The British Journal of Psychiatry (2013)202, 347–351. doi: 10.1192/bjp.bp.112.115931
Maternal depression, antidepressant usein pregnancy and Apgar scores in infantsHans Mørch Jensen, Randi Grøn, Øjvind Lidegaard, Lars Henning Pedersen,Per Kragh Andersen and Lars Vedel Kessing
BackgroundUse of antidepressants during pregnancy has been
antidepressants (OR = 0.53, 95% CI 0.19–1.45). Maternal
associated with a low Apgar score in infants but a
depression before or during pregnancy, without prescription
contribution from the underlying depressive disorder might
of antidepressants, was not associated with a low Apgar
score (OR = 0.44, 95% CI 0.11–1.74). Women who had onlyused antidepressants prior to pregnancy had no increased
rate of a low Apgar score in their subsequent pregnancy,
To estimate the effects of maternal depression and use of
antidepressants during pregnancy on low Apgar scores (<7)5 min after birth.
Use of SSRIs during pregnancy increases the risk of a low
Register study on all pregnant women in Denmark from 1996
Apgar score independently of maternal depression.
to 2006 linking nationwide individualised data from theMedical Birth Register, the Psychiatric Central Register and
H.M.J has been a consultant for Bristol-Myers Squibb,Eli Lilly, Janssen-Cilag, Astra-Zeneca, Lundbeck, Servier,
Merck Sharp & Dohme and Schering-Plough. Ø.L. has
Infants exposed to antidepressants during pregnancy had an
received honoraria for speeches including fees from Bayer
increased rate of a low Apgar score (odds ratio (OR) = 1.72,
Pharma Denmark, MSD Denmark and Theramex, Monaco,
95% CI 1.34–2.20). The increased rate was only found among
and has been expert witness for a plaintiff in a legal US case
infants exposed to selective serotonin reuptake inhibitors
in 2011. L.V.K. has been a consultant for Bristol-Myers
(SSRIs) (OR = 1.96, 95% CI 1.52–2.54), not among those
Squibb, Eli Lilly, Lundbeck, Astra-Zeneca, Pfizer, Wyeth,
exposed to newer (OR = 0.83, 95% CI 0.40–1.74) or older
A substantial number of pregnant women experience depressive
those born with an Apgar score of 7–10.13 Further, an Apgar score
symptoms during pregnancy with prevalence rates of depression
57 at 5 min has been associated with neurological disability,
in the range 7–13%1,2 and 4–7.6% of pregnant women are
including cerebral palsy, epilepsy and cognitive impairment that
treated with antidepressants.1,3 Mental disorders and psychotropic
drugs may influence the development of the fetus, but theassociations are unclear, and mechanisms are poorly understood.
Antidepressants readily cross the placenta barrier potentially
affecting fetal development4 but maternal depressive illness mayalso cause adverse effects on pregnancy outcome. Increased
placental secretion of corticotrophin-releasing hormone resulting
We linked data on all pregnancies from 1996 to 2006 from the
in increased activity within the gestational cortisol system,5 as well
Medical Birth Register with data from the Psychiatric Central
as unhealthy behaviour related to depression such as smoking and
Register, the Medicinal Product Statistics register and Statistics
poor attendance for obstetric care, may have adverse effects.2,3,6
The importance of differentiating the effects of exposure to
The Medical Birth Register16 includes data on date of birth,
maternal depression from the effects of antidepressants has been
gestational age, Apgar score 5 min after birth, birth weight, length
highlighted in recent reviews6–9 but, so far, studies have not
of fetus, maternal smoking status during pregnancy, parity and
sufficiently discriminated between the effects of maternal disease
maternal age on all deliveries in Denmark. Data from births of
and use of drugs in relation to birth outcomes, except from one
more than one child from 1996 to 2006 were included whereas
study10 that revealed an increased risk of low birth weight and
twin births were excluded, implying that the same woman could
respiratory distress even when maternal illness severity was
accounted for. The hypothesis of the present study was that birth
The Medicinal Product Statistics is a nationwide prescription
complications, as reflected in a low Apgar score, are explained by
database containing individual information on all prescriptions
the effect of the maternal disease. We compared the Apgar score in
filled at all Danish pharmacies from 1995 and onwards.17 Data
eight risk groups, classified according to maternal depression and
included and distinguished between ATC codes (Anatomical
exposure to antidepressants, in a nationwide register linkage study.
