2015 Management of Psychotropic Drugs During Pregnancy

STAT E O F T H E A RT R E V I E W
Management of psychotropic drugs

during pregnancy
Margaret S Chisolm, Jennifer L Payne
Department of Psychiatry and
Behavioral Sciences, Johns Hopkins A B S T RAC T
University School of Medicine,
Baltimore, MD, USA
Psychiatric conditions (including substance misuse disorders) are serious, potentially
Correspondence to: J L Payne, life threatening illnesses that can be successfully treated by psychotropic drugs, even
MD, Women’s Mood Disorders
Center, Baltimore, MD 21205, USA during pregnancy. Because few rigorously designed prospective studies have exam-
Jpayne5@jhmi.edu
ined the safety of these drugs during pregnancy, the default clinical recommendation
Cite this as: BMJ 2015;351:h5918
doi: 10.1136/bmj.h5918 has been to discontinue them, especially during the first trimester. However, in the
past decade, as more evidence has accumulated, it seems that most psychotropic
drugs are relatively safe to use in pregnancy and that not using them when indicated
for serious psychiatric illness poses a greater risk to both mother and child, including
tragic outcomes like suicide and infanticide. This review presents an up to date and
careful examination of the most rigorous scientific studies on the effects of psycho-
tropic drugs in pregnancy. The lack of evidence in several areas means that definite
conclusions cannot be made about the risks and benefits of all psychotropic drug
use in pregnancy.
Introduction HOW PATIENTS WERE INVOLVED IN THE CREATION OF THIS

The choice of whether to prescribe a drug during preg- ARTICLE
nancy is a difficult one that must take into account the The authors interviewed patients who presented for
risks and benefits of treatment to the mother and the consultation on the management of psychiatric conditions
unborn infant. These risks and benefits must then be in pregnancy during the writing of this review. Topics
of interest to most patients included a summary of the
compared with the risks posed by the underlying illness
evidence in the literature on the use of antidepressants,
to the mother and child. When the mother is diagnosed
sleep aids, and stimulants during pregnancy. Another
as having an immediately life threatening illness, the common theme included the lack of long term data
choice of whether to prescribe a drug may be obvious. available for exposed children. A patient who was asked to
However, when the mother has an illness that is not give her opinion of this review wrote: “The worry that you
immediately life threatening, such as a psychiatric dis- have potentially hurt your child by taking antidepressants
order, the decision to prescribe becomes more compli- during pregnancy doesn’t end when they hand you a
cated. The literature on pregnancy outcomes for infants ‘healthy’ baby in the delivery room. The reality is that
what mothers with antenatal depression want is someone
exposed to psychiatric drugs in utero is large. This review
with a crystal ball who can reassure us that our children
will summarize what is known (and not known) about will be ok, not just at birth, but in the long term—and
the risks associated with the use of various psychotropic that we didn’t harm them with our medication choices or
drugs during pregnancy to the developing child and sum- our illness.” We gratefully acknowledge the input of our
marize the limitations of the available literature. It will patients.
also discuss the clinical approach to the management of
psychiatric disorders during pregnancy. disorder reported mood symptoms during or after preg-
nancy.5 Furthermore, the risk of relapse during pregnancy
Incidence and prevalence increases when drugs are discontinued. A relapse rate
At one time pregnancy was thought to protect against of 68% was reported in women with major depressive
psychiatric illness, particularly depression.1 2 However, disorder (MDD) who discontinued their drugs during the
for women with pre-existing psychiatric conditions first trimester.6 Bipolar disorder recurred in 81-85.5% of
(including substance misuse disorders), pregnancy and pregnant women who discontinued their mood stabilizers
the postpartum are vulnerable periods when psychiat- compared with 29-37% of those who did not.7 8 About
ric illness may worsen or relapse. About 15% of preg- 50% of patients with schizophrenia relapse if they stop
nant women have a psychiatric illness and 10-13% of taking their drugs. These high rates of relapse suggest that
fetuses are exposed to a psychotropic drug.3 4 Women for many patients treatment is needed during pregnancy
with psychiatric disorders can experience relapse during to prevent recurrence.9‑12 This review will examine what is
pregnancy, even when they are taking the appropriate currently known and not known about the management
drugs. In one study about 50% of women with a mood of psychotropic drugs in pregnancy.
For personal use only 1 of 15

Sources and selection criteria that untreated maternal psychiatric illness during preg-
Studies for this review were identified primarily through nancy is associated with poorer outcomes for the exposed
a search of English language publications listed by Pub- child. Depression during pregnancy has been associated
Med from 1 January 2000 until 16 December 2014. We with low maternal weight gain; increased rates of pre-
used a vetted filter to capture cohort studies, randomized term birth14; low birth weight; increased rates of ciga-
controlled trials, systematic reviews, meta-analyses, and rette, alcohol, and other substance misuse15; increased
other clinically relevant reports of psychotropic drug use ambivalence about the pregnancy; and overall worse
in pregnancy.13 PubMed’s controlled vocabulary terms health status,16 including higher rates of pre-eclampsia
(MeSH) were used to define each of the major concepts and gestational diabetes.17 18 In addition, prenatal expo-
(psychotropic drugs and pregnancy), in addition to rel- sure to maternal stress has been shown to affect infant
evant keyword terms that were searched in the title and temperament.19 Children exposed to perinatal maternal
abstract of the PubMed citation records (available from depression have higher cortisol levels than those whose
the authors on request). Although we limited the search mothers were not depressed,20‑23 and this finding con-
to English language publications, PubMed lists a large tinues through adolescence.23 Importantly, treatment of
number of articles from European and foreign language depression during pregnancy seems to normalize infant
journals, overlaps with other large databases (such as cortisol levels.24 These findings may partially explain
Embase—the European version of Medline), and includes the mechanism underlying the increased vulnerability
Cochrane Library reviews. Additional studies were identi- to psychopathology in children exposed to depression in
fied by a hand search of references from articles identi- utero.25
fied by the original search. This review summarizes the The literature on postpartum depression (PPD), of
most clinically relevant treatment information from the which psychiatric illness during pregnancy is an impor-
literature on this topic. tant risk factor, is even stronger. Adverse outcomes such
as lower IQ, slower language development, increased risk
Controversies and limitations of the literature of attention deficit disorder, and increased risk of behav-
Few studies have been conducted to determine which ioral problems and psychiatric illness are see in the off-
drugs for treating psychiatric disorders are efficacious spring of women with postpartum depression.26 These
during pregnancy, how changes in body weight and findings are often lost or ignored in the debate about
metabolism may affect dosing, and what long term effects whether to use psychotropic drugs during pregnancy.
these drug have on the developing fetus. Although drug This may be because we tend to think about the risks of
use has traditionally been minimized during pregnancy, exposure to psychotropic drugs compared with the risk
it is recognized that drugs may be indicated for certain of no exposure to these drugs, rather than the risks of
“serious” medical conditions, such as asthma and hyper- exposure to psychotropic drugs compared with the risks
tension, even during pregnancy. of exposure to maternal psychiatric illness (which clearly
By contrast, psychiatric conditions have been consid- has consequences for the child). The risks of psychiatric
ered less “serious” and psychotropic drug use during illness during pregnancy to the child should therefore be
pregnancy less necessary and more expendable. How- taken into account when considering the risks and ben-
ever, abrupt discontinuation of psychotropic drugs can efits of drug use during pregnancy.
result in withdrawal symptoms and relapse of psychiatric
illness, and several studies have shown that exposure to FDA pregnancy categories and the new “rule”
psychiatric illness in utero results in poorer outcomes for In December 2014, the Federal Drug Administration pub-
mother and child. lished the final version of the “pregnancy and lactation
An important limitation of the literature is that the use labeling rule” mandating changes to the content and for-
of psychotropic drugs during pregnancy is essentially a mat of prescription drug labeling as they pertain to use
“marker” for a population of women with different risk during pregnancy and lactation. The labeling changes
factors from the general population of pregnant women. went into effect on 30 June 2015 for all new products
These risk factors may influence the outcomes of stud- submitted for FDA approval and will be phased in later
ies attempting to examine the risks of in utero exposure for other drugs and products. The new labeling will con-
of a psychotropic drug to a child. For example, diabe- tain “pregnancy” and “lactation” subsections, which will
tes, obesity, smoking, and substance misuse are more each have three principal components: a risk summary, a
common in people with psychiatric illness than in the clinical considerations section, and a data section. There
general population. Studies that have not controlled for will also be a new subsection entitled “females and males
the underlying psychiatric illness and its risks may find of reproductive potential.” The goal is to provide clinically
associations between psychotropic drugs and outcomes relevant information that will help providers make pre-
that are not caused by exposure to the drug itself, but by scribing decisions and counsel women on the use of drugs
the presence of other risk factors that are highly prevalent during pregnancy and lactation. This system attempts to
in the population of patients who take psychotropic drugs include all currently available information to help clini-
during pregnancy. cians weigh the risks and benefits of prescribing drugs
Another area that is often overlooked in the risk-benefit during pregnancy.
analysis of the use of psychotropic drugs during preg- Because the “rule” will be phased in over time, figs 1-3
nancy is the risk to the fetus and newborn associated with provide a brief summary of the former FDA categories.
untreated maternal psychiatric illness. Evidence shows The categories, which include A, B, C, D, and X, are based

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Fig 1 | Former Food and Drug Administration (FDA) categories of antidepressants used in pregnancy
on the amount of evidence for safety provided by ani- studied enough in humans to warrant placing them in
mal and human studies. The system uses evidence from category A as safe (or in C, D, or X depending on the level
animal studies as part of the definitions for three of the of risk in humans). Oral contraceptives are in category
five categories. Many clinicians assume that there is an X because there is no reason to use them in pregnancy,
increasing level of risk from category A to X, which is not not because there is evidence of associated birth defects.
true. For example, category B drugs simply have not been Drugs in the same category may have vastly different

