late 2023. Manufacturers’ formal advice on drugs in breastfeeding is available in the formal product literature or European Public Assessment Report for individual drugs. Table 7.2 does not include this advice (which is often uninformative), but instead uses primary reference sources. It is worth repeating that it is usually advisable to continue the antidepressant prescribed during pregnancy. Switching drugs postpartum for the purpose of breastfeeding is usually not sensible. Table 7.2 should be used as a guide when initiating treatment postpartum. In each case previous response (and lack of response) to treatment must be considered. 12 - Antipsychotics in breastfeeding Antipsychotics in breastfeeding 13 - Mood stabilisers in breastfeeding Mood stabilisers in breastfeeding 14 - Hypnotics in breastfeeding Hypnotics in breastfeeding 736 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 7 Antipsychotics in breast­feeding Table 7.3 provides information on individual drugs in breastfeeding based on available published data in mid-­2024. Manufacturers’ formal advice on drugs in breastfeeding is available in the SPC or European Public Assessment Report for individual drugs. Table 7.3 does not include this advice (which is often uninformative), but instead uses primary reference sources. It is usually advisable to continue the antipsychotic prescribed during pregnancy. Switching drugs postpartum for the purpose of breastfeeding is usually not sensible. The exception to this is clozapine; clozapine should continue but breastfeeding should be avoided. Table 7.3 should be used as a guide when initiating treatment postpartum. In each case the previous response (and lack of response) to treatment must be considered. Mood stabilisers in breastfeeding Table 7.4 provides information on individual drugs in breastfeeding based on available published data in mid-2024. Manufacturers’ formal advice on drugs in breastfeeding is available in the SPC or European Public Assessment Report for individual drugs. Table 7.4 does not include this advice (which is often uninformative), but instead uses primary reference sources. It is usually advisable to continue the mood stabiliser prescribed during pregnancy. Switching drugs postpartum for the purpose of breastfeeding is usually not sensible. The exception to this is lithium. Lithium should be continued but breastfeeding should not be permitted. Table 7.4 should be used as a guide when initiating treatment postpartum. In each case the previous response (and lack of response) to treatment must be considered. Hypnotics in breastfeeding Table 7.5 provides information on individual drugs in breastfeeding based on available published data in mid-2024. Manufacturers’ formal advice on drugs in breastfeeding is available in the SPC or European Public Assessment Report for individual drugs. Table 7.5 does not include this advice (which is often uninformative), but instead uses primary reference sources. Table 7.1  Summary of recommendations. It is usually advisable to continue whichever drug has been used during pregnancy. When initiating a drug postpartum, previous response and tolerability should be considered Drug group Recommended drugs Antidepressants When initiating an antidepressant postpartum, sertraline may be considered. Other drugs may be used. See Table 7.2. Antipsychotics Women taking clozapine should be advised against breastfeeding and clozapine should be continued When initiating an antipsychotic postpartum, olanzapine or quetiapine may be considered. Other drugs may be used. See Table 7.3. Mood stabilisers Women taking lithium should be advised against breastfeeding and lithium should be continued When initiating a mood stabiliser postpartum, a mood-­stabilising antipsychotic such as olanzapine or quetiapine may be considered. Other drugs may be used. See Table 7.4. Sedatives Best avoided. Use a drug with a short half-­life. See Table 7.5. Table 7.2  Antidepressants in breastfeeding. Drug Infant plasma concentrations Relative infant dose (RID) Reported acute adverse effects in infant Reported developmental effects in infant Agomelatine4,5 Not assessed Not available None reported but not studied None reported but not studied Brexanolone6 Not assessed 1–2% None reported but not studied None reported but not studied Bupropion5,7–14 Undetectable or low 0.2–2% Two reports of seizure-­like activity in 6-­month-­olds. In one of the cases the infant experienced sleep disturbance, severe emesis and somnolence. The infant plasma levels were below the level required for quantification. The mother was also taking escitalopram. None reported but not studied Citalopram2,5,12,15–24 Undetectable to up to 10% of maternal plasma levels   Higher than for fluvoxamine, sertraline, paroxetine and escitalopram, but lower than for fluoxetine 3.56–5.37%5 Sleep disturbance (which resolved on halving maternal dose), colic, decreased feeding, irritability and restlessness   One case of irregular breathing, sleep disorder and hypo-­ and hypertonia; the Infant was exposed to citalopram in utero. Symptoms were attributed to withdrawal syndrome despite the mother continuing citalopram postpartum. None reported   In a study of 78 infants of mothers taking an SSRI or venlafaxine, no difference in weight was noted at 6 months compared with the ‘normative’ weight.   In a study of 11 infants, normal neurodevelopment was observed up to 1 year. One of the children was unable to walk at 1 year, However, neurological status of the child was deemed normal 6 months later. Duloxetine5,12,25–28 <1% of maternal plasma levels <1% Dizziness, nausea and fatigue None reported but not assessed (Continued) Drug Infant plasma concentrations Relative infant dose (RID) Reported acute adverse effects in infant Reported developmental effects in infant Escitalopram5,12,14,29–34 Undetectable or low 3–8.3% Necrotising enterocolitis in 5-­day-­old infant (necessitating intensive care admission and intravenous antibiotic treatment). Infant was exposed to escitalopram in utero. Symptoms were lethargy, decreased oral intake and blood in the stools.   Seizure-­like activity, sleep disturbance, severe emesis and somnolence in 6-­monthold. Mother was also taking bupropion. None reported but not studied Fluoxetine2,5,12,15,24,35–46 Variable: can be >10% of maternal plasma levels. Highest reported levels of SSRIs 1.6–14.6% Colic, excessive crying, decreased sleep, diarrhoea, vomiting, somnolence, decreased feeding, hypotonia, moaning, grunting and hyperactivity   One case of seizure activity at 3 weeks, 4 months and then 5 months. Mother was also taking carbamazepine.   