Therapeutical Chemical classification system) for antidepressant,
The Apgar score at 5 min after birth is a clear index of
antipsychotics, anti-epileptics and ‘other kinds of drugs’. Anti-
problems in adult life; recent studies have shown that infants with
depressants were classified as selective serotonin reuptake
low Apgar scores (57 at 5 min) are at increased risk of a low IQ
inhibitors (SSRIs: fluoxetine, citalopram, escitalopram, paroxetine,
score at age 18,11 never receiving graduation grades12 or attending
sertraline, fluvoxamine: ATC N06AB03–10), newer antidepressants
university and are more likely to have no income from work than
(nefazodone, mirtazapine, venlafaxine, reboxetine: ATC N06AX06,
–11, –16, –18 and –21) or older antidepressants consisting
Logistic regression analyses were applied with Apgar score as
mainly of tricyclic antidepressants (imipramine, clomipramine,
the outcome and risk group as the variable of interest. The
trimipramine, lofepramine, amitriptyline, nortriptyline, doxepin,
analyses were adjusted for the effect of calendar periods (1996,
dosulepin, amoxapine, maprotiline; mianserin, isocarboxazid,
1997, 1998 etc. to 2006), maternal age, parity (first child, second
moclobemide: ATC N06AA02–7, N06AA09–12, N06AA16–17,
child, child number three or more), employment status
N06AA21, N06AX03, N06AF01 and N06AG02).
(employed, unemployed, disability pension and retired, student,
The Danish Psychiatric Central Register is a nationwide
child and others), smoking status (non-smoker, quit smoking,
psychiatric register18 with data from all public mental health services
smoking, unknown), gestational age, gender of the child, birth
both as in- and out-patients. Data extracted were ICD-819 and
weight and use of other medication during pregnancy, including
ICD-1020 codes for depression (i.e. ICD-8 codes 29609 and
use of lithium (yes/no), anti-epileptics (yes/no), antipsychotics
29629, ICD-10 codes DF32.00-DF33.99). Statistics Denmark
(yes/no) and other kinds of medication than antidepressants,
provided data on employment status on a yearly basis for the
lithium, anti-epileptics or antipsychotics (yes/no). In the analysis,
employment status was dichotomised into ‘working and students’v. the remaining groups.
To account for the fact that some women contributed with
more than one live birth, robust standard errors were compared
Pregnant women were divided into eight risk groups according to
with the model-based standard errors. Since the impact of this
their exposure to a diagnosis of depression before the end of
adjustment was minimal, only model-based standard errors are
antidepressant use during pregnancy (see Table 2, Model 1).
Group 1 was the reference group.
Additional analyses were done using three binary variables
(+ diagnosis before end of pregnancy; + antidepressants beforepregnancy; + antidepressants during pregnancy; see Table 1 and
The data-set included all pregnant women in Denmark from 1996
to 2006. Infants with a gestational age of less than 22 weeks were
To avoid assumptions of linearity, Apgar score at 5 min was
excluded from the data resulting in a total of 672 601 live births.
divided into two groups: Apgar score from 0 to 6 and 7 to 10
Data on birth weight were available from 668 144 live births
in accordance with the dichotomisation in prior studies showing
(99.3%) and data on Apgar score at 5 min were available for
poorer intellectual, cognitive, social and clinical outcome related
665 399 live births (98.93 % of all live births) resulting in
664 089 live births with full data on Apgar score and other
Characteristics of pregnant women and offspring according to antidepressant therapy and depressive diagnosis
IQR, interquartile range.
a. Each of the three columns are binary (antidepressant medication before pregnancy (yes/no), antidepressant medication during pregnancy (yes/no), depression diagnosis beforeend of pregnancy: yes/no) and presents data for those patients fulfilling the criteria (yes). The columns are not mutually exclusive.
