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DOI: 10.1111/acps.12479
2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
ACTA PSYCHIATRICA SCANDINAVICA
Clinical overview
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 Lilleblt, 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
Clinical recommendations
Fertile women with a psychiatric disease should be advised before pregnancy whether psychotropic
drugs are needed during pregnancy.
Additional comments
This
is a literature review. More clinical studies are needed for risk estimation of the dierent
psychotropic drugs with long-term follow-up of the children.
Introduction
Drugs and pregnancy: general observations
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
scientic 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
nd unfortunate events and put them in relation to
an apparent inconsistency between professional
information sources and scientic messages.
Consumption of psychotropic drugs during pregnancy
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 childs later development, is not
always well dened. For practical aspects, it may,
however, be assumed that the frequency of con2
genital malformations in the population, as mentioned, is about 34% (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 denition 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 nds that less
than 1% of all congenital malformations are
caused by medicine (3).
The risk of not treating a psychiatric disorder during pregnancy
How many rst trimester exposed without detectable signal do we require before we consider a drug
to be safe? Consensus does not exist in scientic
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 rst trimester without signs
of excess incidence of malformations provide a
good certainty (80% power and 5% level of
signicance) that the real risk is not more than
three times higher than the background risk;
ii) 700 exposed in the rst trimester without signs
of excess incidence of malformations provide a
good certainty (80% power and 5% level of
signicance) that the real risk is not more than
two times higher than the background risk;
iii) 2000 exposed in the rst trimester without signs
of excess incidence of malformations provide a
good certainty (80% power and 5% level of sig-
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-eects 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 dierent maternal
doses of the given drug. Based on the highest concentration, the childs exposure is now estimated as
a weight-adjusted percentage of the mothers 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.
Milkplasma ratio is unt 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 modied in practice by observation of
probable side-eects; 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
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 specically
substantiated.
Results
Non-pharmacological intervention
Larsen et al.
breakdown of lamotrigine by approximately 50%.
Antipsychotics may increase prolactin and result
in infertility. This is specically evident in connection with risperidone and typical antipsychotics,
but can occur in all antipsychotics (73).
Treatment with mood stabilizers
14
Larsen et al.
known high risk of acid reux, endotracheal intubation can be performed.
The actual seizure. As mentioned before, no power
runs through the uterus during stimulation. The
mothers 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 (126128).
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 dicult 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 3.55% in pregnant
women undergoing treatment with an SSRI and
increased from 3.54.5% 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 oers of the
pregnancy care. In the above-mentioned study, no
connection between dose and the risk of malformations is established.
Recall bias/misclassication 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 scientic ndings 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 dicult, 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 conrm 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 dicult to reverse
(130132).
Ascertainment bias. Diagnosing heart malformations represents a specic problem. The frequency
of congenital ventricular septal defect (VSD), is
around 0.5%. Often, these are of no clinical signicance 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.
Stratication and multiple testing. These are necessary scientic 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 signicant
increased risk of congenital malformations in
1370 children of pregnant women exposed to a
SSRI in the rst trimester, OR 1.21 (95% CI
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-eects and
the smallest transfer into the breast milk.
iii) There are casuistic reports of accumulation of
uoxetine in nursed children, and most reports
on symptoms by use of uoxetine 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-eects 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 childs blood.
iv) Escitalopram and uvoxamine 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
Larsen et al.
one single tricyclic antidepressant (TCA)], because
it is not possible to predict how several dierent
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 rst 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
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-
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 dicult 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
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 eect on the newborn childs
health by reducing exposure to SSRI towards the
end of the pregnancy (29).
Persistent pulmonary hypertension (PPHN)
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 womens foetuses had
less growth rate of the head, but not of the rest of
the body. The dierence 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 45 (23). The studies are dicult 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 childs development, and this eect cannot be distinguished
from the eect 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 childs behavioural
problems.
One study should be mentioned to illustrate
the problems of assessing such scientic results:
Croen et al. (54) studied 298 cases of Aspergers
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 childrens 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 diculties
due to Asperger features, which increased the
risk of depression or anxiety and subsequently
and
specific
serotonergic
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
12
treated with antidepressants nds 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 eect 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 eect, 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-eects 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 aects 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 insucient data.
Treatment with agomelatine. Not recommended
due to insucient data.
Treatment with vortioxetin. Not recommended due
to insucient data.
Bipolar aective disorder. At least 40 000
Danes are aected by bipolar aective disorder
13
Larsen et al.
breakdown of lamotrigine by approximately 50%.
Antipsychotics may increase prolactin and result
in infertility. This is specically evident in connection with risperidone and typical antipsychotics,
but can occur in all antipsychotics (73).
Treatment with mood stabilizers
14
Larsen et al.
mations is 7% and of hypospadias is 5%. Valproate may possibly aect 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.
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 (9698). 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 insucient 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 rstgeneration 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.
16
17
Larsen et al.
Aripiprazole: Not recommended during pregnancy due to insucient data.
Risperidone: Data for more than 400 rst 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
ecient ongoing treatment with risperidone.
Paliperidonie: Not recommended due to insucient data. There are few specic 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 insucient data. It can be
clinically indicated to use clozapine during pregnancy for women who have had no eect of another
treatment, and who therefore cannot be switched to
one of the recommended antipsychotics.
Ziprasidone: Not recommended due to insucient data.
Breast-feeding.
Perphenazine: As a rule, breast-feeding is not recommended. There are insucient 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 dened up to 12% in one study.
Amisulpride: Breast-feeding is not recommended
due to insucient data.
Treatment with anxiolytics and hypnotics
19
Larsen et al.
of all with this illness is without hyperactivity and
impulsivity, and the diagnosis can thus be particularly dicult to make. This condition is called
ADD.
ADHD is seen in approximately 35% of all
children. The symptoms change with age, and most
of the aected will become, for example, less restless. Therefore, only 23% 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 conict-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
20
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 ow 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
eects.
Hyperventilation to reduce the seizure threshold
should, however, be avoided, as this would lead to
alkalosis, which complicates the transport of oxygen from the mothers 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
1520 min before ECT. If atropine is given prior
to the treatment to prevent slow heart rate (bradycardia), this may result in poorer oesophageal closing o 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 reux, endotracheal intubation can be performed.
The actual seizure. As mentioned before, no power
runs through the uterus during stimulation. The
mothers 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 (126128).
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 dicult 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 3.55% in pregnant
women undergoing treatment with an SSRI and
increased from 3.54.5% 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 oers of the
pregnancy care. In the above-mentioned study, no
connection between dose and the risk of malformations is established.
Recall bias/misclassication 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 scientic ndings 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 dicult, 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 conrm 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 dicult to reverse
(130132).
Ascertainment bias. Diagnosing heart malformations represents a specic problem. The frequency
of congenital ventricular septal defect (VSD), is
around 0.5%. Often, these are of no clinical signicance 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.
Stratication and multiple testing. These are necessary scientic 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 signicant
increased risk of congenital malformations in
1370 children of pregnant women exposed to a
SSRI in the rst trimester, OR 1.21 (95% CI
Larsen et al.
citalopram in the rst trimester exist. However, the
studies cannot demonstrate an increased general
risk of undesired foetal impact besides neonatal
symptoms and PPHN in newborns (3840, 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 oers 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 Grn, Dr Lars Henning
Pedersen, Dr Vibeke Johansen Linde and student Lykke
Skaarup have no competing interests to report. Rie Lambk
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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