Acta Psychiatr Scand 2015: 132 (Suppl. 445): 1–28
All rights reserved
DOI: 10.1111/acps.12479
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
ACTA PSYCHIATRICA SCANDINAVICA
Clinical overview
Use of psychotropic drugs during pregnancy
and breast-feeding
Larsen ER, Damkier P, Pedersen LH, Fenger-Gron J, Mikkelsen RL,
Nielsen RE, Linde VJ, Knudsen HED, Skaarup L, Videbech P. Use of
psychotropic drugs during pregnancy and breast-feeding.
Objective: To write clinical guidelines for the use of psychotropic drugs
during pregnancy and breast-feeding for daily practice in psychiatry,
obstetrics and paediatrics.
Method: As we wanted a guideline with a high degree of consensus
among health professionals treating pregnant women with a psychiatric
disease, we asked the Danish Psychiatric Society, the Danish Society of
Obstetrics and Gynecology, the Danish Paediatric Society and the
Danish Society of Clinical Pharmacology to appoint members for the
working group. A comprehensive review of the literature was hereafter
conducted.
Results: Sertraline and citalopram are first-line treatment among
selective serotonin reuptake inhibitor for depression. It is recommended
to use lithium for bipolar disorders if an overall assessment finds an
indication for mood-stabilizing treatment during pregnancy.
Lamotrigine can be used. Valproate and carbamazepin are
contraindicated. Olanzapine, risperidone, quetiapine and clozapine can
be used for bipolar disorders and schizophrenia.
Conclusion: It is important that health professionals treating fertile
women with a psychiatric disease discuss whether psychotropic drugs
are needed during pregnancy and how it has to be administered.
E. R. Larsen1, P. Damkier2,
L. H. Pedersen3, J. Fenger-Gron4,
R. L. Mikkelsen5, R. E. Nielsen6,
V. J. Linde7, H. E. D. Knudsen8,
L. Skaarup1, P. Videbech1
1
Department of Affective Disorders, Aarhus University
Hospital, Risskov, 2Department of Clinical Biochemistry
and Pharmacology, Odense University Hospital, Odense,
3
Department of Clinical Medicine – Gynecological/
Obstetric Ward Y, Aarhus University Hospital, Skejby,
4
Neonatal Ward, Sygehus Lillebælt, Kolding, Denmark,
5
Psychiatry in the Capital Region of Denmark, Psychiatric
Centre Copenhagen, Section 6211, Rigshospitalet,
Copenhagen, Denmark, 6Psychiatry, Aalborg University
Hospital, Aalborg, 7Psychiatry in the Capital Region of
Denmark, Psychiatric Centre Copenhagen, Affective
Ward 6203, Rigshospitalet, Copenhagen, Denmark and
8
District Psychiatry Center Psychiatric Center, Hvidovre,
Denmark
Key words: psychotropic drugs; pregnancy; breastfeeding; clinical guidelines; recommendations
Erik Roj Larsen, Department of Affective Disorders,
Aarhus University Hospital, Skovagervej 2, Dk-8240
Risskov, Denmark. E-mail: erlars@rm.dk
Accepted for publication July 6, 2015
Clinical recommendations
• Fertile women with a psychiatric disease should be advised before pregnancy whether psychotropic
drugs are needed during pregnancy.
• Valproate and carbamazepine should be avoided if possible for fertile women.
• If antipsychotics are needed, olanzapine is primarily recommended based on the amount of safety
data, but risperidone, quetiapine and clozapine can be used.
Additional comments
• This
is a literature review. More clinical studies are needed for risk estimation of the different
psychotropic drugs with long-term follow-up of the children.
Introduction
Drugs and pregnancy: general observations
Since the thalidomide scandal, the use of drugs
during pregnancy has been a sensitive and often
controversial topic among patients, politicians,
journalists and health professionals. This has been
reinforced in recent years along with the growth of
the internet and the development of our scientific
methods, resulting in a rapid stream of scientific
1
Larsen et al.
articles in the area. Particularly, the use of psychotropic drugs during pregnancy seems to attract
attention. For instance, in 2011, almost 100 new
scientific articles on the use of selective serotonin
reuptake inhibitors (SSRIs) during pregnancy were
published. These turned out to have far from
always consistent results. The communication of
such results to the individual patient/patient population will very often rest on personal conviction
and philosophy of life with regard to empathy and
risk perception. For the media, it is quite easy to
find unfortunate events and put them in relation to
an apparent inconsistency between professional
information sources and scientific messages.
Consumption of psychotropic drugs during pregnancy
The best Danish data show that between 4 and 9%
of all pregnant women fill at least one prescription
for an antidepressant during pregnancy (Sundhedsstyrelsen www.dkma.dk 2013). A Danish register-based study of more than 800 000 pregnant
women in the period from 1997 to 2009 showed
that 4183 (0.5%) pregnant women were treated
with a SSRI during pregnancy, while 806 (0.1%)
discontinued at least 3 months prior (1). There are
insufficient data for other psychotropic drugs. The
total use of prescription-only medicine during
pregnancy is widespread. A Danish population
study concerning North Denmark Region showed
that the share of first-time pregnant women filling
at least one prescription during pregnancy
increased from 55% to 61% over a 9-year period
from 1999 to 2009 (2).
The perception of teratogenic potential
Congenital abnormalities are common among all
newborns. If everything is included, from small
and harmless abnormalities such as webbing of fingers or toes (syndactyly) to severe and life-threatening abnormalities with abnormal development
of the brain (anencephaly), the incident is approx.
3–4% Therefore, the possibility of a coincidence
between malformation and medication is present,
thus without the causality being proven.
The risk of abortions and malformations
The background frequency of congenital malformations and other unwanted pregnancy outcomes,
such as miscarriage, premature delivery, low birth
weight, neonatal failure to thrive and possible
impact on the child’s later development, is not
always well defined. For practical aspects, it may,
however, be assumed that the frequency of con2
genital malformations in the population, as mentioned, is about 3–4% (3, 4), and that the
incidence of miscarriages in Denmark in women,
who know that they are pregnant, is around 15–
20% (5). However, more recent numbers with a
more stringent definition of severe malformations
reduce the background frequency to around
2.5%, according to statements from the European
Surveilliance of Congenital Abnormalities,
EUROCAT (http://www.eurocat-network.eu). But
this estimate represents a certain under-reporting.
The actual frequency of drug-induced congenital
malformations is unknown. Schardein has
attempted to estimate the risk and finds that less
than 1% of all congenital malformations are
caused by medicine (3).
The risk of not treating a psychiatric disorder during pregnancy
About 10–15% of all pregnant women experience
a depression during pregnancy. The risk of depression seems to be greatest in the last two-thirds (second and third trimester) of the pregnancy. Women
previously known with depressive disorder have an
increased risk of depression in connection with
pregnancy. Pregnancy appears to increase the risk
of anxiety, as 10–30% of pregnant women experience such symptoms. In one-third of the persons
diagnosed with obsessive-compulsive disorder
(OCD), the condition worsens during pregnancy
and immediately thereafter, just like the prevalence
of depressive disorder is higher. Some studies find
that approximately 35% of pregnant women with
a bipolar disorder experience relapse despite medical treatment, whereas 85% experience relapse
without drugs, primarily in the shape of depressive
episodes or mixed episodes with both manic and
depressive symptoms at the same time.
Aims of the study
As we wanted a guideline with a high degree of
consensus among health professionals treating
pregnant women with a psychiatric disease, we
asked the Danish Psychiatric Society, the Danish
Society of Obstetrics and Gynaecology, the Danish
Paediatric Society and the Danish Society of Clinical Pharmacology to appoint members for the
working group. A comprehensive review of the literature was hereafter conducted.
Material and methods
The amount of available knowledge about the
adverse effects of the individual drugs during pregnancy varies greatly depending on the drug’s indi-
Psychotropic drugs during pregnancy and breast-feeding
cation area and for how long it has been marketed.
Casuistic reports only have limited value and cannot demonstrate causal relations, and therefore,
useful data about drug exposure and pregnancy
outcome must be provided through epidemiological studies. Cohort studies, case–control studies
and systematic pharmacovigilance can provide
valuable information. However, none of these
methods are ideal, and the scientific quality of data
will typically vary a great deal. The controlled
prospective cohorts, where the data quality is the
highest, are usually small and insufficient to serve
as a basis for meaningful risk estimation. Therefore, the assessment will often include data, where
doubt can be raised as to the drug dose and duration of the exposure (3, 6, 7), for example unpublished (but typically available to the public) data
from, for example the Swedish Birth Register (8),
various international abnormality registers and
unpublished large cohorts such as Michigan Medicaid (9). A scientific rigorous approach to data will
mean that the attending doctor in most situations
will be left with a limited basis for decision when
choosing a drug for a pregnant patient. Thus, the
total data volume often represents a certain necessary compromise between quality and quantity. In
addition, the predictive value of reproductive animal studies is unknown, and the interpretation of
these is quite complex (3, 6). Therefore, these are
not included to a greater extent in the current
guidelines which are based on human studies.
Risk assessment on the basis of available data
How many first trimester exposed without detectable signal do we require before we consider a drug
to be safe? Consensus does not exist in scientific
societies or from regulatory authorities as to which
level of certainty is acceptable. Using historical
data for the background frequency (applied value:
3.5%) of congenital abnormalities, it is possible to
roughly estimate the following (7, 10):
i) 200 exposed in the first trimester without signs
of excess incidence of malformations provide a
good certainty (80% power and 5% level of
significance) that the real risk is not more than
three times higher than the background risk;
ii) 700 exposed in the first trimester without signs
of excess incidence of malformations provide a
good certainty (80% power and 5% level of
significance) that the real risk is not more than
two times higher than the background risk;
iii) 2000 exposed in the first trimester without signs
of excess incidence of malformations provide a
good certainty (80% power and 5% level of sig-
nificance) that the real risk is not more than 1.5
times higher than the background risk.
If certainty for an even lower risk is demanded,
it will require data for many thousand first trimester-exposed pregnant women. Such data are, however, only available for very few medical products.
FDA’s classification system, which is under a fundamental restructuring (11), has operated with a
very conservative algorithm for the classification
of drugs for use during pregnancy. This has led to
a very low practical applicability of the formal regulatory classification, as only around 30 medical
products have achieved the classification ‘can be
used during pregnancy’ (12).
The above estimates apply to the general risk;
for specific rare malformations, considerably more
cohort data are needed, and these kinds of specific
malformations are therefore typically described in
case–control studies. Neonatal complications and
long-term effects are not included in the above considerations. One example is that in the 1940s,
diethylstilbestrol exposure in utero was found to
lead to an increased risk of uterine cancer, when
the child had become an adult (13).
Classification strategy
In this document, the decision as to whether a drug
may be used during pregnancy without significantly increased risk of malformations is primarily
based on the criteria in EMAS’s guideline. These
recommendations, which are discussed in detail
above, mean in general the following:
i) As a rule, the guideline demands data on at
least 1000 pregnant women without signs of
excess incidence of congenital malformations
to recommend a drug during pregnancy.
ii) In the cases where this data volume is not
available, the recommendations are basically
arranged according to the available amount of
data.
iii) There may be justified deviation from the
above.
The risk of other unwanted foetal impacts is discussed on an ad hoc basis. Data are primarily
obtained from peer-reviewed publications, but in
some cases supplemented with unpublished, but
well-documented available exposure data from the
Swedish Birth Register www.janusinfo.se.
Drugs and breast-feeding: general observations
All drugs under approx. 1000 kDa transfer into
the breast milk. In modern mother-and-child
3
Larsen et al.
medicine, risk assessment in connection with
breast-feeding is primarily based on a quantitative
estimate: how much medication is transferred to
the child during breast-feeding? In the overall
assessment, however, importance is also attached
to available information about possible/probable
side-effects in nursed children.