Antidepressant use in pregnancy and Apgar scores
predictive variables included in the analysis. Among the 664 089
Additional analyses using three binary variables confirmed the
children, 22 155 (3.34%) had a birth weight below 2500 g, and
results as only children of women using antidepressants during
4076 children (0.61%) had an Apgar score after 5 min between 0
pregnancy had an increased risk of a low Apgar score
and 6 whereas 660 013 children had an Apgar score from 7 to 10.
(OR = 1.67, 95% CI 1.30–2.14); unadjusted OR = 1.87 (95% CI
Table 1 shows the characteristics of the 664 089 births
1.41– 2.47) whereas there was no effect of use of antidepressants
according to the mother’s antidepressant therapy and depressive
before pregnancy or a diagnosis of depression (see lower part of
diagnosis. As can be seen from Table 1, for 3916 live births the
Table 2, Model 2). These results did not change, resulting in
mother had a diagnosis of depression before the end of pregnancy.
ORs within the same ranges, when Model 2 was repeated with
For a total of 8375 live births the mother redeemed a prescription
exclusion of preterm births, i.e. gestational age 536 weeks
for antidepressants during pregnancy (Table 1). In 2941 of these
(antidepressants before pregnancy: OR = 0.95, 95% CI 0.79–1.14;
cases only one prescription was redeemed whereas, in 5434 cases,
antidepressants during pregnancy: OR = 1.87, 95% CI 1.41–2.47;
two or more prescriptions were redeemed; for 7208 live births the
diagnosis of depression before end of pregnancy: OR = 0.69,
mother redeemed a prescription for an SSRI, 982 for a newer
antidepressant and 780 for an older antidepressant. Among the
Further analyses of subtypes of antidepressants showed that
664 089 children included, in 7389 (1.11%) cases the mother
only use of SSRIs during pregnancy increased the OR of a low
redeemed a prescription for an antidepressant during the first
Apgar score whereas there was no effect of use of newer anti-
trimester, 3780 (0.57%) during the second trimester and 3246
depressants or older antidepressants during pregnancy (Table 3,
although a formal test of homogeneity resulted in only a
Prior to pregnancy, 33 084 (4.98%) women redeemed
borderline significant difference, P = 0.052). Using antidepressants
prescriptions for antidepressants (Table 1), 59 (0.01%) lithium,
before conception did not significantly increase the OR for a low
2884 (0.43%) anti-epileptics, 1278 (0.19%) antipsychotics and
Apgar score regardless of the type of antidepressant.
450 712 (67.87%) women redeemed prescriptions for other drugs.
There was no differential effect of timing of the use of anti-
Table 2 shows the adjusted odds for a low Apgar score (0–6 v.
depressants during various trimesters (first trimester: OR = 1.16,
7–10) in the risk groups according to logistic regression analyses
95% CI 0.83– 1.63; second trimester: OR = 1.51, 95% CI 0.90–
(Model 1). The only risk group with a significantly increased risk
2.53; third trimester: OR = 1.42, 95% CI 0.85– 2.38), which may
for a low Apgar score 5 min after birth compared with the
be explained by the limited sample size in these analyses.
reference group was risk group 4, i.e. children born of womenwithout a diagnosis of depression, who had redeemed a
prescription for antidepressants before and during pregnancy(OR = 1.72, 95% CI 1.34–2.20). Odds ratios for risk group 3 (no
We found that a low Apgar score was attributed to the use of SSRIs
diagnosis + antidepressants during pregnancy) and risk group 8
during pregnancy and not to the effect of the disease or associated
(a diagnosis of depression + antidepressants before and during
lifestyle factors. Non-SSRI antidepressants were not associated
pregnancy) were also increased but did not differ significantly
with a low Apgar score. No increased rates were found among
from the reference group. If the mother had taken medication
women who used antidepressants prior to pregnancy (but not
during; risk group 2) or who had a diagnosis of depression but
antipsychotics, the OR for a low Apgar score was slightly increased
used no antidepressants during pregnancy (risk groups 5 and 6).