One case of tachypnoea, jitteriness, irritability, fever and compensated metabolic acidosis. Infant plasma levels were in the adult therapeutic range. The authors diagnosed serotonin syndrome. Mother was taking fluoxetine 60mg. Normal weight gain and neurological development have been reported for many infants.   One retrospective study found lower growth curves compared with non-­ exposed infants.   One case of a reduction in platelet serotonin Fluvoxamine5,12,15,47–54 Undetectable to up to half the maternal plasma level 1–2% Neonatal jaundice, severe diarrhoea, mild vomiting, decreased sleep and agitation None reported   In a study of 78 infants of mothers taking an SSRI or venlafaxine, no difference in weight was noted at 6 months compared with the ‘normative’ weight. MAOIs55,56 No published data available at the time of writing Isoniazid = 1.2–18% None reported None reported but not assessed Table 7.2  (Continued) Drug Infant plasma concentrations Relative infant dose (RID) Reported acute adverse effects in infant Reported developmental effects in infant Mianserin5,57 Not assessed Not assessed None reported None reported but not studied Mirtazapine5,12,58,59 Undetectable or low. There was one case of higher mirtazapine plasma levels. Elimination rates may differ between individual infants 0.5–4.4% In a study of 54 infants exposed to mirtazapine in utero, the incidence of poor neonatal adaptation syndrome was significantly diminished in those who were breastfed. None reported   In a study of eight infants, weights for three were observed to be between the 10th to 25th percentiles; all three were noted to also have a low birth weight. Moclobemide5,60,61 Low 3.4% None reported None reported but not studied Paroxetine2,5,12,15,24,39,47,62–71 Undetectable or low 0.5–2.8% Vomiting and irritability which were attributed to severe hyponatraemia   In a study of 72 infants, adverse effects were noted in nine infants. Insomnia, restlessness and constant crying were most commonly reported. None reported   In a study of 78 infants of mothers taking an SSRI or venlafaxine, no difference in weight was noted at 6 months compared with the ‘normative’ weight.   Breastfed infants of 27 women taking paroxetine reached the usual developmental milestones at 3, 6 and 12 months, similar to a control group. Reboxetine5,12,72 Undetectable or low 1–3% None reported In a study of four infants, three reached normal milestones. The fourth had developmental problems thought not to be related to reboxetine. Sertraline5,12,24,39,66,73–81 Undetectable or low. There was one report of an unusually high infant serum level (half maternal serum level). The infant was reported to be ‘clinically thriving’ 0.5–3% Serotonergic overstimulation reported in preterm infant also exposed to sertraline in utero. Symptoms included hyperthermia, shivering, myoclonus, tremor, irritability, high-pitched crying, decreased suckling reflex and reactivity   Withdrawal symptoms (agitation, restlessness, insomnia and an enhanced startle reaction) developed in a breast­fed neonate, after abrupt withdrawal of maternal sertraline. The neonate was exposed to sertraline in utero. None reported   In a study of 78 infants of mothers taking an SSRI or venlafaxine, no difference in weight was noted at 6 months compared with the ‘normative’ weight. (Continued) Drug Infant plasma concentrations Relative infant dose (RID) Reported acute adverse effects in infant Reported developmental effects in infant Trazodone5,82,83 Not assessed 2.8% None reported None reported Tricyclic antidepressants (TCAs)5,15,84–92 Undetectable or low Nortriptyline Amitriptyline    1–3% Clomipramine Adverse effects have not been reported in infants exposed to nortriptyline, clomipramine, imipramine, dosulepin and desipramine through breast milk.   Severe sedation and poor feeding reported with amitriptyline   Poor suckling, muscle hypotonia, drowsiness and respiratory depression reported with doxepin None reported   A study of 15 children did not show a negative outcome in regard to cognitive development in breastfed children 3–5 years postpartum. Venlafaxine5,12,24,39,66,93–100 Undetectable to up to 37% of maternal plasma levels 6–9% (>10% reported in one case)101 Lethargy, jitteriness, rapid breathing, poor suckling and dehydration in an infant also exposed in utero. Symptoms subsided over a week on breastfeeding. Authors suggested that breastfeeding may have helped manage infant withdrawal symptoms postpartum. None reported   In a study of 78 infants of mothers taking an SSRI or venlafaxine, no difference in weight was noted at 6 months compared with the ‘normative’ weight. Vortioxetine 1.1 –1.7%102 1.1–1.8% None reported None reported but not studied MAOI, monoamine oxidase inhibitor; SSRI, selective serotonin reuptake inhibitor. Table 7.2  (Continued) Table 7.3  Antipsychotics in breastfeeding. Drug Infant plasma concentration Estimated daily infant dose as proportion of maternal dose (RID) Acute adverse effects in infant Developmental effects in infant Amisulpride5,96,103–105 10.5% of maternal plasma concentration* 4.7–10.7% None reported None reported Aripiprazole5,106–111 (may lead to reduced milk supply)112,113 4% of maternal plasma concentration* 0.9–8.3% None reported None reported Asenapine No published data available at the time of writing Brexpiprazole (may lead to reduced milk supply)112 No published data available at the time of writing Butyrophenones5,15,39,84,104,114–117 Not reported Haloperidol = 0.2–12% One case of hypersomnia, poor feeding and slowing in motor movements. Mother was also taking risperidone. The effects were noted when haloperidol dose was increased. Delayed development was noted in three infants exposed to a combination of haloperidol and chlorpromazine in breast milk.   