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Fig 2 | Former Food and Drug Administration (FDA) categories of mood stabilizers used in pregnancy
levels of risk or different levels of evidence supporting There is a paucity of data to help guide clinicians’
their categorization. The FDA pregnancy categories there- decisions about drug dosing in pregnancy. The evidence
fore provide a ‘‘quick and dirty’’ assessment but may not that does exist is based mainly on observational studies
provide information that is useful in guiding clinical care. and, given high inter-individual variability, should be
It is hoped that by providing all available information on interpreted with caution.28 When available, therapeutic
the label itself rather than grossly categorizing the infor- monitoring of serum levels may help guide dosing. Oth-
mation into a categorical system, clinicians and patients erwise, clinicians must rely on what is generally known
will make more informed decisions based on the litera- about pharmacokinetic changes in pregnancy and some
ture as a whole. Figure 3 also lists the FDA categories for basic principles. These include using the lowest benefi-
common psychotropic drugs. cial drug dose (dose that provides sufficient maternal
benefit while minimizing fetal exposure),29 frequent
Changes in metabolism and drug clearance during monitoring women’s mental state, and adjusting drug
pregnancy doses as needed.30
Major adaptive physiologic changes occur in a woman’s Antidepressants are the most common psychotropic
gastrointestinal system, cardiovascular system, renal sys- drugs prescribed during pregnancy.31 The literature on
tem, and other systems during pregnancy. These changes antidepressant use during pregnancy and pregnancy
greatly affect the pharmacokinetic processes of drug outcomes is large and exemplifies the problems out-
absorption, distribution, metabolism, and excretion. The lined previously. Several possible negative outcomes
changes begin early and continue to fluctuate throughout have been identified over the past 10 years by studies
the third trimester, resulting in about a 50% increase in that did not control for the underlying psychiatric illness
plasma volume, increased body fat, and increased drug and more properly controlled studies have subsequently
distribution volume. Renal blood flow, glomerular filtra- shown no increased risk of adverse outcomes or have
tion rate, and elimination of drugs also increase,27 and yielded conflicting data. Much of this work has focused
changes in liver enzyme activation occur (for example, on selective serotonin reuptake inhibitors (SSRIs),
CYP1A2 activity decreases; CYP2D6 activity and CYP3A although results from studies on other antidepressants
activity increase). These liver enzyme changes, which are also discussed, as appropriate. The term “antidepres-
are mostly hormone dependent, can either increase or sant” indicates that the study looked at a mixture of anti-
decrease the clearance of drugs, and are highly relevant depressant classes.
to psychotropic drugs, including fluoxetine (metabolized
by CYP2D6) and methadone (CYP3A4). Serotonin reuptake inhibitors
All psychotropic drugs can move from the maternal to Teratogenesis
the placental system, and the distribution of drugs from The rate of major birth defects in the general population
mother to fetus is highly relevant to clinical decisions on is about 3%, and less than 1% of defects are thought to
the dosing of psychotropic drugs in pregnancy.28 29 The be secondary to drug exposure.32 The literature on the
use of multiple drugs carries additional risks (for exam- rate of major birth defects and antidepressant use in
ple, drug-drug interactions, induction or inhibition of pregnancy is complicated by small samples, surveillance
metabolic pathways, adverse effects in pregnancy of bias, and lack of controls for the underlying psychiatric
concomitantly used licit or illicit drugs). illness and associated risk factors33; overall, the results

Fig 3 | Former Food and

Drug Administration
(FDA) categories of
antipsychotic drugs,
antianxiety drugs, opioid
dependence agents, and
adjunctive psychotropic
drugs used in pregnancy.
NAS=neonatal abstinence
syndrome; NICU=neonatal
intensive care unit

are conflicting and inconsistent. A small increase in the Preterm birth and birth weight
absolute risk of rare defects with exposure to SSRIs has Overall, the literature suggests that the rate of preterm
been reported,34 but four meta-analyses examining the birth is higher among mothers who take antidepressants.
risk of major malformations with exposure to SSRIs in the However, most studies did not control for the severity of
first trimester found no significantly increased risk.35‑38 psychiatric illness and other confounding variables found
Data on other types of antidepressant are limited. Most more commonly in those with psychiatric disorders.48 49
studies examining the risks of tricyclic antidepressants A recent systematic review and meta-analysis of 41 stud-
have found no increased risk of malformations, 39‑43 ies found that the pooled adjusted odds ratio was 1.53
although one large epidemiological study found a signifi- for use of antidepressants at any time and 1.96 for third
cant increase in severe malformations (odds ratio 1.36, trimester use.57 Controlling for the diagnosis of depres-
95% confidence interval 1.07 to 1.72).44 With the possi- sion did not eliminate the effect but residual confound-
ble exception of heart defects (see below), several stud- ing could not be ruled out. One study that controlled
ies of bupropion have found no association with major for health habits, depressive disorders, and psychiatric
malformations.45‑47 The data available for other types of illness found a greater risk of preterm birth in women
antidepressants are small but reassuring.48 49 who used SSRIs63 suggesting some biological role.48 49
However, the duration of pregnancy was shortened by
Cardiovascular malformations only three to five days and the overall risk was consid-
Studies have reported no consistent association between ered modest.63 The literature on antidepressant use and
the use of antidepressants during pregnancy and cardio- low birth weight is also complicated by confounding by
vascular malformations. Use of paroxetine during the the underlying illness and results have been inconsist-
first trimester has been associated with a higher risk of ent.48 49 62
cardiac malformations in some studies,46 50 51 but not in
others,34 52 and it remains the most controversial antide- Persistent pulmonary hypertension of the newborn
pressant in terms of recommendations for pregnancy.48 49 In persistent pulmonary hypertension of the newborn
Studies of bupropion have also yielded conflicting results. (PPHN), the resistance of the pulmonary vasculature
The GlaxoSmithKline pregnancy registry found an fails to decrease at birth, resulting in breathing difficulties
increased risk of cardiovascular malformations in both and leading to hypoxia and often intubation. PPHN has a
retrospective and prospective reports, and a second 10-20% mortality rate and causes serious morbidity.64 It
retrospective case-control study found a higher rate of is rare, affecting one to two infants in 1000.65 66 PPHN has
left outflow tract heart defects.53 However, other studies been associated with several factors, including maternal
are reassuring,45 46 and the risk, if real, is small (<1% of smoking,67 diabetes, sepsis, aspiration of meconium, and
exposed infants).53 Importantly, one study found that caesarean section.66
a benzodiazepine plus an SSRI, but not an SSRI alone, Seven studies have looked at the association between
increased the incidence of congenital heart defects,54 and SSRIs and PPHN in the newborn, with conflicting results.
much of the literature has not controlled for other drug The first was published in 2006 and is the basis for the
exposures.48 49 The overall consensus is that the risk of FDA alert issued that year on the possible association
major organ malformations, if it exists, is small in the between SSRIs and PPHN.68 This case-control study
setting of antidepressant monotherapy.55 matched 377 women who had infants diagnosed as
Several studies have shown that the association having PPHN to 836 control women with infants with-
between antidepressants and cardiac defects is prob- out PPHN. Fourteen of the infants with PPHN had been
ably secondary to underlying risk factors in people with exposed to an SSRI after the 20th week of gestation com-
depression. For example, one study found an increased pared with six who did not have PPHN (odds ratio 6.1
risk of cardiovascular malformations in babies whose when adjusted for maternal diabetes, race, and body
mothers were diagnosed as having depression but mass index).68
deferred treatment during pregnancy, indicating that the Six additional studies have since been conducted:
risk is associated with the illness not the drug exposure.56 three found no association between SSRIs and PPHN,69‑71
The largest study to date (>900 000 women)57 found no and three found an association,72‑74 although the odds
association between first trimester antidepressant expo- ratios were lower than 6.1. The most recent study ana-
sure and cardiac malformations when the analyses con- lyzed nearly 3.8 million pregnancies, including 128 950
trolled for the underlying illness, depression. Finally, women who took an antidepressant during pregnancy. It
a meta-analysis of prospective cohort studies found no found an odds ratio of 1.51 (1.35 to 1.69) for an associa-
association between SSRI use in the first trimester and tion between SSRI exposure and PPHN in the unadjusted
heart defects.58 analysis.74 However, when the analyses were adjusted for
potential confounders, the odds ratio was not significant
Spontaneous abortion (1.10, 0.94 to 1.29).
Although the studies in this area are also limited by lack The interpretation of these studies is complicated by
of controlling for the underlying psychiatric illness and the fact that several factors associated with the develop-
associated risk factors, overall results suggest that the use ment of PPHN, including maternal smoking, diabetes,
of antidepressants in early pregnancy is associated with and obesity, are also associated with major depressive
a modestly raised risk of spontaneous abortion.49 59‑ 61 disorder (MDD) and other psychiatric disorders. It is also
Reported odds ratios generally range from 1.4 to 1.6.62 important to consider absolute risk. PPHN occurs in one