The Apgar score 5 min after birth is a clear index of problems
All analyses were repeated without correcting for gestational
in adult life; studies have shown that infants with low Apgar scores
age and birth weight. These analyses resulted in the same findings
(57 at 5 min) are at increased risk of a low IQ score at age 18
as when correcting for gestational age and birth weight with ORs
(OR = 1.35, 95% CI 1.07–1.69),11 never receiving graduation
grades (OR = 1.93, 95% CI 1.75–2.14),12 never attending university
Adjusted odds rate of a low Apgar score (0–6 v. 7–10) according to depressive diagnosis and antidepressant therapy
end of pregnancy before pregnancy during pregnancy
Diagnosis of depression before end of pregnancy
a. The eight groups in Model 1 are mutually exclusive and sum up to 100%. The three groups in Model 2 are not mutually exclusive.
b. Odds ratio adjusted for: maternal age, social status, smoking status, calendar year, gender of newborn, and use of anti-epileptics, antipsychotics and other types of medication.
of other birth complications such as low birth weight35–37 and
Subtypes of antidepressantsa and risk of a low
preterm delivery,38,39 but it should be noted that none of these studieshas taken the potential effect of the depressive illness into account.
We found a lower prevalence of depression (i.e. 0.6%) than
previously reported as we used data from nationwide databases,
which only include information from hospital-based psychiatric
facilities and not from general practitioners. Consequently, we
had data on a diagnosis of depression only for women with more
severe and complicated depressive illnesses. For these women, we
found no association between depression and Apgar score and
thus believe that the effects of milder forms of depression areunlikely. We have no reason to suspect a reverse dose–response
a. According to the Anatomical Therapeutical Chemical (ATC) classification system.
b. Odds ratios adjusted for: maternal age, social status, smoking status, calendar
relationship between depression and birth outcome. Further, the
year, gender of newborn, and use of anti-epileptics, antipsychotics and other types
impact of antidepressants on birth outcome seems to be
In the present study, only 1.26% of the pregnant women were
(OR = 1.14, 95% CI 1.05–1.23) and are more likely to have no
treated with antidepressants. The low percentage is explained by
income from work (OR = 1.19, 95% CI 1.07–1.32) than those born
the fact that data were gathered from 1996 at which time it was
with an Apgar score of 7–10.13 Further, an Apgar score 57 at
uncommon to treat pregnant women with antidepressants. The
5 min has been associated with neurological disability, including
number of women treated with antidepressants during pregnancy
cerebral palsy, epilepsy and cognitive impairment that seems to
in the sample increased steadily each year from 232 in 1996 to
1453 in 2005. The increase in prevalence of pregnant women
A number of studies have demonstrated low Apgar scores in
undergoing treatment is also found in other countries, for
children exposed to SSRIs in utero22–26 whereas the effects of
newer and older antidepressants have not been investigated.27We found that the risk of a low Apgar score was associated
specifically with the use of SSRIs during pregnancy whereas
We used information from national registers with longitudinal
there was no increased risk in relation to the use of newer
data on inhabitants from an entire country. The data in these
antidepressants or older antidepressants (mainly tricyclic anti-
registries are collected prospectively and therefore recall bias is
depressants; Table 3). A recent review28 suggests that antenatal
excluded. In contrast, in retrospective studies the recall of
exposure to antidepressants is associated with a higher risk of
potential treatment with antidepressants during pregnancy may
neonatal adaptation difficulties.22,29 A possible explanation could
be influenced by the prevalence of birth complications. The study
be a direct effect of SSRIs on the development of the fetal brain.