Normal development has also been reported. Cariprazine No published data available at the time of writing Clozapine5,15,39,84,115,118–121 NB avoid 6.5% of maternal plasma concentration* 1.4% Sedation, agranulocytosis, decreased sucking reflex, irritability, seizures and cardiovascular instability There is one report of delayed speech acquisition. The infant was also exposed to clozapine in utero. Iloperidone No published data available at the time of writing Lurasidone No published data available at the time of writing (Continued) Drug Infant plasma concentration Estimated daily infant dose as proportion of maternal dose (RID) Acute adverse effects in infant Developmental effects in infant Lumateperone Published data not available Olanzapine5,15,39,104,122–134 Undetectable or low   One case of plasma levels decreasing over 5 months. The authors proposed that an infant’s capacity to metabolise olanzapine ‘developed rapidly’ around the age of 4 months 1.0–1.6% Somnolence, drowsiness, irritability, tremor, insomnia, lethargy, poor suckling and shaking   One case of jaundice and sedation. Infant was exposed in utero and had cardiomegaly. One case of lower developmental age than chronological age. Mother was taking additional psychotropic medication.   One case of speech delay and one of motor developmental delay   Two cases of failure to gain weight   Normal development has also been reported. Paliperidone No specific data available (see risperidone) Phenothiazines5,15,84,114–116 Variable Chlorpromazine = 0.3% Lethargy Delayed development in three infants exposed to a combination of chlorpromazine and haloperidol Pimavanserin No published data available at the time of writing Quetiapine5,97,131,135–144 Undetectable 0.09–0.1% Excessive sleep. Mother was also taking mirtazapine and a benzodiazepine. In a small study of quetiapine augmentation of maternal antidepressant, there were two cases of mild developmental delays, thought not to be related to quetiapine. Table 7.3  (Continued) Drug Infant plasma concentration Estimated daily infant dose as proportion of maternal dose (RID) Acute adverse effects in infant Developmental effects in infant Risperidone5,117,145–149 Risperidone undetectable 9-­hydoxyrisperidone low Risperidone = 2.8–9.1%   9-­hydoxyrisperidone = 3.46–4.7% One case of hypersomnia, poor feeding and slowing in motor movements. Mother was also taking haloperidol. The effects were noted when haloperidol dose was increased. None reported Sertindole No published data available at the time of writing Sulpiride5,150–154 Not reported 2.7–20.7% None reported None reported but not assessed Thioxanthenes5,15,116,155–157 Not reported Zuclopenthixol = 0.4–0.9% Flupentixol = 0.7–1.75% None reported None reported for flupentixol Not assessed for zuclopenthixol Ziprasidone5,23,116,158 Not reported 0.07–1.2% None reported None reported *A proportion of the drug detected may have been due to placental transfer following in utero exposure. RID, relative infant dose. Table 7.4  Mood stabilisers in breastfeeding. Drug Infant plasma concentration 1.1–7.3% Adverse effects have not been reported for a number of infants.   One case of cholestatic hepatitis, one of transient hepatic dysfunction with hyperbilirubinaemia and elevated GGT. Adverse effects in the first case resolved after discontinuation of breastfeeding and the second resolved despite continued feeding.   One case of seizure-­like activity, drowsiness, irritability and high-­pitched crying. Mother was taking multiple agents.   Poor suckling, poor feeding and two cases of hyperexcitability Carbamazepine5,15,159–169 Generally low although one report of an infant plasma level within adult therapeutic range Lamotrigine5,162,167,170–181 Up to 48% of maternal plasma levels182 9.2–18.3% No adverse effects have been reported in a number of infants.   Seven cases of thrombocytosis   One case of a severe cyanotic episode (preceded by mild episodes of apnoea) requiring resuscitation. Neonatal serum concentration was in the upper therapeutic range. The infant was exposed in utero and the mother was taking a high dose (850mg/ day). One case of normocytic normochromic anaemia and asymptomatic neutropenia.183   In Australia, the Centre for Perinatal Excellence (COPE) recommends close monitoring of the infant and a specialist neonatologist consultation where possible3 Estimated daily infant dose as proportion of maternal dose (RID) Acute adverse effects in infant Developmental effects in infant None reported   A prospective study of children of women with epilepsy found no adverse development at ages 6–36 months. The study assessed outcomes in children exposed to anticonvulsants in utero who were subsequently breastfed compared with those who were not.   A study of 199 infants exposed to antiepileptic medications in utero and through breast milk failed to show a difference in IQ between breastfed and non-­ breastfed infants at the age of 3 years.   A study of 181 children concluded that IQ was not adversely affected by anticonvulsant exposure through breast milk. No abnormalities reported   A prospective study of children of women with epilepsy found that breastfeeding while taking an anticonvulsant was not associated with adverse development of infants at ages 6–36 months. The study assessed outcomes in children exposed to anticonvulsants in utero who were subsequently breastfed compared with those who were not.   A study of 199 infants exposed to antiepileptic medications during breastfeeding failed to show a difference in IQ between breastfed and non-­breastfed infants at the age of 3 years. The infants were exposed to antiepileptic medications in utero.   A study of 181 children concluded that IQ was not adversely affected by anticonvulsant exposure in breast milk.   Three cases of rash. In one case the rash was attributed to eczema, and to soy allergy in another. The third case resolved spontaneously. Drug Infant plasma concentration Estimated daily infant dose as proportion of maternal dose (RID) Acute adverse effects in infant Developmental effects in infant Lithium184 NB avoid Up to 57% of maternal plasma levels 12–30.1% Early feeding problems, increased urea, raised creatinine and non-­specific signs of toxicity   One case of elevated TSH. In utero exposure. One case of cyanosis, lethargy, hypothermia, hypotonia and a heart murmur. In utero exposure   No adverse effects have been reported in others. None reported Topiramate185,186 Undetectable to 20% of maternal plasma levels 3– 35% Diarrhoea None reported but not assessed Valproate5,15,159–162,167,187,188 <2% of maternal plasma levels 1.4–1.7% Thrombocytopenia and anaemia which reversed on stopping breastfeeding. In utero exposure A prospective study of children of women with epilepsy found that breastfeeding while taking an anticonvulsant was not associated with adverse development of infants at ages 6–36 months. The study assessed outcomes in children exposed to anticonvulsants in utero who were subsequently breastfed compared with those who were not.   A study of 199 infants exposed to antiepileptic medications during breastfeeding failed to show a difference in IQ between breastfed and non-­breastfed infants at the age of 3 years. The infants were exposed to antiepileptic medications in utero.   A study of 181 children concluded that IQ was not adversely affected by anticonvulsant exposure through breast milk. GGT, gamma-­glutamyl transferase; RID, relative infant dose; TSH, thyroid-­stimulating hormone. Table 7.5  Hypnotics in breastfeeding. Drug Infant plasma concentration Estimated daily infant dose as proportion of maternal dose (RID) Acute adverse effects in infant Developmental effects in infant Benzodiazepines5,15,39,189–196 Clonazepam: undetectable to 10% of maternal plasma levels197 Clonazepam = 2.8% Diazepam = 0.88–7.1% Lorazepam = 2.6–2.9% Oxazepam = 0.28–1% Sedation, lethargy, weight loss and mild jaundice   One case of persistent apnoea with clonazepam   Restlessness and mild drowsiness with alprazolam   In a telephone survey of 124 women two reported CNS depression in their breastfeeding neonates. One of the children was exposed to benzodiazepines in utero.   No adverse effects have been reported in others. None reported but not studied Promethazine No published data available at the time of writing Zopiclone, zolpidem and zaleplon5,198–200 Zolpidem: undetectable201   Zopiclone and zaleplon: not reported Zaleplon = 1.5% Zopiclone = 1.5% Zolpidem = 0.02–0.18% None reported None reported but not studied RID, relative infant dose. 15 - Stimulants in breastfeeding Stimulants in breastfeeding 16 - References References Prescribing in pregnancy and breastfeeding CHAPTER 7 Stimulants in breastfeeding Table 7.6 provides information on individual drugs in breastfeeding based on available published data in mid-2024. Manufacturers’ formal advice on drugs in breastfeeding is available in the SPC or European Public Assessment Report for individual drugs. Table 7.6 does not include this advice (which is often uninformative), but instead uses primary reference sources. It is usually advisable to continue the drug prescribed during pregnancy. Switching drugs postpartum for the purpose of breastfeeding is usually not sensible. Table 7.6 should be used as a guide when initiating treatment postpartum. In  each case the previous response (and lack of response) to treatment must be considered. References Schoretsanitis G, et al. Excretion of antipsychotics into the amniotic fluid, umbilical cord blood, and breast milk: a systematic critical review and combined analysis. Ther Drug Monit 2020; 42:245–254. Weissman AM, et al. Pooled analysis of antidepressant levels in lactating mothers, breast milk, and nursing infants. Am J Psychiatry 2004; 161:1066–1078. COPE (Centre of Perinatal Excellence). 2023 National Perinatal Mental Health Guideline. 2023; https://www.cope.org.au/health-­ professionals/review-­of-­new-­perinatal-­mental-­health-­guidelines/. Schmidt FM, et al. Agomelatine in breast milk. Int J Neuropsychopharmacol 2013; 16:497–499. Hale TW, et al. Medications and Mothers’ Milk, 20th edn. New York: Springer Publishing Company; 2023. Hoffmann E, et al. Brexanolone injection administration to lactating women: breast milk allopregnanolone levels [30J]. Obstet Gynecol 2019; 133:115S. Briggs GG, et al. Excretion of bupropion in breast milk. Ann Pharmacother 1993; 27:431–433. Chaudron LH, et al. Bupropion and breastfeeding: a case of a possible infant seizure. J Clin Psychiatry 2004; 65:881–882. Nonacs RM, et al. Bupropion SR for the treatment of postpartum depression: a pilot study. Int J Neuropsychopharmacol 2005; 8:445–449. Haas JS, et al. Bupropion in breast milk: an exposure assessment for potential treatment to prevent post-­partum tobacco use. Tob Control 2004; 13:52–56. Baab SW, et al. Serum bupropion levels in 2 breastfeeding mother-­infant pairs. J Clin Psychiatry 2002; 63:910–911. Table 7.6  Stimulants in breastfeeding. Drug Infant plasma concentration Estimated daily infant dose as proportion of maternal dose (RID) Acute adverse effects in infant Developmental effects in infant Atomoxetine No published data available at the time of writing Dexamfetamine202 Undetectable to 14% of maternal plasma level 2.4 –10.6% None reported None reported but not assessed Lisdexamfetamine No published data available at the time of writing Methylphenidate28,203–205 Undetectable 0.16–0.7% None reported None reported Modafinil206,207 Armodafanil = 1.5%208 Modafanil not reported Armodafanil = 4.85%208 Modafanil = 5.3% None reported None reported but not assessed RID, relative infant dose. 748 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 7 12. Berle JO, et al. Antidepressant use during breastfeeding. Curr Womens Health Rev 2011; 7:28–34. 13. Davis MF, et al. Bupropion levels in breast milk for 4 mother-­infant pairs: more answers to lingering questions. J Clin Psychiatry 2009; 70:297–298. 14. Neuman G, et al. Bupropion and escitalopram during lactation. Ann Pharmacother 2014; 48:928–931. 15. Burt VK, et al. The use of psychotropic medications during breast-­feeding. Am J Psychiatry 2001; 158:1001–1009. 16. Lee A, et al. Frequency of infant adverse events that are associated with citalopram use during breast-­feeding. Am J Obstet Gynecol 2004; 190:218–221. 17. Heikkinen T, et al. Citalopram in pregnancy and lactation. Clin Pharmacol Ther 2002; 72:184–191. 18. Jensen PN, et al. Citalopram and desmethylcitalopram concentrations in breast milk and in serum of mother and infant. Ther Drug Monit 1997; 19:236–239. 19. Spigset O, et al. Excretion of citalopram in breast milk. Br J Clin Pharmacol 1997; 44:295–298. 20. Rampono J, et al. Citalopram and demethylcitalopram in human milk; distribution, excretion and effects in breast fed infants. Br J Clin Pharmacol 2000; 50:263–268. 21. Schmidt K, et al. Citalopram and breast-­feeding: serum concentration and side effects in the infant. Biol Psychiatry 2000; 47:164–165. 22. Franssen EJ, et al. Citalopram serum and milk levels in mother and infant during lactation. Ther Drug Monit 2006; 28:2–4. 23. Werremeyer A. Ziprasidone and citalopram use in pregnancy and lactation in a woman with psychotic depression. Am J Psychiatry 2009; 166:1298. 24. Hendrick V, et al. Weight gain in breastfed infants of mothers taking antidepressant medications. J Clin Psychiatry 2003; 64:410–412. 25. Boyce PM, et al. Duloxetine transfer across the placenta during pregnancy and into milk during lactation. Arch Women’s Ment Health 2011; 14:169–172. 26. Briggs GG, et al. Use of duloxetine in pregnancy and lactation. Ann Pharmacother 2009; 43:1898–1902. 27. Lobo ED, et  al. Pharmacokinetics of duloxetine in breast milk and plasma of healthy postpartum women. Clin Pharmacokinet 2008; 47:103–109. 28. Collin-­Lévesque L, et al. Infant exposure to methylphenidate and duloxetine during lactation. Breastfeed Med 2018; 13:221–225. 29. Gentile S. Escitalopram late in pregnancy and while breast-­feeding (Letter). Ann Pharmacother 2006; 40:1696–1697. 30. Castberg I, et al. Excretion of escitalopram in breast milk. J Clin Psychopharmacol 2006; 26:536–538. 31. Rampono J, et  al. Transfer of escitalopram and its metabolite demethylescitalopram into breastmilk. Br J Clin Pharmacol 2006; 62:316–322. 32. Potts AL, et al. Necrotizing enterocolitis associated with in utero and breast milk exposure to the selective serotonin reuptake inhibitor, escitalopram. J Perinatol 2007; 27:120–122. 33. Ilett KF, et al. Estimation of infant dose and assessment of breastfeeding safety for escitalopram use in postnatal depression. Ther Drug Monit 2005; 27:248. 34. Bellantuono C, et al. The safety of escitalopram during pregnancy and breastfeeding: a comprehensive review. Hum Psychopharmacol 2012; 27:534–539. 35. Yoshida K, et al. Fluoxetine in breast-­milk and developmental outcome of breast-­fed infants. Br J Psychiatry 1998; 172:175–178. 36. Lester BM, et al. Possible association between fluoxetine hydrochloride and colic in an infant. J Am Acad Child Adolesc Psychiatry 1993; 32:1253–1255. 37. Hendrick V, et al. Fluoxetine and norfluoxetine concentrations in nursing infants and breast milk. Biol Psychiatry 2001; 50:775–782. 38. Hale TW, et al. Fluoxetine toxicity in a breastfed infant. Clin Pediatr 2001; 40:681–684. 39. Malone K, et al. Antidepressants, antipsychotics, benzodiazepines, and the breastfeeding dyad. Perspect Psychiatr Care 2004; 40:73–85. 40. Heikkinen T, et al. Pharmacokinetics of fluoxetine and norfluoxetine in pregnancy and lactation. Clin Pharmacol Ther 2003; 73:330–337. 41. Epperson CN, et al. Maternal fluoxetine treatment in the postpartum period: effects on platelet serotonin and plasma drug levels in breastfeeding mother-­infant pairs. Pediatrics 2003; 112:e425. 42. Taddio A, et al. Excretion of fluoxetine and its metabolite, norfluoxetine, in human breast milk. J Clin Pharmacol 1996; 36:42–47. 43. Brent NB, et al. Fluoxetine and carbamazepine concentrations in a nursing mother/infant pair. Clin Pediatr (Phila) 1998; 37:41–44. 44. Kristensen JH, et al. Distribution and excretion of fluoxetine and norfluoxetine in human milk. Br J Clin Pharmacol 1999; 48:521–527. 45. Burch KJ, et al. Fluoxetine/norfluoxetine concentrations in human milk. Pediatrics 1992; 89:676–677. 46. Morris R, et al. Serotonin syndrome in a breast-­fed neonate. BMJ Case Rep 2015; 2015:bcr2015209418. 47. Hendrick V, et al. Use of sertraline, paroxetine and fluvoxamine by nursing women. Br J Psychiatry 2001; 179:163–166. 48. Piontek CM, et al. Serum fluvoxamine levels in breastfed infants. J Clin Psychiatry 2001; 62:111–113. 49. Yoshida K, et al. Fluvoxamine in breast-­milk and infant development. Br J Clin Pharmacol 1997; 44:210–211. 50. Hagg S, et al. Excretion of fluvoxamine into breast milk. Br J Clin Pharmacol 2000; 49:286–288. 51. Arnold LM, et al. Fluvoxamine concentrations in breast milk and in maternal and infant sera. J Clin Psychopharmacol 2000; 20:491–492. 52. Kristensen JH, et al. The amount of fluvoxamine in milk is unlikely to be a cause of adverse effects in breastfed infants. J Hum Lact 2002; 18:139–143. 53. Wright S, et al. Excretion of fluvoxamine in breast milk. Br J Clin Pharmacol 1991; 31:209. 54. Uguz F. Gastrointestinal side effects in the baby of a breastfeeding woman treated with low-­dose fluvoxamine. J Hum Lact 2015; 31:371–373. 55. Snider DE, Jr, et al. Should women taking antituberculosis drugs breast-­feed? Arch Intern Med 1984; 144:589–590. 56. Singh N, et al. Transfer of isoniazid from circulation to breast milk in lactating women on chronic therapy for tuberculosis. Br J Clin Pharmacol 2008; 65:418–422. 57. Buist A, et al. Mianserin in breast milk (Letter). Br J Clin Pharmacol 1993; 36:133–134. Prescribing in pregnancy and breastfeeding CHAPTER 7 58. Smit M, et al. Mirtazapine in pregnancy and lactation: data from a case series. J Clin Psychopharmacol 2015; 35:163–167. 59. Smit M, et al. Mirtazapine in pregnancy and lactation – a systematic review. Eur Neuropsychopharmacol 2016; 26:126–135. 60. Buist A, et al. Plasma and human milk concentrations of moclobemide in nursing mothers. Hum Psychopharmacol 1998; 13:579–582. 61. Pons G, et al. Moclobemide excretion in human breast milk. Br J Clin Pharmacol 1990; 29:27–31. 62. Begg EJ, et al. Paroxetine in human milk. Br J Clin Pharmacol 1999; 48:142–147. 63. Stowe ZN, et al. Paroxetine in human breast milk and nursing infants. Am J Psychiatry 2000; 157:185–189. 64. Misri S, et al. Paroxetine levels in postpartum depressed women, breast milk, and infant serum. J Clin Psychiatry 2000; 61:828–832. 65. Ohman R, et al. Excretion of paroxetine into breast milk. J Clin Psychiatry 1999; 60:519–523. 66. Berle JO, et al. Breastfeeding during maternal antidepressant treatment with serotonin reuptake inhibitors: infant exposure, clinical symptoms, and cytochrome p450 genotypes. J Clin Psychiatry 2004; 65:1228–1234. 67. Merlob P, et  al. Paroxetine during breast-­feeding: infant weight gain and maternal adherence to counsel. Eur J Pediatr 2004; 163:135–139. 68. Abdul Aziz A, et al. Severe paroxetine induced hyponatremia in a breast fed infant. J Bahrain Med Soc 2004; 16:195–198. 69. Hendrick V, et al. Paroxetine use during breast-­feeding. J Clin Psychopharmacol 2000; 20:587–589. 70. Spigset O, et al. Paroxetine level in breast milk. J Clin Psychiatry 1996; 57:39. 71. Uguz F, et al. Short-­term safety of paroxetine and sertraline in breastfed infants: a retrospective cohort study from a university hospital. Breastfeed Med 2016; 11:487–489. 72. Hackett LP, et al. Transfer of reboxetine into breastmilk, its plasma concentrations and lack of adverse effects in the breastfed infant. Eur J Clin Pharmacol 2006; 62:633–638. 73. Llewellyn A, et al. Psychotropic medications in lactation. J Clin Psychiatry 1998; 59 Suppl 2:41–52. 