to two infants per 1000 in the general population.65 66 If 2.08), whereas paternal depression was not (1.21, 0.75
SSRI use increases the odds of developing PPHN by six, to 1.96). Maternal depression and antidepressant use did
only 6-12 per 1000 (0.6-1.2%) infants exposed to SSRIs not increase the risk of ASD with intellectual disability
will develop PPHN. Thus 99% of women who take SSRIs but did increase the risk of ASD without intellectual dis-
during pregnancy will give birth to a healthy infant who ability (4.95, 1.85 to 13.23), although not in the absence
does not develop PPHN. of maternal depression (2.1, 0.97 to 4.57). This study did
not control for the underlying psychiatric illness.
Poor neonatal adaptation syndrome (PNAS) The most recent study was a cohort study of 626 875
The first report of “withdrawal” symptoms in babies Danish live births between 1996 and 2005 in which
exposed to antidepressants was published in 1973.75 It information on maternal use of SSRIs before and dur-
is unclear whether “neonatal withdrawal syndrome” is ing pregnancy was linked with a diagnosis of ASD in the
caused by withdrawal or the drug’s toxicity. Thus, the offspring.80 Compared with women who had never used
term poor neonatal adaptation syndrome (PNAS) may be SSRIs, use of SSRIs during pregnancy was not associated
a better description. with an increased risk of ASD (1.20, 0.90 to 1.61). By
The available literature has several limitations includ- contrast, the odds ratio for women who received SSRIs
ing inconsistent definitions, no measurement tool, a lack before but not during pregnancy was 1.46 (1.17 to 1.81),
of blinded ratings, and a lack of studies investigating indicating that the risk is probably due to the underlying
treatment or prevention of the syndrome. Regardless, the illness (depression) and not the use of antidepressants.
FDA instituted a class labeling change in 2004 for SSRI
and SNRI (serotonin-norepinephrine (noradrenaline) Mood stabilizers
reuptake inhibitor) antidepressants warning that third Lamotrigine
trimester exposure may be associated with PNAS. Accord- According to the manufacturer sponsored lamotrigine
ing to the label change, “reported clinical findings have pregnancy registry and other published studies,81 lamo-
included respiratory distress, cyanosis, apnea, seizures, trigine monotherapy does not increase the risk of congen-
temperature instability, feeding difficulty, vomiting, ital defects; however, when combined with valproic acid
hypoglycemia, hypotonia, hypertonia, hyper-reflexia, in pregnancy, the risk estimate was greater than 12.5%
tremor, jitteriness, irritability, and constant crying.” (6.7% to 21.7%). Although these initial findings seemed
This has resulted in many practitioners tapering anti- to offer women a relatively safe alternative to other anti-
depressants before delivery even though it is unclear convulsants in pregnancy, the North American antiepi-
whether this decreases the risk of PNAS or is safe for leptic drug pregnancy registry found that infants who are
the mother. Most cases of PNAS are mild, self limiting, exposed to lamotrigine monotherapy during pregnancy
and not associated with lasting effects.76 Data suggest have a much higher risk of oral cleft defects with a 10.4
that about a third of exposed infants have at least mild fold increase (4.3 to 24.9).82 However, a large study pub-
symptoms consistent with the syndrome, and this risk lished in 2008 found no association.83 The study assessed
increases when multiple agents, particularly benzodiaz- the association between exposure to lamotrigine and oral
epines, are used.77 clefts using a population based case-control design and
Larger, more rigorous studies of the syndrome and data from the EUROCAT congenital malformation regis-
strategies to reduce the occurrence of the syndrome are tries. The study included 3.9 million births from 19 reg-
needed. There is currently insufficient evidence from a istries from 1995 to 2005 and identified 5511 cases of
safety perspective to recommend tapering antidepres- non-syndromic oral cleft. The control group consisted of
sants in the third trimester, particularly in cases of mod- 80 052 cases of non-chromosomal, non-oral cleft mal-
erate to severe maternal mental illness. formations. There was no increased risk of isolated oral
clefts relative to other malformations. Lamotrigine lev-
Autism els may decrease over the course of pregnancy and thus
Several studies have looked at the association between should be monitored and adjusted if needed.84
SSRI use during pregnancy and autism spectrum disor-
ders (ASDs). A case-control study using data extracted Valproic acid
from medical records included 298 children with ASD First trimester exposure to valproic acid is associated
who were matched for sex, birth year, and hospital with with a high rate of malformations (≤10%) including neu-
1507 controls.78 Antidepressant use in the year before ral tube defects, effects on cognition and brain volume,
delivery was associated with double the risk of ASD in craniofacial anomalies, cardiac defects, cleft palate, and
the offspring (odds ratio 2.0, 1.2 to 3.6), with the strong- hypospadias.62 Exposure to valproic acid has also been
est effect found with first trimester exposure (3.5, 1.5 to recently linked with autism in two studies. The first,85 a
7.9). Risk was not increased in children of mothers with prospective case-control study, found an increased risk
a history of mental health treatment who did not use anti- of neurodevelopment disorders in general in children
depressants during pregnancy. exposed to valproate (adjusted odds ratio 6.05, 1.65 to
A nested case-control study examined maternal and 24.53), and autism spectrum disorders were the most
paternal depression and antidepressant use during early common diagnoses. The second was a population based
pregnancy and the risk of ASD in a Swedish cohort of study that found an increased risk of autism spectrum
more than 500 000 children.79 Maternal depression was disorders (odds ratio 4.42%, 1.7% to 4.9%) in children
associated with an increased risk of ASD (1.49, 1.08 to exposed to valproate and to valproate plus other drugs.86

Providers should encourage pregnant women who want rlatively safe in pregnancy and that not using them when
to continue taking an anticonvulsant to take high dose indicated for serious mental illness poses a much greater
folate (4 mg/day), which theoretically reduces the risk risk, including the grave risks of suicide and infanticide.90
of neural tube defects, and to undergo a second trimes- For example, a study examined birth outcomes in a
ter ultrasound to screen for major congenital anomalies. matched cohort of women who did (n=1021) and did
Blood levels of valproic acid should also be monitored. not (n=1021) use antipsychotics in pregnancy, and an
unmatched cohort of women who did (n=1200) and did
Carbamazepine not (n=40 000) use antipsychotics in pregnancy. It found
Carbamazepine also carries an increased risk of malfor- an increased risk of adverse outcomes (preterm birth, ges-
mations (at a rate of 2.2-3.3%), primarily of spina bifida tational diabetes, hypertension, and large for gestational
and other neural tube defects, as well as facial abnormali- age infants) in the unmatched cohort,91 but not in the
ties, skeletal abnormalities, hypospadias, and diaphrag- matched cohort. This may be because of a higher preva-
matic hernia.62 Because carbamazepine is a competitive lence of baseline diabetes and hypertension in women
inhibitor of prothrombin precursors, it may also increase using antipsychotics.92
the risk of neonatal hemorrhage. As with valproic acid, Pharmacokinetics must also be considered when pre-
high dose folate should be taken and screening for mal- scribing antipsychotics in pregnancy. With advancing
formations and therapeutic blood monitoring should be pregnancy, CYP1A2 enzymes are downregulated, doses
carried out. of olanzapine and clozapine may need to be decreased,
while doses of drugs that are metabolized by upregulated
Lithium enzymes may need to be increased.93 Placental transfer
Lithium use during the first trimester has been associ- from mother to fetus is lowest for quetiapine, risperidone,
ated with an increased risk of a serious congenital heart haloperidol, and olanzapine exhibit.94
defect known as Ebstein’s anomaly, which occurs in Antipsychotics may exacerbate the normal metabolic
about 1/1000 live births. The risk of Ebstein’s anomaly changes seen in pregnancy and increase the risk of gesta-
with first trimester exposure was originally thought to tional diabetes. Many antipsychotics, particularly second
be much higher (400 times higher) than baseline, but a generation antipsychotics (SGAs), are associated with
pooled analysis of lithium exposed pregnancies found excessive maternal weight gain, increased infant birth
that this defect occurred in only 1/1000-1/2000 exposed weight, and increased risk of gestational diabetes.93 95
children.87 This translates to greater than 99% of exposed Several cases identified through individual reports, case
children not developing this anomaly. series, and population based observational studies of
Lithium has also been associated with perinatal toxic- gestational diabetes associated with the use antipsy-
ity including case reports of hypotonia, cyanosis, neo- chotics, including clozapine and olanzapine, have been
natal goiter, and diabetes insipidus. For women with reported.9 96 97 Therefore routine ultrasound monitoring
severe bipolar disorder, the risk of recurrence during of fetal size in late pregnancy may be beneficial in women
pregnancy may overshadow the relatively small risk of who are taking these drugs.95 98
Ebstein’s anomaly. For such women, maintenance lithium Evidence on late pregnancy exposure to antipsychotics
therapy during pregnancy may be the most appropriate and longer term developmental outcomes is also lacking, so
course. By contrast, for women with periods of euthymia the risks remain unclear. Drugs taken by the mother at, or
and few past mood episodes, slow tapering of lithium and near, term may accumulate in the fetus and after delivery, a
reintroduction after the first trimester may help reduce the time of immature renal development in the infant, and this
risk of relapse during the postpartum period. could have adverse effects.93 Motor restlessness, dystonia,
Data on the long term outcomes of children exposed hypertonia, and tremor have been noted in infants exposed
in utero are limited, but a follow-up of a small sample of to antipsychotics in utero.96 99 The few studies examining
children up to 5 years found no evidence of cognitive or the association between in utero exposure to first genera-
behavioral problems.88 tion antipsychotics (FGAs) and neurodevelopment have
Lithium levels should be followed closely during preg- shown no difference in IQ or behavioral functioning at
nancy and the dose should be held or reduced with the 5 years.9 100 101 Studies of SGAs have shown associated
initiation of labor. Hydration during delivery should be neurodevelopmental delays at 6 months of age.102 103
adequate and the dosage reduced to pre-pregnancy levels However, a case-control prospective study found that these
(if it was increased during pregnancy), with close moni- delays were no longer evident at 12 months.62 102
toring of serum levels.62
First generation antipsychotics
Antipsychotics FGAs have been available and widely used for more than
A systematic review published in 2004 on the use of 45 years. Although controlled studies are lacking, FGAs
antipsychotics for primary (non-affective) psychosis in have long been used without clear teratogenic or other
pregnancy found no trials meeting the inclusion crite- toxic fetal effects, so these drugs are thought to have a bet-
ria and concluded that “continued use of antipsychotic ter safety profile in pregnancy than SGAs. Although a few
drugs in these women in pregnancy and lactation with- poorly controlled studies have suggested a minimal risk of
out sound evidence raises serious clinical and ethical major congenital malformations associated with the use
concerns.”89 However, in the past decade, as more evi- of FGAs, the consensus is that the risk is minimal.62 96 104
dence has accumulated, it seems that antipsychotics are In particular, the American College of Obstetricians and