The quantitative estimate can be expressed as a
relative infant dose (RID). This is calculated on
the basis of measurements of drug concentrations
in breast milk, preferably at different maternal
doses of the given drug. Based on the highest concentration, the child’s exposure is now estimated as
a weight-adjusted percentage of the mother’s exposure. In these estimates, the child is assumed to
consume 150 ml breast milk per kg per day.
Regarding nortriptyline, which has a relative
weight-adjusted dose of 1%, it is possible to calculate the following:
i) dose of the mother: 100 mg/70 kg = 1.4 mg/
kg;
ii) exposure of the child: 1% of 1.4 mg/
kg = 0.014 mg/kg;
iii) thus, a 5-kg child will be transferred a total of
0.07 mg nortriptyline per day through the
breast milk.
Milk–plasma ratio is unfit to contribute with
meaningful risk assessment and is an obsolete
parameter. In contrast to use during pregnancy,
there are no regulatory guidelines indicating criteria for an acceptable exposure of nursed children.
Internationally, no formal consensus exists either.
As a point of departure, a RID below 10% is
considered compatible with breast-feeding. Most
drugs have a RID below 1% (14). The decision
algorithm is modified in practice by observation of
probable side-effects; drugs with undesirable properties regardless of RID (antineoplastic drugs;
immune-modulating drugs); or drugs with a very
long half-life (risk of accumulation). Finally, it
must be added that regardless of RID, a possible
hypersensitivity in the child towards a given drug
can of course contraindicate the use of it.
Specifically in relation to patients with mental illness
It is a fundamental consideration that exposure
during breast-feeding can be avoided by not
breast-feeding. As a rule, breast-feeding should in
general be established, but in relation to this
patient population, circumstances in clinical practice can speak against breast-feeding, even though
no risk is estimated to be connected with the child
being exposed to the drug via the breast milk in
accordance with the following section. For severely
4
depressed or psychotic patients, breast-feeding can
thus in practice be impossible or even dangerous
for the child.
Disturbed sleep increases the risk of relapse in
many psychiatric disorders. Therefore, it is important that mothers with a mental disorder are
ensured a good circadian rhythm and a good
night’s sleep. This speaks in favour of discontinuing
breast-feeding and of formula feeding the child.
Classification strategy
As a rule, this guideline uses data from Medications and Mothers’ Milk 2012 (14) for the purpose
of quantitative estimates. In certain cases, data
may be supplemented with data from peer-reviewed publications. As a rule, this guideline only
recommends breast-feeding when RID is below
5%, and any deviations from this are specifically
substantiated.
Results
Non-pharmacological intervention
Specific information about the mental condition
can help break the isolation and anxiety often felt
by the affected individuals. If suspecting symptoms
in the mother, an assessment by her own medical
doctor or treatment offer in the municipality
should take place. If depression, severe anxiety,
OCD or psychotic state is suspected, referral is
given to psychiatric evaluation and treatment.
Depending on the severity, the treatment takes
place either in a private practice or at the hospital.
Obstetric wards have established ‘vulnerability
teams’ to help in this situation across Denmark.
When the treatment is initiated, it should first be
assessed if talk therapy can help. Talk therapy may
be the best solution for some conditions to eliminate or reduce the symptoms and to improve family life and the relationship to the unborn child. If
there is no improvement or prospects of improvement with talk therapy, medical treatment must be
introduced. By medical treatment, both supporting
conversations and information are important parts
of the total treatment.
Cognitive and interpersonal therapy has a certain effect on depression. Cognitive therapy can
also be used to treat anxiety and OCD.
Pharmacological intervention
Depression. About 20% of the Danish population
will develop a depression at some point in their
lives. The depressive phase can be divided into
Psychotropic drugs during pregnancy and breast-feeding
varying degrees of severity: mild, moderate and
severe depression where the development can happen acutely in a couple of days or come slowly during months.
In a mild depression, the person is marked by
sadness and fatigue. Sleep disorders may be present in a mild degree, and the interest in, for example, hobbies, studies or work can be slightly
reduced. At this stage, most people are still able to
maintain some study activity or do a job.
In moderate depressions, the low spirits, the fatigue, the sleep disorders and the loss of interests are
more pronounced. The ability to concentrate will
be reduced, and the desire to go to work or to
school will disappear. Some people choose to isolate themselves at home, because they cannot cope
with going out and be among other people, but
also because they lack energy. Things that are used
to make them happy no longer have the same
effect. The depressed person often has thoughts
about death and accidents, some have thoughts
about suicide and are tormented by self-recrimination and guilt. Typically, they have a pronounced
feeling of despair and lack of self-esteem. Likewise,
the sexual desire can also be reduced. The individual can have a tendency to cry a lot, but can also
be tormented by irritability, anger and anxiety.
The appetite may be reduced, but the opposite –
eating for comfort – is also seen.
In the severe depressions, the depressed person
is unable to take care of himself and must often be
assisted in even the most basic tasks. Some are
paralysed to the extent that even facial expressions
disappear and they may stop eating and drinking.
Severe memory problems and poor concentration
are observed. In some cases, delusions and hallucinations emerge, and some persons feel such a pronounced despair that they will attempt to commit
suicide.
The risk of not treating depression in pregnant
women. Historically, a pregnancy, which by most
people is considered to be a happy circumstance, is
believed to protect against mental illness. However, this cannot be substantiated. On the contrary,
it is now generally accepted that pregnant women
have a greater risk of having a depression than
non-pregnant women. About 10–15% of all pregnant women experience a depression during pregnancy. The risk of depression seems to be greatest
in the last two-thirds (second and third trimester)
of the pregnancy. About half of these conditions
will continue after the birth of the child (15).
Women previously known with depressive disorder have an increased risk of depression in connection with pregnancy and in the period immediately
after the birth of the child. The use of prophylactic
treatment with antidepressants during pregnancy
has shown to reduce the risk of relapse from about
70% without prophylactic medical treatment to
approximately 25% with prophylactic medical
treatment (16). Psycho-social and biological factors in connection with the pregnancy probably
play a role in the emergence of the depression, but
clinically, the depressive symptoms do not differ
significantly from the symptoms of non-pregnant
women.
Depression in pregnant women does not only
pose a direct risk to the woman, but also to the
unborn child. Untreated depression in pregnant
women has been linked to an increased risk of
abnormal bleeding during pregnancy, miscarriage,
premature birth, foetal death, pre-eclampsia and
other birth complications as well as the child’s failure to thrive after the birth and decreased breastfeeding initiation (17).
For the woman, the illness can result in poor
nutritional condition, increased alcohol and
tobacco consumption, other unhealthy habits of
life, suicide-related behaviour and regular suicide
attempts (18–20) as well as a poor utilization of the
offers of the pregnancy care. All these factors can
cause harm to her unborn child. Suicide among
pregnant women is rare, but a British study
showed that of all the women who died during
pregnancy, 28% committed suicide (21). Also
abnormal biological factors (e.g. increased concentration of adrenocortical hormone), which are seen
in at least half of the depressed patients, are suspected to be harmful to the foetus, partly by affecting the brain development in the foetus in a
negative way, partly by the fact that the foetus will
later be hypersensitive to stress factors. Thus, an
increased prevalence of depression is shown in 18year-old children of mothers who were not treated
during pregnancy for their depression (22). In children exposed to antidepressants during pregnancy,
no signs of behavioural or emotional problems
were detected when assessed at the age of 4–
5 years. Untreated depression during pregnancy
appears to increase the risk of behavioural problems in the child (23). Finally, a depression which
continues after the birth will affect the mother’s
ability to take care of her child.
Medical treatment of women of child-bearing age with
depression. It is important that medical doctors,
midwives and other healthcare professionals are
aware of any depressive symptoms in pregnant
women. This applies in particularly to women with
a previous depression. According to the guidelines
in the field of the Danish Health and Medicines
5
Larsen et al.
Authority, the possibilities of psychotherapeutic
treatment should always be considered in depression in pregnant women (24). Medical antidepressive treatment can in some cases be necessary and
justified, for instance in case of a severe depression
or in case of high risk of recurrence of the depression if an already initiated medical treatment is discontinued. According to the Danish Health and
Medicines Authority’s guidelines, the treatment
should take place in consultation with a specialist
in psychiatry. The potential benefits and the harmful effects must be balanced against the risk an
insufficiently treated depression poses to the woman
and her unborn child. Moreover, the treatment of
pregnant women with antidepressants should in
Denmark observe the guidelines in the field of the
Danish Health and Medicines Authority.
Anxiety and OCD. About 10–15% of the Danish
population will have a severe anxiety disorder during their lives. These disorders are more frequent
in women than in men and are divided into a number of different types. Social phobia is characterized
by severe nervousness and anxiety if the person
must be together with others. Others experience
anxiety in specific situations, for example when
they have to sit for an exam or speak in front of a
group. Some people will experience panic disorder,
where the anxiety is completely unexpected and in
short-term attacks. Others suffer from agoraphobia, which is characterized by fear to leave home,
to take the bus, to take the train, to be in crowds
or to be alone at home. Even others suffer from
generalized anxiety disorder with constant nervousness and worry.
Obsessive-compulsive disorder is an anxiety disorder which may consist of obsessive thoughts
and/or patterns of compulsive behaviour and
which may vary a lot in terms of both the symptomatology and how much it affects everyday life.
Doubt and uncertainty are key parts of the disorder and can be seriously disabling.
Obsessions are often dramatic, unpleasant
thoughts occurring over and over, causing anxiety,
stress and perhaps feelings of guilt and self-recrimination. Compulsions may consist of washing rituals, compulsion to check, rituals of counting and
visualizing (mental compulsive behaviour), and
that you need to think positive (mental obsessive
thoughts), to manage and organize things in certain ways, symmetry and superstitious rituals.
The risk of not treating anxiety and OCD in pregnant
women. Pregnancy appears to increase the risk of
anxiety, as 10–30% of pregnant women experience
such symptoms. Approximately 4% of pregnant
6
women without previous OCD show signs of OCD
6 weeks after the birth (25). In one-third of the
persons diagnosed with OCD, the condition worsens during pregnancy and immediately thereafter,
just like the prevalence of depressive disorder is
higher (26). Persons diagnosed with OCD appear
to have a prolonged birth and several obstetric
complications (27) as the woman can be so tormented by anxiety or OCD that she is unable to
give birth vaginally. After the birth, OCD can be
seen in, for example, the mother refraining from
bathing or taking care of the child, because she is
abnormally afraid to harm it. Violent fantasies
aimed at the child may appear leading to a tormented and concerned mother fearing she will act
on these fantasies. This is in contrast to the psychotic person who does not worry about this. Both
anxiety and OCD can be treated with good results
with evidence-based psychotherapy. In a few cases,
the treatment with an antidepressant may be indicated. In very rare cases, combination with an
antipsychotic drug may be indicated.
Treatment with SSRI antidepressants
Recommendations. Planned pregnancy and start-up
during pregnancy.
i) Prescription and control of the patient’s treatment should ideally be performed in collaboration with a specialist in psychiatry.
ii) Sertraline and citalopram are first-line treatment among SSRI. The advantage of sertraline is that the treatment apparently can be
continued during breast-feeding without problems.
iii) Fluoxetine is not first-line treatment despite
the highest amount of data, among other
things because of casuistic reports on neonatal
death, and because the drug is released slowly
in the body of the newborns.
iv) Paroxetine may be associated with an
increased prevalence of malformations as well
as neonatal complications and is therefore not
recommended.
v) Escitalopram is not found to constitute any
problems during pregnancy.
vi) Fluvoxamine is not recommended due to limited or no data.