74. Mammen OK, et al. Sertraline and norsertraline levels in three breastfed infants. J Clin Psychiatry 1997; 58:100–103. 75. Altshuler LL, et al. Breastfeeding and sertraline: a 24-­hour analysis. J Clin Psychiatry 1995; 56:243–245. 76. Dodd S, et al. Sertraline analysis in the plasma of breast-­fed infants. Aust N Z J Psychiatry 2001; 35:545–546. 77. Dodd S, et  al. Sertraline in paired blood plasma and breast-­milk samples from nursing mothers. Hum Psychopharmacol 2000; 15:161–264. 78. Epperson N, et al. Maternal sertraline treatment and serotonin transport in breast-­feeding mother-­infant pairs. Am J Psychiatry 2001; 158:1631–1637. 79. Stowe ZN, et al. The pharmacokinetics of sertraline excretion into human breast milk: determinants of infant serum concentrations. J Clin Psychiatry 2003; 64:73–80. 80. Muller MJ, et al. Serotonergic overstimulation in a preterm infant after sertraline intake via breastmilk. Breastfeed Med 2013; 8:327–329. 81. Wisner KL, et  al. Serum sertraline and N-­desmethylsertraline levels in breast-­feeding mother-­infant pairs. Am J Psychiatry 1998; 155:690–692. 82. Verbeeck RK, et al. Excretion of trazodone in breast milk. Br J Clin Pharmacol 1986; 22:367–370. 83. Saito J, et al. Trazodone levels in maternal serum, cord blood, breast milk, and neonatal serum. Breastfeed Med 2021; 16:922–925. 84. Yoshida K, et al. Psychotropic drugs in mothers’ milk: a comprehensive review of assay methods, pharmacokinetics and of safety of breast-­ feeding. J Psychopharmacol 1999; 13:64–80. 85. Misri S, et al. Benefits and risks to mother and infant of drug treatment for postnatal depression. Drug Saf 2002; 25:903–911. 86. Yoshida K, et al. Investigation of pharmacokinetics and of possible adverse effects in infants exposed to tricyclic antidepressants in breast-­ milk. J Affect Disord 1997; 43:225–237. 87. Frey OR, et al. Adverse effects in a newborn infant breast-­fed by a mother treated with doxepin. Ann Pharmacother 1999; 33:690–693. 88. Ilett KF, et al. The excretion of dothiepin and its primary metabolites in breast milk. Br J Clin Pharmacol 1992; 33:635–639. 89. Kemp J, et al. Excretion of doxepin and N-­desmethyldoxepin in human milk. Br J Clin Pharmacol 1985; 20:497–499. 90. Buist A, et al. Effect of exposure to dothiepin and northiaden in breast milk on child development. Br J Psychiatry 1995; 167:370–373. 91. Khachman D, et al. Clomipramine in breast milk: a case study (article in French). J Pharm Clin 2007; 28:33–38. 92. Uguz F. Poor feeding and severe sedation in a newborn nursed by a mother on a low dose of amitriptyline. Breastfeed Med 2017; 12:67–68. 93. Koren G, et al. Can venlafaxine in breast milk attenuate the norepinephrine and serotonin reuptake neonatal withdrawal syndrome. J Obstet Gynaecol Can 2006; 28:299–302. 94. Ilett KF, et al. Distribution of venlafaxine and its O-­desmethyl metabolite in human milk and their effects in breastfed infants. Br J Clin Pharmacol 2002; 53:17–22. 95. Newport DJ, et al. Venlafaxine in human breast milk and nursing infant plasma: determination of exposure. J Clin Psychiatry 2009; 70:1304–1310. 96. Ilett KF, et al. Assessment of infant dose through milk in a lactating woman taking amisulpride and desvenlafaxine for treatment-­resistant depression. Ther Drug Monit 2010; 32:704–707. 97. Misri S, et al. Quetiapine augmentation in lactation: a series of case reports. J Clin Psychopharmacol 2006; 26:508–511. 98. Hendrick V, et al. Venlafaxine and breast-­feeding. Am J Psychiatry 2001; 158:2089–2090. 99. Rampono J, et al. Estimation of desvenlafaxine transfer into milk and infant exposure during its use in lactating women with postnatal depression. Arch Womens Ment Health 2011; 14:49–53. 100. Ilett KF, et  al. Distribution and excretion of venlafaxine and O-­desmethylvenlafaxine in human milk. Br J Clin Pharmacol 1998; 45:459–462. 101. Baldelli S, et  al. Passage of venlafaxine in human milk during 12  months of lactation: a case report. Ther Drug Monit 2022; 44:707–708. 750 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 7 102. Marshall K, et al. Transfer of the serotonin modulator vortioxetine into human milk: a case series. Breastfeed Med 2021; 16:843–845. 103. Teoh S, et al. Estimation of rac-­amisulpride transfer into milk and of infant dose via milk during its use in a lactating woman with bipolar disorder and schizophrenia. Breastfeed Med 2010; 6:85–88. 104. Uguz F. Breastfed infants exposed to combined antipsychotics: two case reports. Am J Ther 2016; 23:e1962–e1964. 105. O’Halloran SJ, et al. A liquid chromatography-­tandem mass spectrometry method for quantifying amisulpride in human plasma and breast milk, applied to measuring drug transfer to a fully breast-­fed neonate. Ther Drug Monit 2016; 38:493–498. 106. Schlotterbeck P, et al. Aripiprazole in human milk. Int J Neuropsychopharmacol 2007; 10:433. 107. Lutz UC, et al. Aripiprazole in pregnancy and lactation: a case report. J Clin Psychopharmacol 2010; 30:204–205. 108. Watanabe N, et al. Perinatal use of aripiprazole: a case report. J Clin Psychopharmacol 2011; 31:377–379. 109. Mendhekar DN, et al. Aripiprazole use in a pregnant schizoaffective woman. Bipolar Disord 2006; 8:299–300. 110. Nordeng H, et al. Transfer of aripiprazole to breast milk: a case report. J Clin Psychopharmacol 2014; 34:272–275. 111. Frew JR. Psychopharmacology of bipolar I disorder during lactation: a case report of the use of lithium and aripiprazole in a nursing mother. Arch Womens Ment Health 2015; 18:135–136. 112. Naughton S, et al. Aripiprazole, brexpiprazole, and cariprazine can affect milk supply: advice to breastfeeding mothers. Australas Psychiatry 2023; 31:201–204. 113. Sahoo MK, et al. Safety profile of aripiprazole during pregnancy and lactation: report of 2 cases. Turk Psikiyatri derg = Turkish journal of psychiatry 2023; 34:133–135. 114. Yoshida K, et al. Breast-­feeding and psychotropic drugs. Int Rev Psychiatry 1996; 8:117–124. 115. Patton SW, et  al. Antipsychotic medication during pregnancy and lactation in women with schizophrenia: evaluating the risk. Can J Psychiatry 2002; 47:959–965. 116. Klinger G, et al. Antipsychotic drugs and breastfeeding. Pediatr Endocrinol Rev 2013; 10:308–317. 117. Uguz F. Adverse events in a breastfed infant exposed to risperidone and haloperidol. Breastfeed Med 2019; 14:683–684. 118. Mendhekar DN. Possible delayed speech acquisition with clozapine therapy during pregnancy and lactation. J Neuropsychiatry Clin Neurosci 2007; 19:196–197. 119. Barnas C, et al. Clozapine concentrations in maternal and fetal plasma, amniotic fluid, and breast milk. Am J Psychiatry 1994; 151:945. 120. Shao P, et al. Effects of clozapine and other atypical antipsychotics on infants development who were exposed to as fetus: a post-­hoc ­analysis. PLoS One 2015; 10:e0123373. 121. Imaz ML, et al. Clozapine use during pregnancy and lactation: a case-­series report. Front Pharmacol 2018; 9:264. 122. Goldstein DJ, et al. Olanzapine-­exposed pregnancies and lactation: early experience. J Clin Psychopharmacol 2000; 20:399–403. 123. Croke S, et al. Olanzapine excretion in human breast milk: estimation of infant exposure. Int J Neuropsychopharmacol 2002; 5:243–247. 124. Gardiner SJ, et al. Transfer of olanzapine into breast milk, calculation of infant drug dose, and effect on breast-­fed infants. Am J Psychiatry 2003; 160:1428–1431. 125. Ambresin G, et al. Olanzapine excretion into breast milk: a case report. J Clin Psychopharmacol 2004; 24:93–95. 126. Lutz UC, et al. Olanzapine treatment during breast feeding: a case report. Ther Drug Monit 2008; 30:399–401. 127. Whitworth A, et al. Olanzapine and breast-­feeding: changes of plasma concentrations of olanzapine in a breast-­fed infant over a period of 5 months. J Psychopharmacol 2010; 24:121–123. 128. Eli Lilly and Company Ltd. Personal correspondence: olanzapine use in pregnant or nursing women. 2011. 129. Gilad O, et al. Outcome of infants exposed to olanzapine during breastfeeding. Breastfeed Med 2010; 6:55–58. 130. Goldstein DJ, et al. Olanzapine use during breast-­feeding. Schizophr Res 2002; 53 Suppl 1:185. 131. Aydin B, et al. Olanzapine and quetiapine use during breastfeeding: excretion into breast milk and safe breastfeeding strategy. J Clin Psychopharmacol 2015; 35:206–208. 132. Stiegler A, et al. Olanzapine treatment during pregnancy and breastfeeding: a chance for women with psychotic illness? Psychopharmacology (Berl) 2014; 231:3067–3069. 133. Var L, et al. Management of postpartum manic episode without cessation of breastfeeding: a longitudinal follow up of drug excretion into breast milk. Eur Neuropsychopharmacol 2013; 23 Suppl 1:S382. 134. Manouilenko I, et al. Long-­acting olanzapine injection during pregnancy and breastfeeding: a case report. Arch Womens Ment Health 2018; 21:587–589. 135. Lee A, et al. Excretion of quetiapine in breast milk. Am J Psychiatry 2004; 161:1715–1716. 136. Gentile S. Quetiapine-­fluvoxamine combination during pregnancy and while breastfeeding (Letter). Arch Womens Ment Health 2006; 9:158–159. 137. Seppala J. Quetiapine (Seroquel) is effective and well tolerated in the treatment of psychotic depression during breast feeding. Eur Neuropsychopharmacol 2004; 7 Suppl 1:S245. 138. Kruninger U, et al. Pregnancy and lactation under treatment with quetiapine. Psychiatr Prax 2007; 34 Suppl 1:S75–S76. 139. Ritz S. Quetiapine monotherapy in post-­partum onset bipolar disorder with a mixed affective state. Eur Neuropsychopharmacol 2005; 15 Suppl 3:S407. 140. Rampono J, et al. Quetiapine and breast feeding. Ann Pharmacother 2007; 41:711–714. 141. Tanoshima R, et al. Quetiapine in human breast milk – population PK analysis of milk levels and simulated infant exposure. J Popul Ther Clin Pharmacol 2012; 19:e259–e298. 142. Yazdani-­Brojeni P, et al. Quetiapine in human milk and simulation-­based assessment of infant exposure. Clin Pharmacol Ther 2010; 87 Suppl 1:S3–S4. 143. Var L, et al. Management of postpartum manic episode without cessation of breastfeeding: a longitudinal follow up of drug excretion into breast milk. Eur Neuropsychopharmacol 2013; 23 Suppl 2:S382. Prescribing in pregnancy and breastfeeding CHAPTER 7 144. Van Boekholt AA, et al. Quetiapine concentrations during exclusive breastfeeding and maternal quetiapine use. Ann Pharmacother 2015; 49:743–744. 145. Hill RC, et al. Risperidone distribution and excretion into human milk: case report and estimated infant exposure during breast-­feeding. J Clin Psychopharmacol 2000; 20:285–286. 146. Aichhorn W, et al. Risperidone and breast-­feeding. J Psychopharmacol 2005; 19:211–213. 147. Ilett KF, et al. Transfer of risperidone and 9-­hydroxyrisperidone into human milk. Ann Pharmacother 2004; 38:273–276. 148. Ratnayake T, et al. No complications with risperidone treatment before and throughout pregnancy and during the nursing period. J Clin Psychiatry 2002; 63:76–77. 149. Weggelaar NM, et al. A case report of risperidone distribution and excretion into human milk: how to give good advice if you have not enough data available. J Clin Psychopharmacol 2011; 31:129–131. 150. Ylikorkala O, et al. Treatment of inadequate lactation with oral sulpiride and buccal oxytocin. Obstet Gynecol 1984; 63:57–60. 151. Ylikorkala O, et al. Sulpiride improves inadequate lactation. BMJ 1982; 285:249–251. 152. Aono T, et al. Augmentation of puerperal lactation by oral administration of sulpiride. J Clin Endocrinol Metab 1970; 48:478–482. 153. Polatti F. Sulpiride isomers and milk secretion in puerperium. Clin Exp Obstet Gynecol 1982; 9:144–147. 154. Aono T, et al. Effect of sulpiride on poor puerperal lactation. Am J Obstet Gynecol 1982; 143:927–932. 155. Matheson I, et al. Milk concentrations of flupenthixol, nortriptyline and zuclopenthixol and between-­breast differences in two patients. Eur J Clin Pharmacol 1988; 35:217–220. 156. Kirk L, et al. Concentrations of Cis(Z)-­flupentixol in maternal serum, amniotic fluid, umbilical cord serum, and milk. Psychopharmacology (Berl) 1980; 72:107–108. 157. Aes-­Jorgensen T, et al. Zuclopenthixol levels in serum and breast milk. Psychopharmacology (Berl) 1986; 90:417–418. 158. Schlotterbeck P, et  al. Low concentration of ziprasidone in human milk: a case report. Int J Neuropsychopharmacol 2009; 12:437–438. 159. Chaudron LH, et al. Mood stabilizers during breastfeeding: a review. J Clin Psychiatry 2000; 61:79–90. 160. Wisner KL, et  al. Serum levels of valproate and carbamazepine in breastfeeding mother-­infant pairs. J Clin Psychopharmacol 1998; 18:167–169. 161. Ernst CL, et al. The reproductive safety profile of mood stabilizers, atypical antipsychotics, and broad-­spectrum psychotropics. J Clin Psychiatry 2002; 63 Suppl 4:42–55. 162. Meador KJ, et al. Effects of breastfeeding in children of women taking antiepileptic drugs. Neurology 2010; 75:1954–1960. 163. Zhao M, et al. [A case report of monitoring on carbamazepine in breast feeding woman]. Beijing Da Xue Xue Bao 2010; 42:602–603. 164. Froescher W, et al. Carbamazepine levels in breast milk. Ther Drug Monit 1984; 6:266–271. 165. Frey B, et al. Transient cholestatic hepatitis in a neonate associated with carbamazepine exposure during pregnancy and breast-­feeding. Eur J Pediatr 1990; 150:136–138. 166. Merlob P, et al. Transient hepatic dysfunction in an infant of an epileptic mother treated with carbamazepine during pregnancy and breastfeeding. Ann Pharmacother 1992; 26:1563–1565. 167. Veiby G, et al. Early child development and exposure to antiepileptic drugs prenatally and through breastfeeding: a prospective cohort study on children of women with epilepsy. JAMA Neurol 2013; 70:1367–1374. 168. Pynnonen S, et al. Carbamazepine and mother’s milk (Letter). Lancet 1975; 2:563. 169. Meador KJ, et al. Breastfeeding in children of women taking antiepileptic drugs: cognitive outcomes at age 6 years. JAMA Pediatr 2014; 168:729–736. 170. Ohman I, et  al. Lamotrigine in pregnancy: pharmacokinetics during delivery, in the neonate, and during lactation. Epilepsia 2000; 41:709–713. 171. Liporace J, et al. Concerns regarding lamotrigine and breast-­feeding. Epilepsy Behav 2004; 5:102–105. 172. Gentile S. Lamotrigine in pregnancy and lactation (Letter). Arch Womens Ment Health 2005; 8:57–58. 173. Page-­Sharp M, et al. Transfer of lamotrigine into breast milk (Letter). Ann Pharmacother 2006; 40:1470–1471. 174. Rambeck B, et al. Concentrations of lamotrigine in a mother on lamotrigine treatment and her newborn child. Eur J Clin Pharmacol 1997; 51:481–484. 175. Tomson T, et al. Lamotrigine in pregnancy and lactation: a case report. Epilepsia 1997; 38:1039–1041. 176. Newport DJ, et al. Lamotrigine in breast milk and nursing infants: determination of exposure. Pediatrics 2008; 122:e223–e231. 177. Fotopoulou C, et al. Prospectively assessed changes in lamotrigine-­concentration in women with epilepsy during pregnancy, lactation and the neonatal period. Epilepsy Res 2009; 85:60–64. 178. Nordmo E, et al. Severe apnea in an infant exposed to lamotrigine in breast milk. Ann Pharmacother 2009; 43:1893–1897. 179. Wakil L, et al. Neonatal outcomes with the use of lamotrigine for bipolar disorder in pregnancy and breastfeeding: a case series and review of the literature. Psychopharmacol Bull 2009; 42:91–98. 180. Birnbaum AK, et al. Antiepileptic drug exposure in infants of breastfeeding mothers with epilepsy. JAMA Neurol 2020; 77:441–450. 181. Kacirova I, et al. A short communication: lamotrigine levels in milk, mothers, and breastfed infants during the first postnatal month. Ther Drug Monit 2019; 41:401–404. 182. Kacirova I, et al. Monitoring of lamotrigine concentrations in mothers, colostrum, and breastfed newborns during the early postpartum period. Biomed Pharmacother 2022; 151:113167. 183. Bedussi F, et al. Normocytic normochromic anaemia and asymptomatic neutropenia in a 40-­day-­old infant breastfed by an epileptic mother treated with lamotrigine: infant’s adverse drug reaction. J Paediatr Child Health 2018; 54:104–105. 184. Newmark RL, et al. Risk-­benefit assessment of infant exposure to lithium through breast milk: a systematic review of the literature. Int Rev Psychiatry 2019; 31:295–304. 752 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 7 185. Westergren T, et al. Probable topiramate-­induced diarrhea in a 2-­month-­old breast-­fed child – a case report. Epilepsy Behav Case Rep 2014; 2:22–23. 186. Gentile S. Topiramate in pregnancy and breastfeeding. Clin Drug Investig 2009; 29:139–141. 187. Piontek CM, et al. Serum valproate levels in 6 breastfeeding mother-­infant pairs. J Clin Psychiatry 2000; 61:170–172. 188. Bjornsson E. Hepatotoxicity associated with antiepileptic drugs. Acta Neurol Scand 2008; 118:281–290. 189. Spigset O, et al. Excretion of psychotropic drugs into breast milk: pharmacokinetic overview and therapeutic implications. CNS Drugs 1998; 9:111–134. 190. Hagg S, et al. Anticonvulsant use during lactation. Drug Saf 2000; 22:425–440. 191. Iqbal MM, et  al. Effects of commonly used benzodiazepines on the fetus, the neonate, and the nursing infant. Psychiatr Serv 2002; 53:39–49. 192. Buist A, et al. Breastfeeding and the use of psychotropic medication: a review. J Affect Disord 1990; 19:197–206. 193. Fisher JB, et al. Neonatal apnea associated with maternal clonazepam therapy: a case report. Obstet Gynecol 1985; 66:34S–35S. 194. Davanzo R, et al. Benzodiazepine e allattamento materno. Med Bambino 2008; 27:109–114. 195. Kelly LE, et al. Neonatal benzodiazepines exposure during breastfeeding. J Pediatr 2012; 161:448–451. 196. Birnbaum CS, et al. Serum concentrations of antidepressants and benzodiazepines in nursing infants: a case series. Pediatrics 1999; 104:e11. 197. Tomson T, et al. Breastfeeding while on treatment with antiseizure medications: a systematic review from the ILAE Women Task Force. Epileptic Disord 2022; 24:1020–1032. 198. Darwish M, et al. Rapid disappearance of zaleplon from breast milk after oral administration to lactating women. J Clin Pharmacol 1999; 39:670–674. 199. Pons G, et al. Excretion of psychoactive drugs into breast milk. Pharmacokinetic principles and recommendations. Clin Pharmacokinet 1994; 27:270–289. 200. Matheson I, et al. The excretion of zopiclone into breast milk. Br J Clin Pharmacol 1990; 30:267–271. 201. Saito J, et al. Presence of hypnotics in the cord blood and breast milk, with no adverse effects in the infant: a case report. Breastfeed Med 2022; 17:349–352. 202. Ilett KF, et al. Transfer of dexamphetamine into breast milk during treatment for attention deficit hyperactivity disorder. Br J Clin Pharmacol 2007; 63:371–375. 203. Hackett LP, et al. Methylphenidate and breast-­feeding. Ann Pharmacother 2006; 40:1890–1891. 204. Bolea-­Alamanac BM, et al. Methylphenidate use in pregnancy and lactation: a systematic review of evidence. Br J Clin Pharmacol 2014; 77:96–101. 205. Marchese M, et al. Is it safe to breastfeed while taking methylphenidate? Can Fam Physician 2015; 61:765–766. 206. Aurora S, et al. Evaluating transfer of modafinil into human milk during lactation: a case report. J Clin Sleep Med 2018; 14:2087–2089. 207. Calvo-­Ferrandiz E, et al. Narcolepsy with cataplexy and pregnancy: a case-­control study. J Sleep Res 2018; 27:268–272. 208. Leggett C, et al. Infant exposure to armodafinil through human milk following maternal use of modafinil. J Hum Lact 2023; 39:218–222.