presents data from almost 665 000 births and is able to adjust for a
The serotonergic network projects from the raphe nuclei and
number of potential confounders including all medication other
arborises over large areas to an array of other nuclei30 comprising
than antidepressants. We had almost complete data with, for
functionally diverse targets; it interacts with other neurotransmitter
example, information on the Apgar scores for 98.9% of infants.
systems31 and plays a role in regulation and developmental signalling
The number of women who did not use antidepressants during
in the organisation of developing neural networks in the central
pregnancy but who previously had used antidepressants or had
nervous system (CNS).32 Antidepressants readily cross the placental
a diagnosis of depression was rather large and consequently the
barrier, exposing the fetal CNS, which from even a very early
statistical power to detect an association between depressive illness
embryonic stage, displays a serotonergic network,4 and effects in
per se and a low Apgar score was high, as reflected by the narrow
offspring after maternal exposure to antidepressants have been
We were able to take into account other possible risk factors
for a low Apgar score (i.e. parity, maternal social status, maternal
smoking status, calendar year, other medication and gestational
Redeeming a prescription does not necessarily mean that the
age). In our models, these factors did not explain the higher
woman actually took the medication, although having paid for
ORs for a low Apgar score for children born of mothers using
it at a pharmacy increases the possibility. The potential exposure
antidepressants during pregnancy. This finding was independent
misclassification tends to underestimate the effect of antidepressant
of whether the mother had a diagnosis of depression or not.
drugs or overestimate the effect of depression among women that
Confounding by unmeasured factors or residual confounding is,
however, still possible but would have to act specifically on the
The timing of maternal depression varied in the study and the
women with depression and who took medication and not on
extent to which women presented with depressive symptoms
the non-medicated controls to explain our main result (see
before compared with during pregnancy may be unclear. In fact,
below). The aim of this study was not to determine whether
3245 women received a diagnosis of depression before pregnancy
pregnant women with depression should be treated with anti-
(with a median period from the time of diagnosis to pregnancy of
depressants or not. The study shows that treating depression does
801 days (quartiles: 346, 1568)) and 918 received a diagnosis
have consequences that should be taken into consideration when a
during pregnancy. It is likely that the former group may have
physician informs a female patient about risk factors enabling her
presented with depressive symptoms of differing severity during
to make an evidence-based decision. Thus, although the probability
pregnancy although only 27% of this group got antidepressants
of a low Apgar score was increased more than 70% in children
during pregnancy. Nevertheless, we can only conclude from our
whose mother had used SSRIs during pregnancy, compared with
results that having a depressive disorder at one point in time
healthy women, the absolute prevalence of a low Apgar score
before the end of pregnancy was not associated with an increased
was still low (1.14%, Table 1). Further, treatment with anti-
risk of a low Apgar score when the pregnant women did not use
depressants during pregnancy has been associated with a number
antidepressants during pregnancy (risk groups 5 and 6 in Table 2).
Antidepressant use in pregnancy and Apgar scores
We cannot exclude the possibility that the risk of a low Apgar
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Association of Apgar score at five minutes with long-term neurologic
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disability and cognitive function in a prevalence study of Danish conscripts.
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and Related Health Problems (ICD–8). WHO, 1967.
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If your family has a history of breast or ovarian cancerLearn about your risk for hereditary breast and ovarian cancer and how you can reduce itDo you have a family history of breast or ovarian cancer?Ask yourself the question. The answer could help you be ready against hereditary cancer. WHAT IS A FAMILY HISTORY OF BREAST OR OVARIAN CANCER?To understand if breast or ovarian cancer runs in y
ª 2011 Adis Data Information BV. All rights reserved. Role of Cannabinoids in Multiple SclerosisJohn P. Zajicek1 and Vicentiu I. Apostu21 Clinical Neurology Research Group, Peninsula College of Medicine and Dentistry, Plymouth, UK2 Clinical Neurology Research Group, Peninsula Medical School, Plymouth, UKAbstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .