Neonatal Morbidity After

Maternal Use of Antidepressant

Drugs During Pregnancy
Ulrika Nörby, MSc Pharm,a,b Lisa Forsberg, MD, PhD,c,d Katarina Wide, MD, PhD,c,d
Gunnar Sjörs, MD, PhD,e Birger Winbladh, MD, PhD,f Karin Källén, PhDa

OBJECTIVES: To estimate the rate of admissions to NICUs, as well as infants’ morbidity and abstract
neonatal interventions, after exposure to antidepressant drugs in utero.
METHODS: Data on pregnancies, deliveries, prescription drug use, and health status of the
newborn infants were obtained from the Swedish Medical Birth Register, the Prescribed
Drug Register, and the Swedish Neonatal Quality Register. We included 741 040 singletons,
born between July 1, 2006, and December 31, 2012. Of the infants, 17 736 (2.4%) had
mothers who used selective serotonin reuptake inhibitors (SSRIs) during pregnancy.
Infants exposed to an SSRI were compared with nonexposed infants, and infants exposed
during late pregnancy were compared with those exposed during early pregnancy only. The
results were analyzed with logistic regression analysis.
RESULTS: After maternal use of an SSRI, 13.7% of the infants were admitted to the NICU
compared with 8.2% in the population (adjusted odds ratio: 1.5 [95% confidence interval:
1.4–1.5]). The admission rate to the NICU after treatment during late pregnancy was 16.5%
compared with 10.8% after treatment during early pregnancy only (adjusted odds ratio: 1.6
[95% confidence interval: 1.5–1.8]). Respiratory and central nervous system disorders and
hypoglycemia were more common after maternal use of an SSRI. Infants exposed to SSRIs
in late pregnancy compared with early pregnancy had a higher risk of persistent pulmonary
hypertension (number needed to harm: 285).
CONCLUSIONS: Maternal use of antidepressants during pregnancy was associated with
increased neonatal morbidity and a higher rate of admissions to the NICU. The absolute risk
for severe disease was low, however.

aCentre of Reproduction Epidemiology, Tornblad Institute, Institution of Clinical Science, Lund University, Lund,
WHAT’S KNOWN ON THIS SUBJECT: Antidepressant
Sweden; bDepartment of E-health and Strategic IT, Health and Medical Care Administration, Stockholm County drug use during pregnancy is associated with
Council, Stockholm, Sweden; cDepartment of Pediatrics, Karolinska University Hospital, Stockholm, Sweden; several neonatal complications. However, the
dDepartment of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm,
severity of the symptoms and to what extent they
Sweden; eDepartment of Women’s and Children’s Health, Uppsala University, Uppsala, Sweden; and fDepartment are caused by the drugs or the disease is still
of Clinical Sciences and Education, Karolinska Institutet, Sachs’ Children’s and Youth Hospital, Stockholm,
Sweden
unclear.
WHAT THIS STUDY ADDS: We have quantified
Ms Nörby and Dr Forsberg planned and designed the study with special emphasis on
antidepressant drugs and neonatal outcomes, respectively; they also drafted the initial the neonatal morbidity for infants exposed to
manuscript. Dr Källén planned and designed the study and was responsible for the data collection antidepressant drugs during pregnancy in a
and statistical analysis; Drs Wide, Sjörs, and Winbladh acted as scientific advisers during the population-based study. Our results support
study process; and all authors critically reviewed and revised the manuscript and approved the a causal relationship between antidepressant
final version as submitted. exposure in utero and need of specialized neonatal
DOI: 10.1542/peds.2016-0181 care and interventions.
Accepted for publication Aug 19, 2016
To cite: Nörby U, Forsberg L, Wide K, et al. Neonatal Morbidity
After Maternal Use of Antidepressant Drugs During Pregnancy.
Pediatrics. 2016;138(5):e20160181