Pregnancy occurring during an existing treatment with
SSRI.
i) Ideally, the patient should be assessed by a
specialist in psychiatry.
ii) In case of pregnancy during an existing
treatment with fluoxetine, change is only
Psychotropic drugs during pregnancy and breast-feeding
recommended if it is considered to be safe in
relation to the patient’s disease.
iii) Regarding treatment with escitalopram, the
treatment can be continued during pregnancy.
iv) Regarding treatment with fluvoxamine,
change to another treatment is recommended,
but only if it is considered to be safe in relation
to the patient’s disease.
v) Paroxetine treatment should only continue
under extraordinary strict indication.
Birth. In treatment with SSRI up to birth, there is
a risk of neonatal complications. These need normally no treatment. Studies have shown an
increased risk of persistent pulmonary hypertension, which, however, occurs very rarely. Overall,
outpatient birth is not recommended, and the parents should receive information about typical
symptoms in the child, so that the child can be
observed and the right treatment initiated. Discontinuation of SSRI is not recommended, if the treatment is still indicated.
Breast-feeding.
i) It is important to be discussed with the pregnant women whether she wants to breast-feed.
In some cases, formula feeding is a good
alternative.
ii) If breast-feeding is wanted, sertraline and
paroxetine are recommended, as these two
drugs have the fewest reported side-effects and
the smallest transfer into the breast milk.
iii) There are casuistic reports of accumulation of
fluoxetine in nursed children, and most reports
on symptoms by use of fluoxetine and citalopram, which are therefore not recommended.
However, in connection with treatment during
pregnancy, the treatment can continue during
breast-feeding provided that information
about possible side-effects in the child is given.
In particular, one must pay attention to lack
of wellbeing, and whether the child achieves
the expected weight gain. In cases of doubt,
the drug can be measured in the child’s blood.
iv) Escitalopram and fluvoxamine are not recommended due to limited or no data.
Advice for pregnant woman not already in
treatment. When advising a pregnant woman
about antidepressive treatment of depression, the
decision is simple in case of mild as well as severe
illness: mild cases should not be treated with drugs
(24), and in severe cases, medical antidepressive
treatment is inevitable. It is the middle group which
causes problems and where non-pharmacological
treatments of course should be considered first,
namely the possibility of evidence-based psychotherapeutic treatment, that is with interpersonal
therapy or cognitive therapy. If this is not sufficient
or possible, the above points should be discussed
thoroughly with the woman, so she can make her
choice on the best basis possible. In particular, it is
important to inform about the risk of congenital
abnormalities in all circumstances, also without the
use of medical treatment. So if the woman chooses
to take drugs and later gives birth to a child with a
birth defect, it does not have to be due to her
choice, but may have occurred anyway.
From everything we know, the problem is particularly heart malformations, but number needed
to treat, one to harm is high. Paroxetine and perhaps also fluoxetine are considered to be the most
risky. Newer drugs should be avoided as we have
at least knowledge about those. With regard to fluoxetine, it should be remembered that it should
not be taken by breast-feeding women due to the
risk of accumulation in the child.
If the woman has previously had an effect of a
particular drug and nothing in particular speaks
against this substance, it should be used. The risk
of neonatal complications should be mentioned, so
that the woman is prepared for them, and in particular, the increased risk of persistent pulmonary
hypertension (PPHN) should be mentioned,
because this complication, although rarely, may be
fatal.
Advice for woman who is in medical treatment, and
who wants to be pregnant. In good time, it should
be considered with the woman if there should be
an attempt to phase out the treatment. These considerations should, among other things, contain an
estimate of the risk of recurrence, how severe the
depression was when it was worst and whether the
woman was suicidal. If the woman has previously
tried to phase out her treatment and it lead to
recurrence, it may speak against trying to phase
out. Also, residual symptoms in spite of treatment
predict recurrence of the depression when phasing
out.
If you choose to phase out, the woman should
be offered careful follow-up to provide quick assistance in the event of recurrence. If the woman is
treated with paroxetine, and phasing out is contraindicated, she should be switched to another
SSRI as an attempt, in accordance with the above.
Some women are treated with several different psychotropic drugs at the same time, for example an
antidepressant and an antipsychotic as a sedative.
Such treatment should as far as possible be simplified to include only one single SSRI [or possibly
7
Larsen et al.
one single tricyclic antidepressant (TCA)], because
it is not possible to predict how several different
substances will interact in the growing foetus.
A routine phasing out of SSRI 2 weeks prior to
the birth to avoid neonatal complications is not
recommended (28, 29).
Advice to woman already in treatment, who discovers
she is pregnant. The decision about what to do
depends on for how long the woman has been
pregnant when she discovers that she is pregnant.
Often, she will be well through the first trimester,
and the risk of severe malformations must be
assumed to be over. Therefore, there will be no
reason to stop the treatment. However, the risk of
PPHN still persists. Therefore, some authors recommend that the drug which the woman is already
treated with is continued to not risk recurrence if
the treatment is changed.
Background
The effect of selective serotonin reuptake inhibitors
(SSRI) for the treatment of depression, OCD and
anxiety is scientifically well documented. Cognitive
therapy and interpersonal psychotherapy are also
well documented in non-pregnant women, and a
few studies have shown they are effective in pregnant women too. Therefore, these types of therapies are in principle preferred in mild to moderate
depression and in anxiety disorders in pregnant
women instead of medical treatment. One of the
problems, however, is that they are often not easily
accessible, among other things, due to a lack of
qualified therapists. In addition to this, not all
respond to psychotherapy. In many studies, the
success rate in non-pregnant women is around
60%. It also often happens that women already in
antidepressive treatment want to become pregnant.
Or that the woman who is treated with SSRI discovers that she is a few weeks to months into her
pregnancy. The general practitioner, obstetricians
and psychiatrists will therefore often have to
advise pregnant women about such a treatment.
What risks are present?
It is well known that the incidence of miscarriages
and stillbirths can be influenced by, for example,
medication intake during pregnancy, even though
it normally occurs very rarely. There may be
neonatal complications, and a relatively new area
is the so-called behavioural teratology, that is
whether the child’s motor, intellectual and
emotional development can be influenced by drugs
given during pregnancy.
8
On the other hand, a number of studies indicate
that untreated depression in itself may harm the
unborn child. However, none of the SSRI drugs
are categorically recommended for the treatment
of depression during pregnancy. All of these drugs
should only be used if the benefits for the pregnant
woman (and her unborn child) outweigh the
potential side-effects.
Miscarriages and stillbirth
It is estimated that around 20% of all pregnancies
end up with a miscarriage, but it is difficult to
assess for certain, as many miscarriages are so
early that they can be confused with a late coming
period. Moreover, the risk depends on the
woman’s age and lifestyle. The frequency of miscarriages, where the woman knows that she is
pregnant, is about 15–20%. The results concerning
the impact of SSRI on the frequency of abortion
are not clear (30).
An important study of 937 women who took
SSRI during pregnancy, compared with a similar
number who did not, showed 13% abortions in the
SSRI group against 8% in the control group (31).
Other studies suggest something similar (32). The
studies are not without methodological problems.
For instance, in the first mentioned study, there
were more smokers and more women who had previously had miscarriages in the group of women
who took SSRI than in the control group.
Possibly, the increased incidence of miscarriage
is specifically associated with paroxetine and venlafaxine. To be on the safe side, the woman, when
advised about choice of treatment, should be
warned about the risk of miscarriage possibly
being increased. In two large studies from Norway
and Denmark, SSRI during pregnancy was not
associated with significantly increased risk of stillbirth or neonatal death (33, 34). A large Danish
register study from 2013 with more than 1 million
pregnancies found a slightly increased risk of miscarriage by the use of antidepressant drugs during
pregnancy, but this risk could not be replicated
when age and mental illness were taken into
account. Hence, no increased risk was found in
using SSRI in pregnant women with depression
compared to women with untreated depression
(35).
Congenital malformations
There are many statements, the majority of epidemiological nature, which shed light on the risk
of congenital malformations in children exposed to
SSRI during pregnancy. These are rather heteroge-
Psychotropic drugs during pregnancy and breast-feeding
neous both in terms of quality and quantity of data
as well as definitions of exposure and outcome.
Therefore, it is difficult to get an overview of
methodological details, multiple stratifications,
odds ratios and incomparability between these
studies. Thus, here comes a short summary of the
largest and best statements:
A very large meta-analysis was published in
2013 (36). More than 50 000 SSRI-exposed pregnant women were included, and no overall
increased risk of congenital abnormalities was
found, RR 0.93 (CI: 0.85–1.02) In studies with outcome data for cardiovascular malformations
including a total of more than 20 000 SSRI-exposed pregnant women, a slightly increased risk
was found, RR 1.36 (CI: 1.08–1.71). A significant
part of this signal is carried by septal defects, RR
1.40 (CI: 1.10–1.77). Some studies – but not all –
have shown a specific increased risk of heart malformations by paroxetine and fluoxetine exposure.
In the meta-analysis, a signal specifically for paroxetine, but not for fluoxetine, was found. Even
though there is no consensus as to whether this is a
real signal, most recommend avoiding these two
drugs during pregnancy. However, there may be
clinical cases where switching treatment from a
current effective treatment with paroxetine or fluoxetine is not rational, because the risk for the
mother with a drug change is greater than the
hypothetical risk for the foetus.
Some important specific studies (all of which are
included in the above meta-analysis) must be
mentioned.
Very large Swedish and Finnish studies show
that if SSRIs are resulting in malformations, they
are located at the heart (37–39). However, this difference is not statistically significant compared to
the background population (40). Heart malformations in general were not found more frequently
than you would expect, but atrium and ventricular
septal defects were more frequent. Among nonmedicated women, the risk was 0.5%, whereas it
was 0.8% among those taking SSRI. Number
needed to treat, one to harm, (NNH) was calculated
to 246. This means that more than 246 women
must be treated with SSRI to cause one additional
case of septal defect. In addition to this, a number
of these are asymptomatic. It cannot be ruled out
that many septal defects were only found, because
the foetuses known to have been exposed to SSRI
during pregnancy were examined extra carefully.
In a methodological elegant Danish register
study, the frequency of heart malformations of the
4183 children exposed to SSRI was compared with
the frequency of children whose mothers had previously been taken SSRI, but who discontinued with
the drug prior to pregnancy and resumed treatment
after the birth. The risk of heart malformations was
increased equally for both groups (1). This suggests
confounding by indication or selection bias, which
means that the abnormalities were not caused by
the SSRI exposure, but by other factors, which are
common for the women who took the drug and the
women who discontinued the treatment. A large
pharmacoepidemiological study from the USA
with 65 000 pregnant women who have used
antidepressants in the first trimester has found no
increased risk of cardiac malformations (41).
Reduced foetal development and premature birth
Some studies, but not all, suggest that the treatment with SSRI during pregnancy can lead to premature birth and that children born at term are
smaller. However, it is difficult to estimate as some
studies show that untreated depression in itself
may result in premature birth and low birth
weight. To be on the safe side, however, information about the risk should be provided (42, 43).
Complications in connection with the birth
Between 15 and 30% of children whose mothers
have taken a SSRI in the last time up to the birth
will hours to days after birth show symptoms,
which possibly are discontinuation symptoms (44).
These comprise, among other things, irritability,
quivering, limpness, and trouble to suck or sleep.
Spasms have also been seen (36). The symptoms
cease spontaneously and require generally no treatment, but serious cases requiring treatment, however, occur. The significance of the symptoms is
first and foremost that they can be confused with
similar symptoms of serious diseases, such as low
blood glucose and brain damage, and there may be
problems in relation to the establishment of breastfeeding or mother-and-child bonding. Therefore,
in some obstetrics wards, the children are observed
for about 24 h, before mother and child are discharged. If the symptoms are especially pronounced, you can choose to observe the child in a
neonatal ward. A Danish study of children born to
SSRI-treated mothers showed lower average
Apgar score and a higher degree of hospitalization
on neonatal wards for these children compared
with control children (45). A Danish register study
from 2013 shows that the use of SSRI increases the
risk of low Apgar score independent of the
mother’s depression (46). In principle, the symptoms can occur in connection with all types of
SSRI, but one study has found paroxetine to be
particularly frequently associated with these (47).
9
Larsen et al.
The woman should be informed about the risk that
the child can have these symptoms, and what she
should do in this case. A register study of more
than 120 000 newborns from the period 1998 to
2001 showed no effect on the newborn child’s
health by reducing exposure to SSRI towards the
end of the pregnancy (29).
Persistent pulmonary hypertension (PPHN)
In the minutes after the birth, a number of changes
occur in the child’s circulatory system. This process is controlled, among other things, by prostaglandins, and it is expected that serotonin outside
the central nervous system also participates. This
may be due to the properties of this substance on
blood vessels. A number of aspects and diseases
can interfere with this important process. Maldevelopment of the lungs, diaphragmatic hernia and
meconium aspiration can thus among many diseases and conditions result in PPHN, but studies
indicate that the risk is increased if the mother is in
treatment with SSRI after the 20 pregnancy week.
The symptoms appear immediately after the birth
and include dyspnoea and cyanosis. The condition
can often be treated, but is serious and potentially
life-threatening.
A recent population-based cohort study from
the Nordic countries comprised 1.6 million newborn babies born after pregnancy week 33. The frequency of PPHN among non-exposed children was
1.2 per 1000, whereas among children exposed to
SSRIs after week 20, it was 3 per 1000. This gives
an adjusted odds ratio of 2.1 (95% CI 1.5–3.0).
The risk was increased roughly in the same degree
for all types of SSRI, which implies that it is a class
effect (48). Other small studies have also pointed to
an increased risk of this condition. A new metaanalysis of PPHN showed that early exposure to
SSRI does not increase the risk, whereas exposure
late in the pregnancy (after week 20) increases the
risk by a factor 2.50 (95% Cl 1.32–4.73), the absolute frequency was 2.9 to 3.5 per 1000 newborns,
which lead to NNH being between 286 and 351
(49). The increased risk can probably be eliminated
if the mother can do without SSRI in, for example,
the last month before the birth. However, the
problem is that the risk of relapse is increased just
as she is about to give birth.
Brain development and emotional development
In experimental animal models, primarily for
rodents, SSRI affects the early brain development.
A prospective study of 99 pregnant women who
10
used SSRI and 570 pregnant women with depressive symptoms who took no antidepressive drugs
showed that untreated depression was associated
with lower rate of growth of the foetus’ body and
head, whereas the treated women’s foetuses had
less growth rate of the head, but not of the rest of
the body. The difference between the head size of
the two groups was, however, only 4 mm (50). A
small MRI study of 33 children who had been
exposed to SSRI suggested that they had an
increased incidence of the so-called Chiari malformation type 1, which is caused by herniation of the
cerebellar tonsils into the spinal canal and which
may be asymptomatic or cause, for example headache. The result is interesting, but must be replicated before therapeutic consequences can be
taken (51).
Unfortunately, only few human follow-up data
for many types of antidepressants exist, but the
existing studies show no correlation between the
drug and the brain development of the foetus
measured with regard to intelligence development
and on a number of emotional and motor parameters. An American study (52) and a Danish (53),
however, found associations with slightly delayed
motor development. In a follow-up on the Danish
study, however, no correlation was found between
exposure to antidepressants and behaviour at the
age of 4–5 (23). The studies are difficult to interpret due to the many sources of error. For example, the depression in the mother, according to
several studies, can in itself delay the child’s development, and this effect cannot be distinguished
from the effect of the drug. Such a correlation
was found in the before-mentioned Danish study,
where maternal depression, probably after the
birth, was a predictor for the child’s behavioural
problems.
One study should be mentioned to illustrate
the problems of assessing such scientific results:
Croen et al. (54) studied 298 cases of Asperger’s
syndrome (AS) and found that 6.7% of the
women who had a child with this syndrome had
taken SSRI during pregnancy, whereas only
3.3% of healthy children’s mothers had taken
SSRI. This means that the frequency of AS
seems to have doubled if the mother took SSRI.
Fortunately, the risk of AS is very low: approximately 0.26 per 1000 children. So, even if the
risk is doubled, it is still very low. The authors
do not rule out that what they show is in fact a
genetic predisposition for AS: the women who
received treatment had psychological difficulties
due to Asperger features, which increased the
risk of depression or anxiety and subsequently
Psychotropic drugs during pregnancy and breast-feeding
SSRI treatment. At the same time, their children
had an increased risk of AS, as there is a considerable hereditary element in the disease. Another
possibility is that the children’s illness is caused
by the mother’s illness and not her treatment,
that is that her depression disturbed the development of their connection with other people. In a
Danish register study of more than 600 000 children, no link was found between exposure to
antidepressant drugs in utero and autism spectrum disorders (55). The problems relating to
change of the child’s behaviour during childhood
is important to be aware of in future, so that
new and more thorough studies can be designed
to obtain certain knowledge. Furthermore, it is a
major problem in the existing studies that the
child is only followed until it was 5–10 years old.
However, one study shows that the worser the
depressive symptoms the woman had during
pregnancy, the greater the risk that her child had
had a depression at the age of 18 (22).
Treatment with serotonin norepinephrine reuptake inhibitors
Recommendations. Planned pregnancy and start-up
during pregnancy. Venlafaxine and duloxetine are
not recommended as first-line treatment during
pregnancy. For venlafaxine, however, the data volume is extensive and meets the criteria, but cannot
match the number of studies of SSRI. The data are
insufficient regarding duloxetine.
Pregnancy occurring during an existing treatment. Venlafaxine is not recommended as firstline treatment during pregnancy. The same applies
to duloxetine. Ongoing clinical satisfactory treatment with venlafaxine should be continued. Ongoing duloxetine treatment should be changed.
However, if the woman has not previously
responded to other treatment, it calls for a continuation of the ongoing treatment.
Breast-feeding. As a rule, venlafaxine is not recommended as RID is around 7–8%, although
side-effects have not been described in the nursed
child. Duloxetine can be used as RID is around
1%. No side-effects have been described in
nursed children.
Background. There are only scarce data on the use
of these drugs during pregnancy. No studies have
been published of possible long-term effects on the
child after exposure in foetal life. One prospective
comparative study of 150 women using venlafaxine
(56) and a case series with 11 women have been
published, overall, without signs of teratogenicity
(57).
Regarding venlafaxine, Swedish data for more
than 1600 first trimester-exposed pregnant women
show no increased risk of unwanted foetal impact.
Regarding duloxetine, data exist for around 350
first trimester-exposed pregnant women (58–60).
There are casuistic reports on problems in newborns, but there are no comparative studies. Swedish statements of women who have used serotonin
norepinephrine reuptake inhibitors (SNRI) found
that the symptoms in newborns reminded very
much about those seen during treatment with an
SSRI. This study found no signs of teratogenicity,
but rather an increased risk of premature birth (61).
A large pharmacoepidemiological study from
the USA with 6900 women exposed to SNRI
found no significant increased risk of heart malformations in the child after checking for confounders
as physical illness in the mother (41).
Venlafaxine has been detected in the blood of
nursed infants without detectable effects on the
children. However, only data on a total of 12
exposed children have been published (62).
Treatment with noradrenergic
antidepressant (NaSSA)
and
specific
serotonergic
Recommendations. Planned pregnancy and start-up
during pregnancy. Due to inadequate data, mirtazapine and mianserin are not recommended during pregnancy.
Pregnancy occurring during an existing treatment. Mirtazapine and mianserin are not recommended during pregnancy. However, if the woman
has not previously responded to other treatment, it
calls for a continuation of the ongoing treatment.
Breast-feeding. Due to inadequate data, mirtazapine and mianserin are not recommended during
breast-feeding.
Background. Mirtazapine and mianserin exhibit
their antidepressant effect by impacting the
monoaminergic system in the brain. There are only
scarce data on the use of these drugs during pregnancy. No studies have been published on possible
long-term effects on the child after exposure during
pregnancy. In a prospective follow-up study of 104
women who took mirtazapine, but where 35% also
took another type of antidepressant drug, sedative
drugs or mood-stabilizing drug, there were no
signs of teratogenicity (63). Increased risk of
premature birth on a par with other antidepressive
11
Larsen et al.
drugs and increased risk of miscarriage were
found. But this may be a matter of confounding by
indication.
Treatment with tricyclic antidepressants
Recommendations. In general, tricyclic antidepressants are not recommended as first-line treatment
of a depression. The data volume for some TCAs
meets the criteria, but significantly more data exist
on the use of SSRI in pregnant women and women
breast-feeding.
Planned pregnancy and start-up during pregnancy. Tricyclic antidepressants (amitriptyline, clomipramine,
imipramine and nortriptyline) do not seem to be
associated with an increased risk of malformations.
The data volume of these drugs meets the criteria
stated in the introduction. The other TCAs cannot
be recommended due to scarce data.
Pregnancy
occurring
during
an
existing
treatment. Plasma monitoring of TCAs should be
carried out continuously during the pregnancy, for
example every 3 months, as there may be a risk that
the conversion of TCA is changed, so that concentration in the blood becomes higher than intended.
Birth. Tricyclic antidepressants are associated with
an increased risk of temporary impact on the child
just after the birth. The newborn child may present
with symptoms in the shape of increased crying,
constipation, problems with urinating and nausea.
Breast-feeding. RID for amitriptyline, nortriptyline, clomipramine and imipramine is about 1–3%.
No serious side-effects are reported in nursed children by maternal treatment with amitriptyline, clomipramine, imipramine and nortriptyline.
Background. Tricyclic antidepressants. Some of
the substances are chemically related. For example,
amitriptyline is metabolized to nortriptyline and
similarly, clomipramine and imipramine share the
same basic structure. Only scarce or no human
data have been published on the use of maprotiline
and dosulepin during pregnancy.
Previous studies suggested a possible association
between malformations of the extremities and the
use of clomipramine, imipramine, nortriptyline or
amitriptyline during pregnancy (64). Subsequent
studies, including three prospective and a large
case series, however, have not been able to confirm
the association. The studies are based on about
400 exposed, but with very different study design
(65). A Swedish register study of 14 821 women
12
treated with antidepressants finds that clomipramine leads to an increased risk (OR: 1.84) for ventricular septal defect and atrial septal defect (39).
But at the same time, it is stated that there may be
a confounding by indication, which is why it is recommended to avoid start-up in case of planned
pregnancy, whereas there is no reason to discontinue during a pregnancy. There are no signs of teratogenic effect of doxepin, which, however, is
based on scarce and unpublished data from a monitoring programme. Symptoms compatible with a
discontinuation reaction in newborns exposed to
imipramine or clomipramine are described. No
reports of symptoms after exposure to amitriptyline or nortriptyline are published. One case of urinary retention in a newborn child exposed to
nortriptyline in utero as well as one case of neonatal paralytic ileus after exposure to doxepin and
chlorpromazine in the third trimester is described.
There are a few studies concerning the development of children until preschool age, who during
pregnancy have been exposed to TCA (66). Two
studies have not been able to demonstrate impact
of IQ, language or behavioural development after
exposure to TCA. Within the group of TCAs, nortriptyline has been recommended, partly due to
less pronounced cholinergic effect, and partly due
to the fact that it is possible to measure the concentration in the blood and thus reliably determine
the right dose.
Amitriptyline, nortriptyline, desipramine and
clomipramine have not been found in the blood of
nursed infants, and no side-effects in the child are
described. Doxepin has been associated with symptoms of the child, including drowsiness and vomiting. Dosulepin is measured in breast milk as well
as in the blood of nursed children, but no side-effects in the child have been reported. Maprotiline
can be measured in breast milk, but otherwise only
scarce data are available. It is uncertain whether
TCA affects the brain development. There are no
signs of serious problems in their childhood after
exposure in the pregnancy assessed on the basis of
two studies with a total of 116 exposed (66).
Treatment with monoamine oxidase inhibitors. Not
recommended due to insufficient data.
Treatment with agomelatine. Not recommended
due to insufficient data.
Treatment with vortioxetin. Not recommended due
to insufficient data.
Bipolar affective disorder. At least 40 000
Danes are affected by bipolar affective disorder
Psychotropic drugs during pregnancy and breast-feeding
(previously called manic-depressive disorder). The
term ‘bipolar’ covers the disorder’s two poles, the
manic and the depressive pole. All people experience mood swings, but in the case of bipolar disorder, the mood swings are extreme and exaggerated.
This can result in behaviour, which can be socially
disabling or life-threatening. The disorder most
often appears at the age of 16–18 years or in the
early adulthood, and it affects an equal amount of
men and women. People with bipolar disorder are
often diagnosed many years after the onset of the
disease.
Persons with a bipolar disorder have a risk of suicide of 10–15%, and the symptoms are often accompanied by other mental problems such as anxiety
and abuse. Due to the cyclic phases of the disorder
and the risk of relapse, preventive mood-stabilizing
treatment will often be indicated. Untreated, the disorder often has serious consequences for the individual and the family in the form of serious financial,
work-related and social costs.
What is mania?. In the manic phase, the mood is
elevated, and the person is most often described as
being ‘all keyed up’ with abnormally elevated
energy level and as being socially flattering and
charming bordering towards a socially inappropriate behaviour with a lack of understanding of limits. The manic phase is divided into degrees of
severity: hypomania, moderate mania and severe
mania. Generally, mania can occur very suddenly
and develop either in a few hours or in a few
weeks.
In the hypomanic (mild manic) phase, the person is more active, committed and energetic than
usual. At the same time, the person is more optimistic, outgoing and speaks more. However, there
may also be an increased tendency towards irritability. Many people with bipolar disorder
describe the hypomanic state as being very productive and actually a good state to be in.
In a moderate manic phase, the symptoms
increase in strength. The person is hyperactive, has
several projects running at the same time, and is
restless and uneasy, and the need for sleep is often
decreased. There may be an increased ideation and
problems with sticking to one subject at a time.
The person can easily lose the thread and be distracted. Some people become more intrusive, irritable or angry if their many ideas are rejected. The
person is usually excited, has an increased self-esteem, may experience an increased sexual desire
and develop an increased spending of money without thinking about the consequences. In the same
way, some people begin to behave irresponsibly
and recklessly.
In the severe manic phase, the symptoms are
extremely pronounced: the person sleeps no more
than 3–4 h, is in constant activity, is out of control
and has a feeling of being invincible. The condition
can be associated with severe anxiety, but the person can also be threatening, aggressive and explosive. In some cases, there may be psychotic
symptoms such as delusions and hallucinations. In
untreated cases, a mania can result in so-called
acute delirium, which is a life-threatening condition in which the person is extremely troubled and
restless, the body temperature rises and the person
may lose a lot of fluid. At worst, the condition can
result in circulatory collapse and death.
The risk of not treating the bipolar condition in pregnant women. The risk of relapse of depression or
mania seems to be highest in month 4–9 of the
pregnancy. Some studies find that approximately
35% experience relapse despite medical treatment,
whereas 85% experience relapse without drugs,
primarily in the shape of depressive episodes or
mixed episodes with both manic and depressive
symptoms at the same time (67). If the mother is
not treated, the foetus can risk being exposed to
larger concentration of stress hormones, especially
if the patient with bipolar condition is destabilized.
Disorder breakout in the mother can have serious
consequences for her child, as it results in an
increased risk of excessive use of alcohol, tobacco
and illegal drugs, poor nutrition, sexually transmitted diseases, suicide, reduced maternal care for the
child and physical violence against the child (19,
68–71).
Medical treatment of women of child-bearing age with
bipolar disorder. The possibility of pregnancy
should always be discussed with this group of
women. Furthermore, psychotropic drugs specifically problematic during pregnancy, such as valproate and carbamazepin, should be avoided.
Evidence of the preventive effect is poor for valproate and carbamazepin, which is why they
should primarily be used in the treatment of acute
mania if other treatments have appeared to be ineffective or not tolerated (72). At the same time, it
must be ensured that the woman is not pregnant.
Valproate also increases the risk of polycystic
ovary syndrome, which can cause irregular periods
and infertility. Oral contraceptives should be taken
into consideration in the event of valproate treatment, partly to inhibit the development of polycystic ovary syndrome, partly as safe contraception.
At start-up and discontinuation of oral contraceptives containing oestrogen, it has to be taken into
consideration that the oestrogen increases the
13
Larsen et al.
breakdown of lamotrigine by approximately 50%.
Antipsychotics may increase prolactin and result
in infertility. This is specifically evident in connection with risperidone and typical antipsychotics,
but can occur in all antipsychotics (73).
Treatment with mood stabilizers
Recommendations. Planned pregnancy and start-up
during pregnancy.
i) Prescription and control of the patient’s treatment should be performed in collaboration
with a specialist in psychiatry, ideally in a specialist clinic in the regional psychiatric.
ii) Lithium is still a cornerstone in the treatment
of bipolar disorder, and as the absolute risk of
teratogenic damage is small, it is recommended to use lithium if an overall assessment
finds an indication for mood-stabilizing treatment during pregnancy.
iii) Valproate and carbamazepin are contraindicated during pregnancy due to the high risk of
neural tube defects.
iv) In bipolar disorder with primarily or exclusively manic episodes, lithium, olanzapine,
risperidone, quetiapine and clozapine can be
used. Alternatively perphenazine*.
v) In bipolar disorder with primarily depressive
episodes or without manic episodes during
many years, lamotrigine may be used. In general, use of doses up to 300 mg is recommended. Special caution is recommended in
the case of higher doses, where serum measurement is recommended each month.
vi) Antidepressants are generally not recommended in bipolar disorder, as the effect of this
is much debated.
Pregnancy occurring during an existing treatment. The patient should be assessed by a specialist in psychiatry. The indication for medical
treatment during pregnancy of women with bipolar disorder depends, among other things, on the
following factors:
i) The general evidence of the effect of maintenance treatment of various drugs.
ii) The generally increased risk of relapse/development of new episodes during and after
*After Trilafon (perphenazine) has been deregistered in Denmark,
patients can be treated with the similar drug Peratsin instead. The medical doctor may apply for general permission to prescribe Peratsin
‘Orion’ 2, 4 and 8 mg via the Danish Health and Medicines Authority
(http://laegemiddelstyrelsen.dk/da/topics/godkendelse-og-kontrol/
udleveringstilladelser). A copy of the permit is handed out to the
patient, and the pharmacist can then hand out the drug.
14
pregnancy with and without mood-regulating
drugs.
iii) Risk of teratogenic damage for the individual
drugs.
iv) The individual patient’s course of illness (time
of onset, current age, the number of illness episodes, type and severity of affective episodes,
any previous course of pregnancy).
v) Effect and possible side effects of mood-stabilizing drug for the individual patient.
On the basis of items 1–5, a professional assessment of the patient’s individual risk of affective
episodes vs. teratogenic damages is made, forming
the basis for the decision of the patient and spouse
regarding medical treatment during pregnancy.
Background. Pharmacological treatment of bipolar disorder during pregnancy is a highly specialized function, which according to the Danish
Health and Medicines Authority should only be
undertaken in specialist clinics for affective disorders. Guidance in medical treatment of pregnant
women requires thorough knowledge of the patient
and the specific illness course, of special risk factors and of the treatment. This should take place
in close cooperation with obstetrics wards.
Pregnancy does not protect against new episodes, and discontinuation of mood-stabilizing
drugs during pregnancy increases the risk of
relapse considerably (67). In principle, it is recommended to use the lowest possible effective dose of
mood-stabilizing drug as well as to use as few
drugs at the same time as possible. One must be
aware that an increase of dose often is necessary in
the third trimester, where the blood volume is
increased by approximately 30% (74). Plasma
monitoring is recommended, for example with
blood test every month, among other things
because several of the liver’s enzyme systems have
increased activity during pregnancy, which means
that for instance, lamotrigine breaks down more
quickly.
As the plasma volume and the kidneys’ filtration
speed are increased during pregnancy and normalized immediately after the birth, it means that it
may be necessary to increase the lithium dose during pregnancy and similarly reduce immediately
after the birth.
General evidence of the effect of maintenance treatment of various drugs. The evidence of maintenance treatment can be summed up on the basis of
new guidelines from the World Federation of Societies of Biological Psychiatry (75). Lithium is the
drug with the best evidence for a mood-stabilizing
Psychotropic drugs during pregnancy and breast-feeding
effect in bipolar disorder. Quetiapine has, as
lithium, shown mood-stabilizing effect in relation
to the prevention of depression, mania and mixed
episodes, whereas there is less evidence that olanzapine prevents depressive episodes. Aripiprazole
does not prevent depressive episodes, but only
manic and mixed episodes, like all other atypical
antipsychotics. Valproate is effective in the event
of acute mania, whereas the evidence of the preventive effect on mania is poor. Lamotrigine prevents in particular depressive episodes.
General risk of relapse/development of new episodes
during and after pregnancy with and without mood-stabilizing drugs. No randomized studies are available, which have compared the effect of moodstabilizing medical treatment versus no treatment
during pregnancy. However, there is a considerable risk of development of affective episodes during and after pregnancy.
During pregnancy. The largest and best conducted
study is from Viguera et al. In a prospective nonrandomized trial, they found that 71% of a total of
89 women with a known bipolar disorder developed a new affective episode during pregnancy
(67). Most episodes were depressive or mixed episodes, and 47% appeared in the first trimester.
Women who discontinued with medical treatment
immediately before pregnancy had two times
increased risk of developing new episodes and were
ill five times as many weeks during pregnancy compared with women who continued the mood-stabilizing medical treatment.
After pregnancy. A Danish register-based study
showed that 26.9% of women with known bipolar
disorder were hospitalized within a period of
1 year after the birth of the child. The greatest risk
of hospitalization was 10–19 days after the birth
(76). Patients with bipolar disorder have an
increased risk of developing a postpartum psychosis (77), particularly in the first 4 weeks after
the birth of the child. The risk of relapse is eight
times higher in the first months after the birth,
which increases the need for close follow-up and
support in this period. In the event of acute mania
during pregnancy, antipsychotics or ECT is used,
which does not affect the foetus inappropriately,
and which is described further in a later section.
Risk of teratogenic damage for the individual
drugs. Lithium: The risk of Ebstein’s anomaly
(right ventricular hypoplasia and displacement of
the tricuspid valve) in children is 1 : 20 000. In
children exposed to lithium in the first trimester,
the risk seems to be between 1 : 1000 and 1 : 2000,
which is 10–20 times increased compared to the
risk of the background population (71, 78–80), but
in absolute figures still a very small risk. A recent
meta-analysis published in Lancet identified 62
studies of possible teratogenic effects of lithium
(81). The risk of Ebstein’s anomaly was not statistically significantly increased among children
exposed to lithium compared to the risk among
unexposed children, but the estimate is uncertain
due to the low number of cases with Ebstein’s
anomaly. The article also refers to a case–control
study of children born with malformations in general, which did not find statistically significantly
more women treated with lithium in the malformation group (6 of 10 698) compared with the control
group of children without malformations (5 of
21 546) (82). Lithium must still be considered a
cornerstone in the treatment of bipolar disorder,
and as the absolute risk of teratogenic damage is
small, it is recommended to use lithium if an overall assessment finds an indication for mood-stabilizing treatment during pregnancy (83).