Gynecologists (ACOG) states that “no significant terato- epine use in pregnancy.110 111 On the basis of population
genic effect has been documented with chlorpromazine, based health data, infants exposed to an SSRI in com-
haloperidol, and perphenazine” and suggest that the use bination with a benzodiazepine may have a higher inci-
of piperazine phenothiazines (such as trifluoperazine and dence of congenital heart defects even when controlling
perphenazine) may have especially limited teratogenic for maternal illness characteristics (adjusted odds ratio
potential.104 1.18, 0.18 to 2.18).112
More recently, in utero exposure to FGAs has been When considering the risks and benefits of benzodi-
associated with an increased risk of premature delivery, azepines, clinicians should also consider the risks of
compared with both a cohort of women exposed to SGAs untreated insomnia and anxiety in pregnancy, which may
(0.54, 0.33 to 0.87) and women not exposed to known lead to physiologic effects as well as a reduced level of self
teratogenic, fetotoxic, or insufficiently studied drugs care, worsening mood, and impaired functioning. Given
(1.96, 1.29 to 2.98). Exposure in the third trimester has the consequences of untreated psychiatric symptoms and
been associated with transient extrapyramidal symptoms the limited and controversial risks associated with the
and withdrawal symptoms.105 In 2011 the FDA issued a use of benzodiazepine, some women with overwhelming
drug safety communication for all antipsychotics regard- anxiety symptoms or sleep disturbance may find that the
ing the potential risks of abnormal muscle movements benefits outweigh any theoretical risks.
and withdrawal symptoms in exposed infants.106 Guide-
lines from the American Academy of Pediatrics recom- Gabapentin
mend the use of high potency FGAs to minimize maternal Several studies have indicated that there is no increased
anticholinergic, hypotensive, and antihistaminergic risk of major congenital malformations with gabapen-
effects of low potency antipsychotics.107 For example, tin.113 114 A more recent study published in 2013 also
postural hypotension may occur with low potency antip- found no increased risk of malformations but found
sychotics, especially during mid-pregnancy, necessitat- higher rates of preterm birth, low birth weight, and
ing close monitoring of blood pressure.93 These 2000 admission to neonatal intensive care.115 In general,
guidelines also recommended against the use of depot although not approved for the treatment of anxiety,
antipsychotics because of the lack of flexibility in dosing gabapentin is considered to be a safe alternative for the
and to limit prolonged exposure of the neonate to drugs management of anxiety symptoms during pregnancy.
with potentially toxic effects.
Pregabalin
Second generation antipsychotics Like gabapentin, pregabalin is not approved for the treat-
Evidence suggests that SGAs are no safer to use in preg- ment of anxiety but is clinically useful in decreasing anxi-
nancy than FGAs. The best studied FGA is olanzapine, ety symptoms. It is less well studied than gabapentin but
for which global safety pregnancy surveillance data sug- there is currently no known association with an increased
gest no difference in outcomes compared with the gen- risk of malformations.
eral population.108 However, there is concern that fetal
exposure to these newer drugs may increase infant birth Buspirone
weight and the risk of being born large for gestational Animal reproduction studies have not shown evidence
age.95 Several studies suggest that the use of SGAs in preg- of teratogenesis but no data are available for humans.
nancy is associated with an increased risk of hypoglyce-
mia.109 However this may be due to higher baseline rates Medication assisted treatment for substance dependence
of diabetes in women prescribed antipsychotics,91 92 rein- ACOG and other professional organizations recommend
forcing the need for a thorough evaluation and appropri- annual screening of all patients for misuse of prescription
ate glucose monitoring of women prescribed these drugs. drugs, including early prenatal screening of all pregnant
patients.116 The standard of care for opioid dependent
Clozapine pregnant women includes use of an opioid agonist, an
Clozapine has been associated with floppy baby syn- intervention known as medication assisted treatment.
drome and it is recommended that infants with in utero This approach reduces illicit opioid use and pregnancy
exposure to clozapine be monitored for agranulocytosis related morbidity and mortality, and it improves neona-
weekly for the first 6 months of life.96 tal outcomes.117‑121 Opioid detoxification in pregnancy is
recommended only for women who decline opioid agonist
Antianxiety agents therapy or when no other options are available.122 123
Benzodiazepines
Studies of benzodiazepine use during pregnancy have Methadone
produced contradictory and controversial results. Benzo- Until recently, the practice in the US was to treat pregnant
diazepine use during pregnancy has been associated with women with opioid dependency with methadone only.
case reports of perinatal toxicity, including temperature This was based on several randomized controlled trials
dysregulation, apnea, reduced Apgar scores, hypotonia, (RCTs) that showed a threefold reduction in heroin use
and poor feeding. In addition, early studies identified an and threefold increase in substance misuse treatment
increased risk of oral cleft palate defects. However, more retention in general populations of opioid dependent
recent prospective and retrospective studies have shown people receiving methadone compared with no ago-
no increased risk of cleft lip or palate with benzodiaz- nist therapy.124 125 There was also a lack of evidence

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Fig 4 | “Rules of thumb” for use in designing a clinical treatment plan for pregnant women with psychiatric illness155
suggesting increased risk of congenital malformations or in women treated with methadone and buprenorphine.
adverse pregnancy outcomes with the use of methadone Three were double blind with adequate concealment of
in pregnancy, with the exception of neonatal abstinence the randomization arm; three of four had a dropout rate
syndrome (NAS).126 of 30-40%.132 The most rigorous (n=131), the Maternal
Methadone exposure puts neonates at risk of NAS, a Opioid Treatment: Human Experimental Research study,
condition characterized by dysfunction of the autonomic found that infants born to women treated with metha-
nervous system, central nervous system, gastrointesti- done required significantly more morphine (mean dose
nal system, and respiratory system. The incidence of NAS 10.4 v 1.1 mg), had a significantly longer hospital stay
ranges from 55% to 94% and is unrelated to maternal (17.5 v 10.0 days), and had a significantly longer dura-
methadone dose.118 127 Most neonates with NAS require tion of treatment for NAS (9.9 v 4.1 days) than those born
inpatient detoxification, often in an intensive care unit. to women treated with buprenorphine.133
Little is known about long term neurodevelopmental out- Studies suggest that methadone may be superior for
comes in these neonates, although several longitudinal maternal treatment retention but that NAS may be shorter
studies have shown no differences in cognitive perfor- in infants whose mothers use buprenorphine.132 Opioid
mance in adult children of opioid dependent mothers dependent pregnant women in whom buprenorphine
receiving methadone compared with children of matched should be considered include those for whom methadone
maternal controls.128 is unavailable, those who decline methadone, those who
Although the pharmacokinetics of methadone is have responded well in the past or are currently stabi-
known to be altered in pregnancy, there is little to guide lized on buprenorphine, and those who are naive to opi-
therapeutic drug monitoring. Clinicians should monitor oid agonist therapy.123 126 Although studies suggest that
patients closely for withdrawal symptoms and adjust both methadone and buprenorphine are safe for use in
maternal methadone dosages as needed.129 pregnant women,133‑135 they do not support a shift from
methadone to buprenorphine for methadone treated
Buprenorphine patients who become pregnant.130 136‑ 138
The literature on buprenorphine (a partial mu agonist) One question that remains is the role of buprenorphine
in pregnancy is limited but growing.123 130 131 Four RCTs plus naloxone in pregnancy. A chart review of pregnant
(n=271) have compared maternal and neonatal outcomes women using this combination product (n=10) found no

/(9(/$ significant adverse maternal or neonatal outcomes; how-

ever, given the paucity of data on the safety and efficacy of
%DVHGRQJRRGDQGFRQVLVWHQWVFLHQWLƟFHYLGHQFH this product when used in pregnancy, clinicians are usually
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Q9DOSURDWHH[SRVXUHLQSUHJQDQF\LVDVVRFLDWHGZLWKDQLQFUHDVHGULVNRIIHWDODQRPDOLHVLQFOXGLQJ nation to buprenorphine when they become pregnant.139 140
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Naltrexone
Q&DUEDPD]HSLQHH[SRVXUHLQSUHJQDQF\LVDVVRFLDWHGZLWKIHWDOFDUEDPD]HSLQHV\QGURPH,WVKRXOGEH
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maternal health or congenital malformations, data on
naltrexone use in pregnant humans is lacking. Birth out-
comes were normal in the 25 cases of prenatal naltrexone
/(9(/% implant exposure that have been reported.141 Potential
clinical problems of starting naltrexone in pregnancy
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include the risk of opioid withdrawal associated with
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Q3UHQDWDOEHQ]RGLD]HSLQHH[SRVXUHLQFUHDVHGWKHULVNRIRUDOFOHIWDOWKRXJKWKHDEVROXWHULVNLQFUHDVHG induced opioid withdrawal increases the risk of fetal
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and delivery.141 Supervised opioid withdrawal to create
UHSURGXFWLYHVDIHW\SURƟOHUHODWLYHWRDOWHUQDWLYHPRRGVWDELOL]HUV an opioid-free period before naltrexone induction poses
Q,ILQDGHTXDWHO\WUHDWHGRUOHIWXQWUHDWHGPDWHUQDOSV\FKLDWULFLOOQHVVPD\UHVXOWLQSRRUFRPSOLDQFH similar risks and increases the risk of maternal relapse
ZLWKSUHQDWDOFDUHLQDGHTXDWHQXWULWLRQH[SRVXUHWRDGGLWLRQDOGUXJVRUKHUEDOUHPHGLHVLQFUHDVHGXVH and potential overdose. Naltrexone also poses challenges
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for pain management during labor and delivery as well as
postpartum. Thus, although there is insufficient evidence
/(9(/& to support beginning naltrexone treatment in pregnancy
for opioid or alcohol dependence, if a woman is already
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using naltrexone with benefit, the risk of discontinuation
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SV\FKLDWULFLOOQHVVGXULQJSUHJQDQF\ Antihistamines
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Antihistamines are widely available and are often used
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WKHSRVWSDUWXPSHULRG during pregnancy to treat nausea and insomnia. These
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drugs include diphenhydramine, doxylamine, hydrox-
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Q&RQVLGHUIHWDODVVHVVPHQWZLWKIHWDOHFKRFDUGLRJUDSK\LQSUHJQDQWZRPHQH[SRVHGWROLWKLXPLQWKH published in 2014 of antihistamines and birth defects
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identified two cohort (n=31) and eight case-control
(n=23) studies that found an association between pre-
*5$'(62)(9,'(1&( natal antihistamine exposure and congenital malforma-
tions.142 However, methodological concerns were raised
,(YLGHQFHREWDLQHGIURPDWOHDVWRQHSURSHUO\GHVLJQHGUDQGRPL]HGFRQWUROOHGWULDO
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regarding selection of the study populations, uncon-
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RQHFHQWHURUUHVHDUFKJURXS exposure and presence of malformations.142 143
,,(YLGHQFHREWDLQHGIURPPXOWLSOHWLPHVHULHVZLWKRUZLWKRXWWKHLQWHUYHQWLRQ'UDPDWLFUHVXOWVLQ Although more than 90% of pregnant women report
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using over the counter antihistamines to treat insom-
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FRPPLWWHHV nia,144 a recent systematic review of the use of sleep
promoting drugs during pregnancy identified only two
/(9(/62)5(&200(1'$7,216 studies on prenatal antihistamine exposure.145 One found
no association between exposure and congenital malfor-
/(9(/$ /(9(/% /(9(/& mations,54 and the other examined sleep and mood out-
comes.146 Sleep agents including eszopiclone, ramelteon,
5HFRPPHQGDWLRQVDUH 5HFRPPHQGDWLRQVDUH 5HFRPPHQGDWLRQVDUH
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and zolpidem have not been associated with major organ
FRQVLVWHQWVFLHQWLƟFHYLGHQFH VFLHQWLƟFHYLGHQFH DQGH[SHUWRSLQLRQ malformations,145 but zolpidem use for longer than 90
days has been associated with a significantly increased
risk of low birth weight (odds ratio 1.39, 1.17 to 1.64),
Fig 5 | Major recommendations from the American College of Obstetricians and Gynecologists
(ACOG),155 according to the level of evidence preterm birth (1.49, 1.28 to 1.74), and cesarean delivery
(1.74, 1.59 to 1.90).147
Stimulants
A systematic review published in 2014 identified three
articles (41 methylphenidate pregnancy exposures),
all of which involved polypharmacy with known terato-
genic drugs or drugs of misuse, so the findings of various

congenital malformations and adverse birth outcomes RESEARCH QUESTIONS

were not considered generalizable.148 Although reduced • Can maternal plasma drug concentrations be predicted on
fetal survival in rats has been reported,149 the data on the the basis of pharmacokinetic and pharmacogenetic models
safety of prenatal exposure to atomoxetine in humans so that individualized drug regimens can be designed?
are also limited.150 The 2014 systematic review did not • What are the long term outcomes for children exposed in
include the results of three population based Danish utero to various classes of psychotropic drugs?
cohort studies (n=186 methylphenidate or atomoxetine; • Should antidepressants be tapered before delivery?
n=480 methylphenidate, modafinil, and atomoxetine; • Is buprenorphine plus naloxone equivalent to
n=222 methylphenidate alone).151‑153 The first study buprenorphine alone in the management of opioid
found that prenatal exposure was associated with an addiction in pregnant women? Does this combination pose
additional risks to the fetus?
increased risk of spontaneous abortion (adjusted relative
risk 1.55, 1.03 to 2.36) and lower Apgar scores (2.06,
1.11 to 3.82).151 The second found that prenatal exposure Conclusion
was associated with increased risk of elective termina- The interpretation of the literature on the association
tions of pregnancy by maternal request (odds ratio 4.70, between psychotropic drug use during pregnancy and
3.77 to 5.85) and by special indication (2.99, 1.34 to outcomes for the exposed baby is complicated by the
6.67) and of miscarriage (2.07, 1.03 to 2.36).152 However, associated risk factors and behaviors that may also influ-
the women using stimulants were more likely to be young, ence outcomes. Large, well designed and controlled stud-
single, less well educated, receiving social security, and ies have shown that most classes of psychotropic drugs
taking other psychotropics. The third study found that seem to be relatively safe during pregnancy. Untreated
first trimester exposure was associated with no increased psychiatric disorders during pregnancy have associated
risk of major congenital malformations.153 risks for both mother and child and these risks need to
be considered in the risk-benefit analysis of psychotropic
General approach to the management of psychotropic drug use during pregnancy. However, psychotropic drugs
drugs during pregnancy should not be precipitously stopped, and a comprehen-
Ideally, plans for the treatment of a patient’s psychiatric sive evaluation and individualized treatment plan is
disorder during pregnancy should be in place before the needed for these patients. Future work should focus on
woman becomes pregnant. However, as many as 50% of the proper management of psychotropic drugs during
pregnancies are unplanned in the US,154 so practitioners pregnancy, including prophylactic dosing strategies and
often need to make treatment decisions for patients who management before and after delivery. Finally, to defini-
are already pregnant. tively answer the question of whether exposure in utero
Given the data indicating that psychiatric illness poses to psychotropic drugs affects outcomes for the child, we
risks for both the mother and child, the treatment priority need more centralized birth registries with better systems
should be to keep the mother psychiatrically well during for procuring data on potential confounders.
pregnancy. Every case should be considered individually. Contributors: Both authors planned, conducted, and prepared for
The patient’s psychiatric history, severity of symptoms, publication all the review work described in this article; they both act as
guarantors. Both authors also accept full responsibility for the work and the
response to drugs, and wishes regarding drug use dur- conduct of the study, had access to the data, and controlled the decision
ing pregnancy all play an important role in designing a to publish. The authors acknowledge the assistance of informationist
course of clinical care during pregnancy. Figure 4 shows Blair Anton who contributed to the search strategy and research assistant
Elizabeth Uible who organized the literature identified by the search.
the “rules of thumb” for designing a clinical treatment
Competing interests: We have read and understood BMJ policy on
plan for pregnant women with psychiatric illness. declaration of interests and declare the following: MSC: no support from
any organization for the submitted work and no competing interests. JLP:
Guidelines No support from any organization for the submitted work. JLP has received
legal consulting fees from Astra Zeneca, Johnson and Johnson, Pfizer, and
ACOG issued “Guidelines on the use of psychotropic med-
Eli Lilly.
ications during pregnancy and lactation” in 2008 and
Provenance and peer review: Commissioned; externally peer reviewed.
reaffirmed them in 2012.156 Figure 5 lists the main recom-
1 Kendell RE, Kemp IW. Winter-born v summer-born schizophrenics. Br J
mendations. These guidelines focus on recommendations Psychiatry 1987;151:499-505.
based on available evidence for the management of spe- 2 Grof P, Robbins W, Alda M, et al. Protective effect of pregnancy in women
with lithium-responsive bipolar disorder. J Affect Disord 2000;61:31-9.
cific psychotropic drugs. In 2009, the American Psychi- 3 Marcus SM, Flynn HA, Blow FC, et al. Depressive symptoms among
atric Association issued a joint statement with ACOG on pregnant women screened in obstetrics settings. J Womens Health
(Larchmt) 2003;12:373-80.
the management of depression during pregnancy which 4 Andersson L, Sundstrom-Poromaa I, Bixo M, et al. Point prevalence
focuses on the use of antidepressants during pregnancy of psychiatric disorders during the second trimester of pregnancy: a
population-based study. Am J Obstet Gynecol 2003;189:148-54.
and presents treatment algorithms for women with MDD 5 Payne JL. Antidepressant use in the postpartum period: practical
who are contemplating pregnancy, currently pregnant considerations. Am J Psychiatry 2007;164:1329-32.
but not taking drugs, and currently pregnant and taking 6 Cohen LS, Altshuler LL, Harlow BL, et al. Relapse of major depression
during pregnancy in women who maintain or discontinue antidepressant
drugs.55 In 2014, the National Institute for Health and treatment. JAMA 2006;295:499-507.
Care Excellence in the UK also issued guidelines on the 7 Viguera AC, Whitfield T, Baldessarini RJ, et al. Risk of recurrence in women
with bipolar disorder during pregnancy: prospective study of mood
clinical management of antenatal and postnatal mental stabilizer discontinuation. Am J Psychiatry 2007;164:1817-24; quiz
health.157 These guidelines focus on the clinical manage- 1923.
8 Viguera AC, Nonacs R, Cohen LS, et al. Risk of recurrence of bipolar
ment of mental health problems in the perinatal period disorder in pregnant and nonpregnant women after discontinuing lithium
rather than specific drug recommendations. maintenance. Am J Psychiatry 2000;157:179-84.

9 Barnes TR; Schizophrenia Consensus Group of British Association 40 Nulman I, Rovet J, Stewart DE, et al. Neurodevelopment of children exposed
for Psychopharmacology. Evidence-based guidelines for the in utero to antidepressant drugs. N Engl J Med 1997;336:258-62.
pharmacological treatment of schizophrenia: recommendations from 41 Pastuszak A, Schick-Boschetto B, Zuber C, et al. Pregnancy outcome
the British Association for Psychopharmacology. J Psychopharmacol following first-trimester exposure to fluoxetine (Prozac). JAMA
2011;25:567-620. 1993;269:2246-8.
10 Davis J, Janicak P, Singla A, et al. Maintenance antipsychotic medication. 42 Simon GE, Cunningham ML, Davis RL. Outcomes of prenatal
In: Barnes T, ed. Antipsychotic drugs and their side-effects. Academic antidepressant exposure. Am J Psychiatry 2002;159:2055-61.
Press, 1993:183-203. 43 Ramos E, St-Andre M, Rey E, et al. Duration of antidepressant use during
11 Gilbert PL, Harris MJ, McAdams LA, et al. Neuroleptic withdrawal in pregnancy and risk of major congenital malformations. Br J Psychiatry
schizophrenic patients. A review of the literature. Arch Gen Psychiatry 2008;192:344-50.
1995;52:173-88. 44 Reis M, Kallen B. Delivery outcome after maternal use of antidepressant
12 Viguera AC, Baldessarini RJ, Hegarty JD, et al. Clinical risk following abrupt drugs in pregnancy: an update using Swedish data. Psychol Med
and gradual withdrawal of maintenance neuroleptic treatment. Arch Gen 2010;40:1723-33.
Psychiatry 1997;54:49-55. 45 Chun-Fai-Chan B, Koren G, Fayez I, et al. Pregnancy outcome of women
13 US National Library of Medicine. Search strategy used to create the exposed to bupropion during pregnancy: a prospective comparative
systematic reviews subset on PubMed. www.nlm.nih.gov/bsd/pubmed_ study. Am J Obstet Gynecol 2005;192:932-6.
subsets/sysreviews_strategy.html. 46 Cole JA, Modell JG, Haight BR, et al. Bupropion in pregnancy and the
14 Li D, Liu L, Odouli R. Presence of depressive symptoms during early prevalence of congenital malformations. Pharmacoepidemiol Drug Saf
pregnancy and the risk of preterm delivery: a prospective cohort study. 2007;16:474-84.
Hum Reprod 2009;24:146-53. 47 Alwan S, Reefhuis J, Botto LD, et al. Maternal use of bupropion and risk for
15 Zuckerman B, Amaro H, Bauchner H, et al. Depressive symptoms during congenital heart defects. Am J Obstet Gynecol 2010;203:52.e1-6.
pregnancy: relationship to poor health behaviors. Am J Obstet Gynecol 48 Byatt N, Deligiannidis KM, Freeman MP. Antidepressant use in pregnancy:
1989;160:1107-11. a critical review focused on risks and controversies. Acta Psychiatr Scand
16 Orr ST, Blazer DG, James SA, et al. Depressive symptoms and indicators 2013;127:94-114.
of maternal health status during pregnancy. J Womens Health (Larchmt) 49 Yonkers KA, Blackwell KA, Glover J, et al. Antidepressant use in pregnant
2007;16:535-42. and postpartum women. Annu Rev Clin Psychol 2014;10:369-92.
17 Field T, Diego M, Hernandez-Reif M. Prenatal depression effects on the 50 Kallen BA, Otterblad Olausson P. Maternal use of selective serotonin
fetus and newborn: a review. Infant Behav Dev 2006;29:445-55. re-uptake inhibitors in early pregnancy and infant congenital
18 Field T, Diego M, Hernandez-Reif M. Prenatal depression effects and malformations. Birth Defects Res A Clin Mol Teratol 2007;79:301-8.
interventions: a review. Infant Behav Dev 2010;33:409-18. 51 Kallen B, Otterblad Olausson P. Antidepressant drugs during pregnancy
19 Davis EP, Glynn LM, Dunkel Schetter C, et al. Corticotropin-releasing and infant congenital heart defect. Reprod Toxicol 2006;21:221-2.
hormone during pregnancy is associated with infant temperament. Dev 52 Louik C, Lin AE, Werler MM, et al. First-trimester use of selective
Neurosci 2005;27:299-305. serotonin-reuptake inhibitors and the risk of birth defects. N Engl J Med
20 Ashman SB, Dawson G, Panagiotides H, et al. Stress hormone levels of 2007;28;356:2675-83.
children of depressed mothers. Dev Psychopathol 2002;14:333-49. 53 Alwan S, Friedman JM. Safety of selective serotonin reuptake inhibitors in
21 Diego MA, Field T, Hernandez-Reif M, et al. Prepartum, postpartum, and pregnancy. CNS Drugs 2009;23:493-509.
chronic depression effects on newborns. Psychiatry 2004;67:63-80. 54 Reis M, Kallen B. Combined use of selective serotonin reuptake inhibitors
22 Essex MJ, Klein MH, Cho E, et al. Maternal stress beginning in infancy and sedatives/hypnotics during pregnancy: risk of relatively severe
may sensitize children to later stress exposure: effects on cortisol and congenital malformations or cardiac defects. A register study. BMJ Open
behavior. Biol Psychiatry 2002;52:776-84. 2013;3:e002166.
23 Halligan SL, Herbert J, Goodyer IM, et al. Exposure to postnatal depression 55 Yonkers KA, Wisner KL, Stewart DE, et al. The management of depression
predicts elevated cortisol in adolescent offspring. Biol Psychiatry during pregnancy: a report from the American Psychiatric Association
2004;55:376-81. and the American College of Obstetricians and Gynecologists. Gen Hosp
24 Brennan PA, Pargas R, Walker EF, et al. Maternal depression and infant Psychiatry 2009;31:403-13.
cortisol: influences of timing, comorbidity and treatment. J Child Psychol 56 Jimenez-Solem E, Andersen JT, et al. Exposure to selective serotonin
Psychiatry 2008;49:1099-107. reuptake inhibitors and the risk of congenital malformations: a nationwide
25 O’Connor TG, Ben-Shlomo Y, Heron J, et al. Prenatal anxiety predicts cohort study. BMJ Open 2012;2:e001148.
individual differences in cortisol in pre-adolescent children. Biol 57 Huybrechts KF, Sanghani RS, Avorn J, et al. Preterm birth and
Psychiatry 2005;58:211-7. antidepressant medication use during pregnancy: a systematic review
26 Grace SL, Evindar A, Stewart DE. The effect of postpartum depression on and meta-analysis. PLoS One 2014;9:e92778.
child cognitive development and behavior: a review and critical analysis 58 Wang S, Yang L, Wang L, et al. Selective serotonin reuptake inhibitors
of the literature. Arch Womens Ment Health 2003;6:263-74. (SSRIs) and the risk of congenital heart defects: a meta-analysis of
27 Seeman MV. Gender differences in the prescribing of antipsychotic drugs. prospective cohort studies. J Am Heart Assoc 2015;4:e001681
Am J Psychiatry 2004;161:1324-33. 59 Ross LE, Grigoriadis S, Mamisashvili L, et al. Selected pregnancy and
28 Pavek P, Ceckova M, Staud F. Variation of drug kinetics in pregnancy. Curr delivery outcomes after exposure to antidepressant medication: a
Drug Metab 2009;10:520-9. systematic review and meta-analysis. JAMA Psychiatry 2013;70:436-43.
29 DeVane CL, Stowe ZN, Donovan JL, et al. Therapeutic drug monitoring of 60 Hemels ME, Einarson A, Koren G, et al. Antidepressant use during
psychoactive drugs during pregnancy in the genomic era: challenges and pregnancy and the rates of spontaneous abortions: a meta-analysis. Ann
opportunities. J Psychopharmacol 2006;20:54-9. Pharmacother 2005;39:803-9.
30 Tracy TS, Venkataramanan R, Glover DD, et al; National Institute for Child 61 Nakhai-Pour HR, Broy P, Berard A. Use of antidepressants during
Health and Human Development Network of Maternal-Fetal-Medicine pregnancy and the risk of spontaneous abortion. CMAJ 2010;182:1031-
Units. Temporal changes in drug metabolism (CYP1A2, CYP2D6 and 7.
CYP3A activity) during pregnancy. Am J Obstet Gynecol 2005;192:633-9. 62 Pearlstein T. Use of psychotropic medication during pregnancy and the
31 Hanley GE, Oberlander TF. The effect of perinatal exposures on the infant: postpartum period. Womens Health (Lond Engl) 2013;9:605-15.
antidepressants and depression. Best Pract Res Clin Obstet Gynaecol 63 Yonkers KA, Norwitz ER, Smith MV, et al. Depression and serotonin
2014;28:37-48. reuptake inhibitor treatment as risk factors for preterm birth.
32 Cunningham FG, Leveno KJ, Bloom SL, et al. Williams obstetrics, McGraw Epidemiology 2012;23:677-85.
Hill, 2010. 64 Walsh-Sukys MC, Tyson JE, Wright LL, et al. Persistent pulmonary
33 Byatt N, Hicks-Courant K, Davidson A, et al. Depression and anxiety among hypertension of the newborn in the era before nitric oxide: practice
high-risk obstetric inpatients. Gen Hosp Psychiatry 2014;36:644-9. variation and outcomes. Pediatrics 2000;105:14-20.
34 Alwan S, Reefhuis J, Rasmussen SA, et al; National Birth Defects 65 Hageman JR, Adams MA, Gardner TH. Persistent pulmonary hypertension
Prevention Study. Use of selective serotonin-reuptake inhibitors in of the newborn. Trends in incidence, diagnosis, and management. Am J
pregnancy and the risk of birth defects. N Engl J Med 2007;356:2684-92. Dis Child 1984;138:592-5.
35 Rahimi R, Nikfar S, Abdollahi M. Pregnancy outcomes following exposure 66 Hernandez-Diaz S, Van Marter LJ, Werler MM, et al. Risk factors for
to serotonin reuptake inhibitors: a meta-analysis of clinical trials. Reprod persistent pulmonary hypertension of the newborn. Pediatrics
Toxicol 2006;22:571-5. 2007;120:e272-82.
36 Addis A, Koren G. Safety of fluoxetine during the first trimester of 67 Bearer C, Emerson RK, O’Riordan MA, et al. Maternal tobacco smoke
pregnancy: a meta-analytical review of epidemiological studies. Psychol exposure and persistent pulmonary hypertension of the newborn. Environ
Med 2000;30:89-94. Health Perspect 1997;105:202-6.
37 Einarson TR, Einarson A. Newer antidepressants in pregnancy and rates 68 Chambers CD, Hernandez-Diaz S, Van Marter LJ, et al. Selective serotonin-
of major malformations: a meta-analysis of prospective comparative reuptake inhibitors and risk of persistent pulmonary hypertension of the
studies. Pharmacoepidemiol Drug Saf 2005;14:823-7. newborn. N Engl J Med 2006;354:579-87.
38 O’Brien L, Einarson TR, Sarkar M, et al. Does paroxetine cause cardiac 69 Andrade SE, McPhillips H, Loren D, et al. Antidepressant medication
malformations? J Obstet Gynaecol Can 2008;30:696-701. use and risk of persistent pulmonary hypertension of the newborn.
39 Davis RL, Rubanowice D, McPhillips H, et al. Risks of congenital Pharmacoepidemiol Drug Saf 2009;18:246-52.
malformations and perinatal events among infants exposed to 70 Wichman CL, Moore KM, Lang TR, et al. Congenital heart disease
antidepressant medications during pregnancy. Pharmacoepidemiol Drug associated with selective serotonin reuptake inhibitor use during
Saf 2007;16:1086-94. pregnancy. Mayo Clin Proc 2009;84:23-7.

71 Wilson KL, Zelig CM, Harvey JP, et al. Persistent pulmonary hypertension 103 Johnson KC, LaPrairie JL, Brennan PA, et al. Prenatal antipsychotic
of the newborn is associated with mode of delivery and not with exposure and neuromotor performance during infancy. Arch Gen
maternal use of selective serotonin reuptake inhibitors. Am J Perinatol Psychiatry 2012;69:787-94.
2011;28:19-24. 104 American College of Obstetricians and Gynecologists. Practice bulletin:
72 Kallen B, Olausson PO. Maternal use of selective serotonin re-uptake clinical management guidelines for obstetrician-gynecologists number
inhibitors and persistent pulmonary hypertension of the newborn. 92, April 2008 (replaces practice bulletin number 87, November 2007).
Pharmacoepidemiol Drug Saf 2008;17:801-6. Use of psychotropic medications during pregnancy and lactation. Obstet
73 Kieler H, Artama M, Engeland A, et al. Selective serotonin reuptake Gynecol 2008;111:1001-20.
inhibitors during pregnancy and risk of persistent pulmonary 105 Habermann F, Fritzsche J, Fuhlbruck F, et al. Atypical antipsychotic
hypertension in the newborn: population based cohort study from the five drugs and pregnancy outcome: a prospective, cohort study. J Clin
Nordic countries. BMJ 2012;344:d8012. Psychopharmacol 2013;33:453-62.
74 Huybrechts KF, Bateman BT, Palmsten K, et al. Antidepressant use late in 106 Food and Drug Administration. Drug safety communication:
pregnancy and risk of persistent pulmonary hypertension of the newborn. antipsychotic drug labels updated on use during pregnancy and risk of
JAMA 2015;313:2142-51. abnormal muscle movements and withdrawal symptoms in newborns.
75 Webster PA. Withdrawal symptoms in neonates associated with maternal www.fda.gov/Drugs/DrugSafety/ucm243903.htm#sa.
antidepressant therapy. Lancet 1973;2:318-9. 107 American Academy of Pediatrics. Committee on Drugs.Use of
76 Moses-Kolko E, Bogen D, Perel J, et al. Neonatal signs after late in psychoactive medication during pregnancy and possible effects on the
utero exposure to serotonin reuptake inhibitors: literature review and fetus and newborn. Pediatrics 2000;105:880-7.
implications for clinical applications. JAMA 2005;293:2372-83. 108 Brunner E, Falk DM, Jones M, et al. Olanzapine in pregnancy and
77 Oberlander TF, Misri S, Fitzgerald CE, et al. Pharmacologic factors breastfeeding: a review of data from global safety surveillance. BMC
associated with transient neonatal symptoms following prenatal Pharmacol Toxicol 2013;14:38.
psychotropic medication exposure. J Clin Psychiatry 2004;65:230-7. 109 Gentile S. Clinical utilization of atypical antipsychotics in pregnancy and
78 Croen LA, Grether JK, Yoshida CK, et al. Antidepressant use during lactation. Ann Pharmacother 2004;38:1265-71.
pregnancy and childhood autism spectrum disorders. Arch Gen Psychiatry 110 Iqbal MM, Sobhan T, Ryals T. Effects of commonly used benzodiazepines
2011;68:1104-12. on the fetus, the neonate, and the nursing infant. Psychiatr Serv
79 Rai D, Lee BK, Dalman C, et al. Parental depression, maternal 2002;53:39-49.
antidepressant use during pregnancy, and risk of autism spectrum 111 Lin AE, Peller AJ, Westgate MN, et al. Clonazepam use in pregnancy
disorders: population based case-control study. BMJ 2013;346:f2059. and the risk of malformations. Birth Defects Res A Clin Mol Teratol
80 Hviid A, Melbye M, Pasternak B. Use of selective serotonin reuptake 2004;70:534-6.
inhibitors during pregnancy and risk of autism. N Engl J Med 112 Oberlander TF, Warburton W, Misri S, et al. Major congenital
2013;369:2406-15. malformations following prenatal exposure to serotonin reuptake
81 Cunnington M, Tennis P; International Lamotrigine Pregnancy Registry inhibitors and benzodiazepines using population-based health data.
Scientific Advisory Committee. Lamotrigine and the risk of malformations Birth Defects Res B Dev Reprod Toxicol 2008;83:68-76.
in pregnancy. Neurology 2005;64:955-60. 113 Holmes LB, Hernandez-Diaz S. Newer anticonvulsants: lamotrigine,
82 Holmes LB, Wyszynsk DF, Baldwin EJ. Increased risk for non-syndromic topiramate and gabapentin. Birth Defects Res A Clin Mol Teratol
cleft palate among infants exposed to lamotrigine during pregnancy. Birth 2012;94:599-606.
Defects Research Part A Clin Mol Teratol 2006;76:318. 114 Molgaard-Nielsen D, Hviid A. Newer-generation antiepileptic drugs and
83 Dolk H, Jentink J, Loane M, et al; EUROCAT Antiepileptic Drug Working the risk of major birth defects. JAMA 2011;305:1996-2002.
Group. Does lamotrigine use in pregnancy increase orofacial cleft risk 115 Fujii H, Goel A, Bernard N, et al. Pregnancy outcomes following
relative to other malformations? Neurology 2008;71:714-22. gabapentin use: results of a prospective comparative cohort study.
84 Clark CT, Klein AM, Perel JM, et al. Lamotrigine dosing for pregnant Neurology 2013;80:1565-70.
patients with bipolar disorder. Am J Psychiatry 2013;170:1240-7. 116 American College of Obstetricians and Gynecologists Committee on
85 Bromley RL, Mawer GE, Briggs M, et al. The prevalence of Health Care for Underserved Women, American Society of Addiction
neurodevelopmental disorders in children prenatally exposed to Medicine. ACOG committee opinion no. 524: opioid abuse, dependence,
antiepileptic drugs. J Neurol Neurosurg Psychiatry 2013;84:637-43. and addiction in pregnancy. Obstet Gynecol 2012;119:1070-6.
86 Christensen J, Gronborg TK, Sorensen MJ, et al. Prenatal valproate 117 Wong S, Ordean A, Kahan M. Substance use in pregnancy. J Obstet
exposure and risk of autism spectrum disorders and childhood autism. Gynaecol Can 2011;33:367-84.
JAMA 2013;309:1696-703. 118 Fullerton CA, Kim M, Thomas CP, et al. Medication-assisted treatment
87 Cohen LS, Friedman JM, Jefferson JW, et al. A reevaluation of risk of in utero with methadone: assessing the evidence. Psychiatr Serv 2014;65:146-
exposure to lithium. JAMA 1994;271:146-50. 57.
88 Jacobson SJ, Jones K, Johnson K, et al. Prospective multicentre study of 119 Jones HE, O’Grady KE, Malfi D, et al. Methadone maintenance vs.
pregnancy outcome after lithium exposure during first trimester. Lancet methadone taper during pregnancy: maternal and neonatal outcomes.
1992;339:530-3. Am J Addict 2008;17:372-86.
89 Webb RT, Howard L, Abel KM. Antipsychotic drugs for non-affective 120 Kaltenbach K, Berghella V, Finnegan L. Opioid dependence during
psychosis during pregnancy and postpartum. Cochrane Database Syst pregnancy. Effects and management. Obstet Gynecol Clin North Am
Rev 2004;2:CD004411. 1998;25:139-51.
90 Robinson GE. Treatment of schizophrenia in pregnancy and postpartum. J 121 Kandall SR, Doberczak TM, Jantunen M, et al. The methadone-maintained
Popul Ther Clin Pharmacol 2012;19:e380-6. pregnancy. Clin Perinatol 1999;26:173-83.
91 Vigod SN, Gomes T, Wilton AS, et al. Antipsychotic drug use in pregnancy: 122 Winklbaur B, Kopf N, Ebner N, et al. Treating pregnant women
high dimensional, propensity matched, population based cohort study. dependent on opioids is not the same as treating pregnancy and opioid
BMJ 2015;350:h2298. dependence: a knowledge synthesis for better treatment for women and
92 Khalifeh H, Dolman C, Howard LM. Safety of psychotropic drugs in neonates. Addiction 2008;103:1429-40.
pregnancy. BMJ 2015;350:h2260. 123 Jones HE, Fischer G, Heil SH, et al. Maternal opioid treatment: human
93 Seeman MV. Clinical interventions for women with schizophrenia: experimental research (MOTHER)—approach, issues and lessons
pregnancy. Acta Psychiatr Scand 2013;127:12-22. learned. Addiction 2012;107(suppl 1):28-35.
94 Newport DJ, Calamaras MR, DeVane CL, et al. Atypical antipsychotic 124 Mattick RP, Breen C, Kimber J, et al. Methadone maintenance therapy
administration during late pregnancy: placental passage and obstetrical versus no opioid replacement therapy for opioid dependence. Cochrane
outcomes. Am J Psychiatry 2007;164:1214-20. Database Syst Rev 2009;3:CD002209.
95 Newham JJ, Thomas SH, MacRitchie K, et al. Birth weight of infants after 125 Mattick RP, Breen C, Kimber J, et al. Methadone maintenance therapy
maternal exposure to typical and atypical antipsychotics: prospective versus no opioid replacement therapy for opioid dependence. Cochrane
comparison study. Br J Psychiatry 2008;192:333-7. Database Syst Rev 2002;4:CD002209.
96 Gentile S. Antipsychotic therapy during early and late pregnancy. A 126 Alto WA, O’Connor AB. Management of women treated with
systematic review. Schizophr Bull 2010;36:518-44. buprenorphine during pregnancy. Obstet Gynecol 2011;205:302-8.
97 Reis M, Kallen B. Maternal use of antipsychotics in early pregnancy and 127 Jones HE, Jansson LM, O’Grady KE, et al. The relationship between
delivery outcome. J Clin Psychopharmacol 2008;28:279-88. maternal methadone dose at delivery and neonatal outcome:
98 Paton C. Prescribing in pregnancy. Br J Psychiatry 2008;192:321-2. methodological and design considerations. Neurotoxicol Teratol
99 Coppola D, Russo LJ, Kwarta RF, et al. Evaluating the postmarketing 2013;39:110-5.
experience of risperidone use during pregnancy: pregnancy and neonatal 128 Kaltenbach K, Finnegan LP. Developmental outcome of children born
outcomes. Drug Saf 2007;30:247-64. to methadone maintained women: a review of longitudinal studies.
100 Altshuler LL, Cohen L, Szuba MP, et al. Pharmacologic management of Neurobehav Toxicol Teratol 1984;6:271-5.
psychiatric illness during pregnancy: dilemmas and guidelines. Am J 129 Shiu JR, Ensom MH. Dosing and monitoring of methadone in pregnancy:
Psychiatry 1996;153:592-606. literature review. Can J Hosp Pharm 2012;65:380-6.
101 Thiels C. Pharmacotherapy of psychiatric disorder in pregnancy and 130 Jones HE, Finnegan LP, Kaltenbach K. Methadone and buprenorphine
during breastfeeding: a review. Pharmacopsychiatry 1987;20:133-46. for the management of opioid dependence in pregnancy. Drugs
102 Peng M, Gao K, Ding Y, et al. Effects of prenatal exposure to atypical 2012;72:747-57.
antipsychotics on postnatal development and growth of infants: 131 Jones HE, Heil SH, Baewert A, et al. Buprenorphine treatment of opioid-
a case-controlled, prospective study. Psychopharmacology (Berl) dependent pregnant women: a comprehensive review. Addiction
2013;228:577-84. 2012;107(suppl 1):5-27.