Antiepileptics: Generally, there is a correlation
between dose and the risk of malformations, which
is why it is important to evaluate whether the pregnant woman can be treated with a lower dose during pregnancy (84).
Lamotrigine: Lamotrigine used as monotherapy
appears to constitute a low risk (71, 85, 86), even
though a few reports as the North American
Antiepileptic Drug Pregnancy Register indicate an
increased risk of cleft lip and palate increasing
from 1 : 500 among the population to 1 : 120 (87,
88). The risk seems to be increased in a dose of
more than 300 mg/day (89, 90), as the risk of heart
malformations and hypospadias increases to 1%.
The plasma level of lamotrigine falls by 60–65% in
second to third trimester (90, 91) and should be
monitored closely during the pregnancy, for example with blood test every month. After the birth,
the serum concentration of lamotrigine increases
again. Prophylactic treatment with folic acid (5 mg
daily) should be initiated in case of pregnancy wish
to prevent neural tube defects. Treatment with
folic acid will continue in the first trimester (92). In
general, use of lamotrigine up to 300 mg is recommended. Special caution is recommended in the
case of higher doses, where serum measurement is
recommended each month.
Valproate and carbamazepine: The risk of neural
tube defect using carbamazepine over 1000 mg is
2% (90). When using valproate below 700 mg, the
risk of neural tube defects is 1% and over 700 mg
2%. When using over 1500 mg valproate, the risk
of multiple malformations is 7%, of heart malfor15
Larsen et al.
mations is 7% and of hypospadias is 5%. Valproate may possibly affect the foetal brain, and a
high association between valproate exposure in
utero and later risk of autism is found (93). The use
of valproate and carbamazepine is contraindicated
during pregnancy.
unshakable conviction which is considered unrealistic or impossible. The delusions are grouped
according to which theme they concerns, for example persecution, megalomania, physical illness etc.
A psychosis increases the risk of suicide, social isolation and exclusion from the labour market.
Breast-feeding. Lithium: RID is very high, between
12 and 30%. Nursed children achieve plasma
which is up to 24–72% of the mother’s (94). Use of
lithium during breast-feeding is usually not recommended, but the drug can be used under close
observation of the child and possibly guided by
measurements of the concentration of lithium in
the breast milk. Lithium can lead to dehydration,
exhaustion, hypotonia and electrocardiographic
changes in the child.
Valproate: Breast-feeding is possible. RID is 1–
2%. No side-effects have been described in nursed
children.
Carbamazepine: Breast-feeding is possible. RID
is 4–6%. No side-effects have been described in
nursed children.
Lamotrigine: Breast-feeding is possible at doses
of no more than 200 mg daily. RID is relatively
high from 9 to 18%. Nursed children achieve
plasma concentrations of approximately 30% of
the mother’s. Many courses without side-effects in
nursed children are described. One case of neonatal apnoea is described where the mother had
850 mg daily.
Generally, antidepressants should not be used in
bipolar disorder, as it is still being debated whether
there is evidence for this (95).
The risk of not treating the psychotic condition in pregnant women. The risk of a non-planned pregnancy
is increased in women with psychotic disorders.
Approximately 60% of women with such a condition will carry out a pregnancy (96–98). Data on
the risk of relapse of psychotic symptoms in pregnant women with a general psychotic disorder are
not present, but the risk of relapse is 65% in pregnant women with schizophrenia. The attending
medical doctor should inform the woman of risks
of the current treatment already before any pregnancy, explain about a possible need for change of
medicine during pregnancy and inform her about
the risk of abrupt discontinuation of medical treatment, such as insufficient nutrition, pregnancy complications and an increased risk of drug abuse (99).
If the woman has a desire for pregnancy, but the
medical treatment is considered suboptimal in relation to this, safe contraception must be agreed
upon until changes in medical treatment have been
made, and the initial risk of relapse by change of
medicine is over. If the woman is already pregnant,
a detailed plan must be made for collaboration
between relevant parties, such as own medical
doctor, psychiatrist, obstetrician and municipal
partners.
In the treatment with antipsychotics, an increase
in prolactin can be seen. The risk is highest in firstgeneration antipsychotics and risperidone, amisulpride and paliperidone. The increased prolactin
levels may cause breast tension, milk secretion,
irregular periods and reduced fertility.
In addition to focus on the pharmacological
treatment, the psychosocial support for the woman
must be optimized to ensure that the pregnancy
runs as smoothly as possible and to minimize the
risk of recurrence of the psychotic symptoms.
After the birth of the child, psychological conditions in connection with expectations and fear
from the woman and her family as well as the
physical and psychological pressure to care for a
newborn can contribute to an increased risk of
relapse.
Psychoses. This group of disorders is divided into
three subgroups consisting of schizophrenia, acute
psychoses and chronic psychoses. Around 25 000
people in Denmark are diagnosed with schizophrenia. In the course of a lifetime, 1% of the population will be diagnosed with schizophrenia. For the
majority of people with schizophrenia, the disorder
manifests itself between the ages of 16 and
25 years, but the disorder is also seen in children
and elderly. The gender distribution is equal, however, with a tendency that women have a higher age
at onset and a milder course than men. The disorder affects the ability to think, feel and perceive
reality correctly, and there will often be problems
with entering into relations with others. The most
noticeable symptoms are hallucinations and delusions. By hallucinations, the person, for example,
hears voices which speak about the person in question, and hallucinations in other sensory forms
may also occur, for example olfactory, gustatory
and tactile. Delusions are characterized by an
16
Medical treatment of women of child-bearing age with
psychotic disorder. An increased incidence of premature birth has been described among people
treated with antipsychotics, but it is unclear
whether this is due to the pharmacological treat-
Psychotropic drugs during pregnancy and breast-feeding
ment, or whether it is an expression of the underlying illness (100, 101). However, the risk is not
increased by the use of atypical antipsychotics as
opposed to the use of first-generation antipsychotics. This may, however, be due to the fact that
it is the most seriously ill women who use first-generation antipsychotics (100, 101). Addition of anticholinergics against side-effects from antipsychotics
appears to increase the risk of malformations and
should if possible be avoided (102).
There are known metabolic side-effects of
antipsychotics, but the risk of metabolic complications in the newborn has not been clarified (100,
103, 104). An increased risk of hypoglycaemia in
newborns has been found if the mother has been
treated with atypical antipsychotics during the
pregnancy (103, 104). The metabolic side-effects
from treatment with antipsychotics should be
assessed on an ongoing basis in the mother, as the
risk of diabetes is increased.
In children who have been exposed to antipsychotics during the foetal stage, increased waking
state, restlessness, crying and sleep problems (histaminergic rebound) and increased saliva secretion
and diarrhoea (anticholinergenic rebound) immediately after the birth can be observed.
Treatment with antipsychotics
Recommendations. Planned pregnancy and start-up
during pregnancy. Olanzapine is primarily recommended based on the amount of safety data. Other
conditions may, however, be of importance for the
choice of drug, including metabolic risk profile.
Earlier, perfenazine† was recommended, but data
for olanzapine, quetiapine and risperidone are
comparable with this and do not indicate an
increased risk of congenital malformations. ECT
may be considered.
Pregnancy occurring during an existing treatment. The pregnant woman will most often be in
treatment with an atypical antipsychotic. As
described below, data for a number of medicinal
products are available, and the need for change
will depend on a specific assessment of the patient’s
risk of recurrence compared to the product’s risk
profile.
Breast-feeding. RID is typically in the range of 0–
2% for most of the antipsychotics, and side-effects
in nursed children are only described exceptionally.
Factual data for all the drugs, however, are not
†
Regarding prescription of perphenazine – see under treatment with
mood stabilizers.
available (14). We refer to the specific drug descriptions below.
Background. Prescription and control of patients
undergoing treatment with antipsychotics should
be performed in collaboration with specialist in
psychiatry. In 2011, FDA issued a general warning
in relation to the use of antipsychotics during pregnancy, primarily due to an increased incidence of
extrapyramidal symptoms and discontinuation
symptoms (9). The first symptoms indicate that the
brain of the child as well as of the mother is
affected. The data volume for use during pregnancy is significantly smaller for antipsychotics
compared with antidepressants, and in fact, only
olanzapine meets the requirements of this guideline’s formal criteria of more than 1000 exposed
pregnant women. The body’s enzyme systems have
increased activity during pregnancy, which may
lead to olanzapine and clozapine being metabolized quicker than normal. Certain antipsychotics,
such as haloperidol and perfenazine, have a reasonable defined therapeutic window, which is why
it is recommended to regularly measure antipsychotics in the blood, for example every 3 months
during the pregnancy.
An increased incidence of premature birth has
been described among women treated with
antipsychotics, but it is unclear whether this is due
to the pharmacological treatment, or whether it is
an expression of the underlying illness (confounding by indication) (100, 101).
Newer
antipsychotics. Pregnancy. Olanzapine:
Olanzapine is the newer antipsychotic with the
most data for use during pregnancy. Data for
about 1100 first trimester exposed show no signs of
excess incidence of undesired foetal impact (105,
106). Treatment with olanzapine during pregnancy
can be used if there is a clear indication for this.
Dose during the last part of the pregnancy should
be kept as low as possible. A case report has found
an increased risk of changed glucose tolerance
during pregnancy in the mother (107).
Quetiapine: About 450 cases of pregnant women
treated with quetiapine have been reported. No
pattern of malformations which could indicate a
specific teratogenic effects of quetiapine is
observed, and no increased prevalence of malformations compared to baseline risk is seen (8, 105,
108, 109). The safety and the effect of quetiapine
during pregnancy are insufficiently described, and
the treatment is not recommended as a rule. However, there may well be clinical courses, where it is
not rational to switch from an efficient ongoing
treatment with quetiapine.
17
Larsen et al.
Aripiprazole: Not recommended during pregnancy due to insufficient data.
Risperidone: Data for more than 400 first trimester pregnant women treated with risperidone
show no increased risk of malformations (8, 105,
108). As a rule, risperidone is not recommended
during pregnancy, as the safety is inadequately
established. However, there may well be clinical
courses, where it is not rational to switch from an
efficient ongoing treatment with risperidone.
Paliperidonie: Not recommended due to insufficient data. There are few specific data, but extrapolation from risperidone data is to some extent
acceptable, as paliperidone is the active metabolite
of risperidone.
Clozapine: About 200 cases of pregnant women
treated with clozapine have been reported. No pattern of malformations is observed. Clozapine is not
recommended due to insufficient data. It can be
clinically indicated to use clozapine during pregnancy for women who have had no effect of another
treatment, and who therefore cannot be switched to
one of the recommended antipsychotics.
Ziprasidone: Not recommended due to insufficient data.
Breast-feeding.
Olanzapine: Can be used. RID is below 2%, and
no side-effects have been described in nursed children.
Quetiapine: Can be used. RID is below 1%, and
side-effects in nursed children are not reported.
Aripiprazole: Can be used. RID is below 1%, and
side-effects in nursed children are not described.
Risperidone: As a rule, not recommended. RID is
between 3 and 9%.
Paliperidone: Not recommended due to insufficient
data.
Clozapine: As a rule, not recommended. RID is
below 2%, but because of the side-effect profile,
clozapine is not recommended during breast-feeding (14, 110).
Ziprasidone: Not recommended due to insufficient
data.
Older antipsychotics. Pregnancy.
Perphenazine: Data exists for 500 exposed without
signs of increased incidence of undesired foetal
impact. In addition, there are some data for perphenazine administered in lower doses as a
antiemetics.
Haloperidol: Not recommended. Data exist for
about 300 first trimester-exposed without signs of
significantly increased incidence of malformations.
18
One child of 188 lacked development of left hand
(111).
Amisulpride: Not recommended due to insufficient
data.
Breast-feeding.
Perphenazine: As a rule, breast-feeding is not recommended. There are insufficient data for transfer into the breast milk, but in one case, however,
the transfer of perfenazine was found to be low
(112).
Haloperidol: Breast-feeding is not recommended.
RID is poorly defined – up to 12% in one study.
Amisulpride: Breast-feeding is not recommended
due to insufficient data.
Treatment with anxiolytics and hypnotics
Recommendations. Planned pregnancy and start-up
during pregnancy. It is recommended to avoid benzodiazepines during pregnancy if possible, as the
results of the available data are conflicting regarding the risk of malformations. As hypnotic, zolpidem and zopiclone can be used for a short period.
Pregnancy occurring during an existing treatment. Benzodiazepines are not recommended during pregnancy. It must be considered whether
phasing them out can be planned. If using them,
whether the mother can carry out a pregnancy
without the drugs must be balanced against the
risk for the child.
Birth. Use close to birth can result in discontinuation symptoms in the child or a limp child who is
affected by the drug.
Breast-feeding. Benzodiazepines during breastfeeding are not recommended due to the risk of
drowsiness of the child.
Background. If the treatment with anxiolytics or
hypnotics during pregnancy is deemed necessary,
the data volume is largest for diazepam. Due to the
risk of withdrawal symptoms in the newborn child,
the treatment with fixed scheduled doses of benzodiazepines should be avoided in the last month of
the pregnancy.
Hypnotics. The hypnotics zolpidem and zopiclone
are not actual benzodiazepines. Data exist for
more than 1000 exposed children (8) without signs
of an increased incidence of malformations,
whereas an abstract has described an increased
incidence of miscarriages and premature birth
Psychotropic drugs during pregnancy and breast-feeding
(113). Any treatment with these hypnotics should
be of short duration.
Benzodiazepines. Benzodiazepines and benzodiazepine analogues are frequently used as add-on
treatment in patients with a mental disorder. Benzodiazepines are also used in patients who have
not been diagnosed with a mental disorder, however, more often in a short period.
A study with data from the Swedish Birth Register found 1979 children who had been exposed to
benzodiazepines during the pregnancy. The conclusion of this study was that maternal use of benzodiazepines may increase the risk of low birth
weight or premature birth and cause symptoms at
the birth in the shape of drowsiness, but no strong
teratogenic potential is found, in relation to neither
cleft lip nor palate. The same is found in an American cohort study of 2793 women (114, 115).
A meta-analysis of 1 051 376 persons, of which
4342 were exposed to benzodiazepines in the first
trimester, examined the risk of malformations in
general and of heart malformations and did not
find an increased incidence (116). In the study,
benzodiazepines were analysed as a group and not
as single drugs. A systematic review of Bellantuono
analysed the individual drugs (117), but due to the
scarce data, no clear recommendation can be
made.
Previous studies have raised suspicion of an
increased risk of cleft lip and palate by exposure to
individual benzodiazepine drugs during first trimester of the pregnancy (118). Exposure to clonazepam has been reported in 140 cases without an
increased risk of malformations being found,
whereas exposure to chlordiazepoxide in a study of
201 patients was associated with an increased incidence of heart malformations (119), a result which
is not confirmed in a smaller study of 88 depressed
patients who took chlordiazepoxide in high doses
for suicidal purposes (117). Chlordiazepoxide is
used for instance in detoxification in relation to
alcohol abuse. This means that to a high extent,
there is a risk of confounding by indication when
the risk of the foetus is assessed.
Studies of the use of diazepam are ambiguous,
as some studies show an increased risk of malformations of arms and legs, rectal/anal stenosis/atresia, heart malformations and other congenital
malformations (117). A subanalysis of data, where
only women who had been prescribed diazepam
were included, found no increased risk of malformations. In the last part of the analysis, women
who had self-reported the use of the drug were
excluded. One of the reasons for the described
increased risk could be recall bias.
Use of nitrazepam is described for 100 women
who took an overdose of the drug (120) and an
increased risk of malformations as well as a significantly increased risk of miscarriage are found.
Use of lorazepam and bromazepam is associated
with an increased risk of anal atresia (OR 6.19)
and other malformations in the intestinal system
(OR 6.15) compared with other benzodiazepines
(117), but the absolute risk of exposure is, however, still very low with a NNH around 590. A British study from 2014 of more than 375 000 live
births found that the risk of major malformations
in general was 2.7%, whereas the risk of using different benzodiazepines did not increase the general
risk of malformations (121).
The malformations described have not suggested
a specific pattern of malformations of the individual drugs. The importance of recall bias and confounding by indication is unclarified for most of
the described studies, as data are often based on
reports of side-effects and malformations.
If there is indication for the use of benzodiazepines in the first trimester, use of diazepam is
considered most safe (117). When using benzodiazepines later in the pregnancy, the risk of drowsiness and overdose of the newborn must be taken
into consideration with special focus on the
extended half-life in preterm infants (122). By use
of high doses of benzodiazepines. an increased risk
of miscarriage has been found for alprazolam, diazepam, chlordiazepoxide and nitrazepam when
examining patients who have attempted suicide
with the mentioned drugs.
Brain development and emotional development. Use
of benzodiazepines and their influence are not
widely examined.
Treatment with pregabalin
Pregnancy. Pregabalin is a relatively new drug.
The data are insufficient, for which reason it cannot be recommended during pregnancy.
Breast-feeding. There are no data for transfer
into the breast milk, and breast-feeding is not
recommended.
Pregabalin is used to treat anxiety disorders,
cramps and fibromyalgia and is released
unchanged via the kidneys. The release is probably
increased during the pregnancy, but no larger studies are available. In newborns, the half-life is 14 h
instead of the usual 5–7 h for pregabalin.
ADHD. AD stands for attention deficit and H for
hyperactivity and D for disorder. About one-third
19
Larsen et al.
of all with this illness is without hyperactivity and
impulsivity, and the diagnosis can thus be particularly difficult to make. This condition is called
ADD.
ADHD is seen in approximately 3–5% of all
children. The symptoms change with age, and most
of the affected will become, for example, less restless. Therefore, only 2–3% of the adult population
is expected to have ADHD in a noticeable degree.
ADHD has long been known and treated in children. To make the diagnosis in adults, the symptoms must have been present before the age of 7,
and they must have been permanent until
adulthood.
Persons with ADHD will often be characterized by impulsive behaviour, lack of perseverance and conflict-ridden relations to the
surroundings, and they have an increased risk of
developing other mental disorders such as
depression, anxiety and OCD personality disorder or abuse (123).
The risk of not treating ADHD in pregnant women. Women with ADHD often have worsening of
ADHD symptoms premenstrually. On the other
hand, the symptoms often diminish during pregnancy, which has the advantage that you will
most often be able to take a break from the
central nervous system (CNS) stimulants, drugs
that speed up physical and mental processes,
without major problems without major problems
(123).
Treatment with methylphenidate and atomoxetine
Recommendations. Planned pregnancy and start-up
during pregnancy. As a rule, the treatment is not
recommended. In case of disorder requiring treatment, methylphenidate should be preferred.
Pregnancy occurring during an existing treatment. The treatment indication should be considered.
Atomoxetine
treatment
should
be
discontinued, alternatively switched to methylphenidate.
Background. Methylphenidate. Pregnancy: In all,
data are available from more than 500 first trimester-exposed pregnant women without signs
of increased incidence of congenital malformations. A Danish overview article described 180
children exposed to the risk of methylphenidate
and found four heart malformations (including
two ventricular septal defects and one with univentricular heart) corresponding to a risk of
20
2.2%, which should be compared with the risk
of the background population of 3.5%. A recent
Danish register study, whose data do not overlap the data in the above-mentioned study,
found no increased incidence of congenital malformations in 220 children exposed in the first
trimester (124).
Breast-feeding: For methylphenidate, RID is
below 1%. No side-effects have been described in
nursed children.
Atomoxetine.
Pregnancy: The data volume for atomoxetine is
insufficient, and treatment with this drug is therefore not recommended.
Breast-feeding: Atomoxetine is not recommended
due to insufficient data.
ECT for pregnant and breast-feeding women
Recommendations. Planned pregnancy and start-up
during pregnancy. Depending on the degree of the
mental illness, first talk therapy and medical treatment will be offered. ECT for pregnant women,
however, is considered an effective treatment,
which very rarely causes problems in relation to
the pregnant woman or the foetus. It is a treatment
which must be carefully considered in pregnant
women with severe symptoms, such as psychotic
depression, high risk of suicide or catatonia which
may be life-threatening.
Breast-feeding. There are no problems in using
ECT to breast-feeding women, except that the
child must be observed for, whether it is affected
by the drug which the mother has been anaesthetized with.
Background. With ECT, you avoid long-term
medical treatment, which may affect the unborn
child, and at the same time, the treatment is
very effective. However, only scarce reports
exist shedding light on the question of efficiency
and side-effects of the mother and the foetus.
Thus, the literature reports around 340 cases
where ECT has been used for pregnant women
(125).
Effect of ECT treatment. In the cases where the
effect of the treatment has been stated, the total
incidence of partial and full response was 84% for
depression with or without psychotic symptoms.
When schizophrenia or schizophreniform disorder
was treated, the frequency of at least partial
Psychotropic drugs during pregnancy and breast-feeding
response was 61%. These response rates as well as
the average number of treatments at 10.7 correspond to the conditions in non-pregnant women.
Thus, the treatment is by all accounts extremely
efficient assessed on the basis of this relatively
modest material.
Side-effects in the foetus. Out of 339 cases, 25 cases
of abnormalities in utero and at birth have been
described, but in many of these cases, the abnormality probably arose before or long after the ECT
treatment. In 11 cases, the complications were
probably related to ECT. The most common complication was 8 cases of temporary low pulse. The
only death, which this overview article connected
with ECT, was a case where the mother had longterm seizures (status epilepticus) secondary to the
treatment (125). Nine deaths are considered to be
non-related to ECT, namely one newborn had
peritonitis and died 8 weeks after the last treatment, two died due to congenital transposition of
the large blood vessels, which had been seen by
ultrasound before ECT, and one died 2 days after
the birth several months after the last ECT. One
foetus died in a car accident, and three died of congenital abnormalities leading to a cyst in the lungs
and a total lack of development of the brain. The
latter cases are probably not related to ECT, as the
treatment was used in the second and third trimester and not in the first trimester, where the organs
are formed. A case report from 2007 described the
birth of a child with multiple haemorrhages in the
brain, where the mother had received seven ECT
in the weeks 20–34.
Cardiac arrhythmia in utero. Regarding non-mortal
abnormalities, there were 8 cases of arrhythmias in
the foetus, for example decelerations in the cardiotocography (CTG, the electronic monitoring of
foetal heart rate and the contractions of the
woman in labour) which are suspected to be
related to ECT. The arrhythmias occurred at a frequency of approximately 2.7% and were probably
caused by low oxygen supply. However, it is not
stated whether the woman prior to the treatments
were ventilated with pure oxygen, which is the procedure today.
Side-effects in relation to the mother. Twenty
women had complicated pregnancies in connection
with the ECT treatment: partly the above-mentioned case of long-term seizures (status epilepticus), partly cases of blood in the urine
(haematuria), a miscarriage and contractions or
premature birth, and finally, one case of vaginal
bleeding, abdominal pain and abruptio placentae.
It cannot be ruled out that some of these complications might be related to ECT.
Braxton Hicks and initiation of birth. In 3.5% of
the cases, contractions or premature birth was
reported. This is not caused by the electric current
from the ECT apparatus, because it does not pass
through the uterus, but may possibly be due to
release of the hormone oxytocin from hypothalamus. In the event of contractions, beta-adrenergic
agonists can be used to stop them.
Recommendations on the basis of the literature. Prior
to the treatment, an obstetrician is conferred with
among other things with regard to monitoring the
foetus with CTG, and whether the treatment is to
take place in maternity ward.
Positioning of the mother. It is presumably important that women in late pregnancy are positioned
with a slightly elevated right hip, so that the uterus
is pushed to the left, and pressure on the large vessels in the body (aorta and vena cava) is avoided.
This will result in improved blood flow of the
placenta.
Anaesthetics. The most commonly used anaesthetics in Denmark are barbiturates, although propofol is also used occasionally. Both types of drugs
work with very short half-lives, cross the placental
barrier and can be found in the foetus’ blood.
There is no suspicion of teratogenicity, but the use
of the drugs must of course be avoided immediately before the birth, because they can dull the
child. The seizure activity is usually attenuated
with succinylcholine, which, however, hardly
crosses the placenta and has no known teratogenic
effects.
Hyperventilation to reduce the seizure threshold
should, however, be avoided, as this would lead to
alkalosis, which complicates the transport of oxygen from the mother’s haemoglobin to the foetus’.
Aspiration risk. It has been suggested that pregnant women who received ECT had a greater risk
of aspiration from the ventricle. However, among
the cases described in the literature there are no
cases of pneumonia caused by aspiration. Some
hospitals tend to increase pH in the stomach, for
example by giving sodium citrate or similar antacid
15–20 min before ECT. If atropine is given prior
to the treatment to prevent slow heart rate (bradycardia), this may result in poorer oesophageal closing off and may in principle increase the risk of
aspiration. Therefore, use of atropine in pregnant
women is not recommended. In women with
21
Larsen et al.
known high risk of acid reflux, endotracheal intubation can be performed.
The actual seizure. As mentioned before, no power
runs through the uterus during stimulation. The
mother’s seizures during ECT are not as such
harmful to the child, but low oxygen saturation
may, of course, be. Therefore, it is important to
limit the length of the seizure if it is prolonged, just
like an extended seizure condition (status epilepticus) of course must be able to be treated. First
choice will most often be diazepam. Normally, the
woman will, however, not experience low oxygen
saturation during the seizure, which can be determined by pulse oximetri, and the child will therefore not be missing oxygen (126–128).
Discussion
Bias and confounding
The above-described problem concerning the quality and validity of available data makes this topic
extremely sensitive to bias. Important biases,
which can complicate the interpretation of data,
are described as follows.
Confounding by Indication. Is it the treatment or
the disease itself which increases the risk of undesired foetal impact? This is a difficult problem
which is not always easy to solve despite sophisticated epidemiological methods (6, 7, 129). Above
the individual diseases, the risk of not treating the
disease in question is reviewed. An example of this
problem should be mentioned here: A Danish register study found that the risk of malformations
was increased from the normal 3.5–5% in pregnant
women undergoing treatment with an SSRI and
increased from 3.5–4.5% in pregnant women who
discontinued with a SSRI at least 3 months before
the pregnancy (1). The increased risk could indicate confounding by indication. For example,
depression is known to be associated with an
unhealthy lifestyle (smoking and alcohol consumption) as well as poor utilization of the offers of the
pregnancy care. In the above-mentioned study, no
connection between dose and the risk of malformations is established.
Recall bias/misclassification of exposure. Some data
collection takes place by contacting the pregnant
women long after the exposure to a given drug.
There is a risk that women giving birth to healthy
children are less likely to remember exposure to
drugs as women giving birth to children with malformations. However, this kind of bias is mini-
22
mized
a
great
deal
in
more
recent
pharmacoepidemiological studies.
On the other hand, one is dependent on valid
and complete information in the available registers
containing information on congenital malformations and other unwanted pregnancy outcomes (6,
7, 129). If prescription statements are used, one
cannot be sure that the pregnant woman has actually taken the collected drug.
Publication and citation bias. Of course, a general
and fundamental bias is the fact that positive scientific findings are easier published than negative.
However, within the area of this report, it has
considerable serious consequences, as a positive
signal announced once is very difficult, in practice,
to exorcise despite several subsequent negative
studies. Thus, an early published signal will often
be cited to a considerable extent, although later
studies cannot confirm the original results. This
means that the results from an early published,
typically smaller scale study with a positive signal
for a given malformation will be elevated to
contain a truth value very difficult to reverse
(130–132).
Ascertainment bias. Diagnosing heart malformations represents a specific problem. The frequency
of congenital ventricular septal defect (VSD), is
around 0.5%. Often, these are of no clinical significance and close spontaneously without having
been diagnosed. With recent years’ focus on heart
malformations and SSRIs, there is a high risk that
children born to mothers in SSRI treatment will be
subjected to echocardiography where a malformation will be discovered which you do not know the
importance of and which would not otherwise have
been detected. This ascertainment bias is documented in a Canadian study (133). It will pull in
the opposite direction if a heart abnormality for
instance increases the risk of miscarriage or often
leads to termination of the pregnancy if it is
detected prenatally. In this way, an underestimation of the risk will occur.
Stratification and multiple testing. These are necessary scientific and statistical tools which contribute
to shedding light on the studied contexts and generate hypotheses. These techniques are, however,
also double-edged swords which may compromise
a clinically meaningful interpretation of the data:
i) A Danish population study of the use of SSRI
during pregnancy (40) found no significant
increased risk of congenital malformations in
1370 children of pregnant women exposed to a
SSRI in the first trimester, OR 1.21 (95% CI
Psychotropic drugs during pregnancy and breast-feeding
0.91–1.62). There was no significantly
increased risk of congenital heart malformations as OR was 1.44 (95% CI 0.86–2.40). By
further stratification of five different specific
heart malformations, however, a signal for
ventricular septal defect, OR 1.99 (95 % CI
1.13–3.53), was observed.
ii) A Finnish population study of the use of SSRI
during pregnancy (38) found no significantly
increased risk of congenital malformations in
6881 children of pregnant women exposed to a
SSRI in the first trimester, OR 1.08 (95% CI
0.96–1.22). The publication mentions no less
than 96 odds ratios with associated confidence
intervals for general and specific estimates of
connections between SSRI drugs and specific
malformations, including 7 odds ratios for
specified heart malformations. Among the 96
analyses, three statistically significant associations were present:
a) Paroxetine and right outflow tract defects (3
cases), OR 4.68 (95% CI 1.48–14.74).
b) Fluoxetine and isolated VSD (19 cases), OR
2.03 (95% CI 1.28–3.21).
c) Citalopram and neural tube defects (absolute number is not specified), OR 2.46 (95%
CI 1.20–5.07).
Typically, such positive results will be mentioned
in abstracts and find their way to the media. Those
kinds of studies are published constantly. Of
course, they contribute considerably to our total
amount of knowledge, but if you react uncritically
on every result of this type, there is a high risk of
over-interpretation with unfortunate noticeable
clinical consequences as a result. Interpretation of
such analyses is difficult, especially if they are not
specifically defined in advance as the results in this
case, in principle, are only hypothesis generating.
Regardless of the results, they should be replicated
in other studies before any clinical significance can
be reasonably attributed.
Regulatory matters. The summary of product
characteristics (SPC) is an integrated part of the
marketing authorization. The SPC binds the manufacturer in relation to the marketing, but it is not
binding in relation to the medical doctors’ clinical
use of the drug, or in relation to use during pregnancy. The SPC is based on the available knowledge on a given drug at the time of the
introduction (134). With regard to use of the drugs
during pregnancy, typically only few human data
are available, and reference is typically made to
animal experiments to the extent they have been
carried out. The manufacturer is obligated to
update these information with regard to ongoing
collection or publication of knowledge. The manufacturer’s interest in relation to use during pregnancy is clearly of defensive character, and the
motivation to classify a drug as usable during pregnancy is thus almost non-existing, primarily due to
medico legal considerations (135, 136).
Since 2009, an EMA (European Medicines
Agency) guideline specifically in this area has
existed, which describes the requirements which
must be met in order for a given drug to have
added specific recommendations during pregnancy
(137, 138). The proposed statistical estimates with
associated proposal(s) for recommendation text
are rather conservative:
i) More than 300 pregnant women without signs
of excess incidence of undesired foetal impact
must be examined to eliminate that the risk
actually has increased by a factor 10. Recommendation text: ‘The risk of malformations in
humans is unlikely, but the level of evidence is
low’.
ii) More than 1000 pregnant women without
signs of excess incidence of undesired foetal
impact must be examined to eliminate that the
risk actually has increased by a factor 2. Recommendation text: ‘The risk of malformations
in humans is unlikely, the level of evidence is
high’.
The problem is, of course, the interpretation of
this type of data, where the producer’s interest is
extraordinarily conservative, which is not necessarily identical with the patient’s and the unborn
child’s best interests. In addition, there is still not
always consistency in the summaries of the product
characteristics for the same active ingredients. For
example, SPC for two different citalopram
products:
Published data on pregnant women (more than
2500 pregnancy outcomes among treated) do not
indicate malformations or foetal/neonatal toxicity.
However, citalopram should not be used during
pregnancy, unless it is absolutely necessary and, if
so, only after careful consideration of the benefits
and the risks (139).
Respectively:
Not recommended for pregnant women, as experience with regard to the use of citalopram for pregnant women is insufficient (140).
This last text is given for three of nine citalopram products. Factually, reproducible and concordant peer-reviewed pharmacoepidemiological
data for at least 10 000 children exposed to
23
Larsen et al.
citalopram in the first trimester exist. However, the
studies cannot demonstrate an increased general
risk of undesired foetal impact besides neonatal
symptoms and PPHN in newborns (38–40, 141).
Counselling possibilities. At psychiatric hospitals
in Denmark, there are often opportunities for
advice on psychopharmacological treatment of
pregnant and breast-feeding women. Other possibilities are departments of clinical pharmacology,
where you can obtain further information. Many
obstetric wards have special offers for pregnant
women, where advice and guidance can also be
obtained. It is important that fertile women with
a psychiatric disease are advised before pregnancy if psychotropic drugs are needed during
pregnancy. Valproate and carbamazepine should
be avoided if possible for fertile women. If
antipsychotics are needed, olanzapine is primarily
recommended based on the amount of safety
data, but risperidone, quetiapine and clozapine
can be used.
Declaration of interest
Dr Erik Roj Larsen, Dr Poul Videbech, Dr Hans Eyvind
Dahl Knudsen, Dr Jesper Fenger Grøn, Dr Lars Henning
Pedersen, Dr Vibeke Johansen Linde and student Lykke
Skaarup have no competing interests to report. Rie Lambæk
Mikkelsen has taught for the following companies: AbbVie
A/S, Otsuka Pharma Scandinavia AB, Novartis Healthcare
A/S, Lundbeck Pharma A/S and AstraZeneca A/S. Rene
Ernst Nielsen has received teaching fee from Bristol-Myers
Squibb, Astra Zeneca, Janssen & Cilag, Servier, Otsuka Pharmaceuticals and Eli Lilly, and has been a member of Advisory
Boards for Astra Zeneca, Lundbeck, Otsuka Pharmaceuticals,
Takeda, Eli Lilly and Medivir. Per Damkier has served as
expert witness for Accord Healthcare Ltd in a Norwegian law
suit concerning patent validity for an extended release
formulation of ‘Quetiapine’
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