132 Minozzi S, Amato L, Bellisario C, et al. Maintenance agonist treatments 146 Khazaie H, Ghadami MR, Knight DC, et al. Insomnia treatment in the third
for opiate-dependent pregnant women. Cochrane Database Syst Rev trimester of pregnancy reduces postpartum depression symptoms: a
2013;12:CD006318. randomized clinical trial. Psychiatry Res 2013;210:901-5.
133 Jones HE, Kaltenbach K, Heil SH, et al. Neonatal abstinence syndrome after 147 Wang LH, Lin HC, Lin CC, et al. Increased risk of adverse pregnancy
methadone or buprenorphine exposure. N Engl J Med 2010;363:2320-31. outcomes in women receiving zolpidem during pregnancy. Clin Pharmacol
134 Jones HE, Johnson RE, Jasinski DR, et al. Buprenorphine versus methadone Ther 2010;88:369-74.
in the treatment of pregnant opioid-dependent patients: effects on the 148 Bolea-Alamanac BM, Green A, Verma G, et al. Methylphenidate use
neonatal abstinence syndrome. Drug Alcohol Depend 2005;79:1-10. in pregnancy and lactation: a systematic review of evidence. Br J Clin
135 Fischer G, Ortner R, Rohrmeister K, et al. Methadone versus Pharmacol 2014;77:96-101.
buprenorphine in pregnant addicts: a double-blind, double-dummy 149 Humphreys C, Garcia-Bournissen F, Ito S, et al. Exposure to attention
comparison study. Addiction 2006;101:275-81. deficit hyperactivity disorder medications during pregnancy. Can Fam
136 Jones HE, Martin PR, Heil SH, et al. Treatment of opioid-dependent Physician 2007;53:1153-5.
pregnant women: clinical and research issues. J Subst Abuse Treat 150 Dadashova R, Silverstone PH. Off-label use of atomoxetine in adults: is it
2008;35:245-59. safe? Ment Illn 2012;4:e19.
137 Unger A, Jung E, Winklbaur B, et al. Gender issues in the pharmacotherapy 151 Bro SP, Kjaersgaard MI, Parner ET, et al. Adverse pregnancy outcomes
of opioid-addicted women: buprenorphine. J Addict Dis 2010;29:217-30. after exposure to methylphenidate or atomoxetine during pregnancy. Clin
138 Stine SM, Heil SH, Kaltenbach K, et al. Characteristics of opioid-using Epidemiol 2015;7:139-47.
pregnant women who accept or refuse participation in a clinical trial: 152 Haervig KB, Mortensen LH, Hansen AV, et al. Use of ADHD medication
screening results from the MOTHER study. Am J Drug Alcohol Abuse during pregnancy from 1999 to 2010: a Danish register-based study.
2009;35:429-33. Pharmacoepidemiol Drug Saf 2014;23:526-33.
139 Debelak K, Morrone WR, O’Grady KE, et al. Buprenorphine + naloxone in 153 Pottegard A, Hallas J, Andersen JT, et al. First-trimester exposure to
the treatment of opioid dependence during pregnancy—initial patient methylphenidate: a population-based cohort study. J Clin Psychiatry
care and outcome data. Am J Addict 2013;22:252-4. 2014;75:e88-93.
140 Soyka M. Buprenorphine use in pregnant opioid users: a critical review. 154 Mosher WD, Bachrach CA. Understanding US fertility: continuity and
CNS Drugs 2013;27:653-62. change in the national survey of family growth, 1988-1995. Fam Plann
141 Jones HE, Chisolm MS, Jansson LM, et al. Naltrexone in the treatment Perspect 1996;28:4-12.
of opioid-dependent pregnant women: the case for a considered and 155 Payne JL, Meltzer-Brody S. Antidepressant use during pregnancy:
measured approach to research. Addiction 2013;108:233-47. current controversies and treatment strategies. Clin Obstet Gynecol
142 Gilboa SM, Ailes EC, Rai RP, et al. Antihistamines and birth defects: a 2009;52:469-82.
systematic review of the literature. Expert Opin Drug Saf 2014;13:1667-98. 156 American College of Obstetricians and Gynecologists. Practice bulletin:
143 Fejzo MS, Magtira A, Schoenberg FP, et al. Antihistamines and other clinical management guidelines for obstetrician-gynecologists number
prognostic factors for adverse outcome in hyperemesis gravidarum. Eur J 92, April 2008 (replaces practice bulletin number 87, November 2007).
Obstet Gynecol Reprod Biol 2013;170:71-6. Use of psychotropic medications during pregnancy and lactation. Obstet
144 Black RA, Hill DA. Over-the-counter medications in pregnancy. Am Fam Gynecol 2008;111:1001-20.
Physician 2003;67:2517-24. 157 Howard LM, Megnin-Viggars O, Symington I, et al; Guideline Development
145 Okun ML, Ebert R, Saini B. A review of sleep-promoting medications used Group. Antenatal and postnatal mental health: summary of updated NICE
in pregnancy. Am J Obstet Gynecol 2015;212:428-41. guidance. BMJ 2014;349:g7394.

2015 Management of Psychotropic Drugs During Pregnancy

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2015 Management of Psychotropic Drugs During Pregnancy

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STAT E O F T H E A RT R E V I E W

Management of psychotropic drugs

Introduction HOW PATIENTS WERE INVOLVED IN THE CREATION OF THIS

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c­ongenital malformations and adverse birth outcomes RESEARCH QUESTIONS

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congenital malformations and adverse birth outcomes RESEARCH QUESTIONS