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PEDIATRICS Volume 138, number 5, November 2016:e20160181 ARTICLE
Treatment with antidepressant with exposure primarily during late PDR are classified according to the
drugs during pregnancy is linked pregnancy.1,2,12,19,22 Anatomical Therapeutic Chemical
to neonatal complications such as classification system.
respiratory distress, hypoglycemia,
METHODS Antidepressant exposure was defined
and central nervous system (CNS)
as drugs belonging to Anatomical
disorders, as well as preterm birth, The study was register based, Therapeutic Chemical class N06A
low birth weight, and low Apgar combining data from the Swedish (antidepressants). These drugs were
scores.1–21 The neonatal problems Medical Birth Register (MBR),35 the divided into subgroups on the basis
are mostly transient2,3,9,10,22 Prescribed Drug Register (PDR),36 of their pharmacologic properties.
but may require treatment in a the Swedish Neonatal Quality For the main results, we focused the
NICU.1,4,6,12 Proposed mechanisms Register (SNQ),37 and the Perinatal analyses on SSRIs (N06AB), which
are withdrawal effects5,22,23 or Revision South Register (PRS).38 constituted 79% of the reported
serotonergic overstimulation Linkage between the registers was antidepressant drug intake.
syndrome.5,22 It is unclear to what accomplished by using the Swedish
extent these complications are personal identification numbers. The use of antidepressants was
caused by the antidepressant Our study population consisted of allocated into any use (exposure at
drugs6,11,13,16,18,19 or by the all singleton births in Sweden (a any time during or 1 month before
underlying disease.24–27 Persistent total of 741 040 infants) registered the pregnancy), late use (drugs
pulmonary hypertension in the in the MBR between July, 1, 2006, dispensed during the last 90 days of
newborn (PPHN) is a potentially serious and December, 31, 2012. An outline the pregnancy with or without early
but rare complication associated of the study design is presented in use), and early use only (exposure 1
specifically with selective serotonin Supplemental Fig 1. month before and during pregnancy
reuptake inhibitors (SSRIs).28–30 but not during the last 90 days of the
All pregnant women in Sweden are pregnancy). Supplemental Table 5
Indications for SSRI treatment are offered free antenatal care. At their provides details of the antidepressant
depressive and anxiety disorders, initial visit, in 90% of the cases in drug exposure.
both of which are common in the first trimester,35 the women
the pregnant population.31,32 are interviewed by their midwife, We also collected data on the
Approximately 4% of pregnant and information regarding height, following neurotropic drugs known
women in Sweden and 6% in the weight, medications, and smoking or suspected to cause neonatal
United States undergo treatment habits are prospectively collected problems similar to antidepressants:
with SSRIs,32–34 and their use is and registered in the MBR. During antiepileptics, opioids,
increasing.33,34 the second trimester, the women are psycholeptics, and centrally acting
offered a free ultrasound examination sympathomimetics.21 Mild sedatives
The aim of the present study was
to check for multiple pregnancies, (alimemazine, promethazine,
to analyze the severity of neonatal
congenital malformations, and to propiomazine, and hydroxyzine)
complications (primarily measured
obtain an expected date of delivery. were classified separately from the
as admissions to the NICU) after
In total, the MBR contains data on neurotropic drugs.
fetal exposure to antidepressant
drugs, with a special focus on SSRIs. antenatal care, delivery, and the
pediatric examination of the newborn Neonatal Outcomes
By combining data from national
health registers with Swedish child for >97% of all births. The MBR Data on admissions to neonatal
quality registers on neonatal was used in the present study to wards were extracted from the
care, comprehensive information obtain information on maternal and national SNQ37 that covers all 37
was obtained regarding the fetal background characteristics. NICUs in Sweden. Because the south
infants’ morbidity on a population of Sweden was not included in the
Drug Exposure
level. Another objective was to SNQ until 2012, data from this region
differentiate the neonatal effects Data on prescription drug exposure were collected from the PRS38 for the
of the drug treatment from the were acquired from the MBR years 2006 to 2011. Both registers
impact of the women’s psychiatric (midwife interview) and the PDR. comprise detailed information on
conditions, as far as possible. This The PDR stores data on all drugs infants treated at neonatal wards.
approach was undertaken by prescribed in ambulatory care and The infants’ diagnoses were obtained
comparing exposure to SSRIs in late dispensed at a Swedish pharmacy from SNQ/PRS and MBR, where
pregnancy versus early pregnancy but does not include medications they are registered according to
only because neonatal adaption used for in-patient care in hospitals.36 the International Classification of
problems have been associated The drugs registered in the MBR and Diseases, 10th Revision. We also

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2 NÖRBY et al
collected diagnoses from the SNQ means. Tests of homogeneity of the Admission to NICU
that are recorded via checkboxes ORs across the antidepressant groups Infants exposed to SSRIs were more
in the infant’s medical record. A were based on weighted sums of the often treated at a NICU than infants
comprehensive list of neonatal squared deviations of the stratum- not exposed to antidepressants
outcomes and data sources is specific log-ORs from their weighted (OR: 1.5 [95% CI: 1.4–1.5]; number
available in Supplemental Table 6. means. needed to harm [NNH]: 29; adjusted
The care at NICUs in Sweden for maternal factors) (Table 2).
Differences regarding the length of
corresponds to the American Adjustment for fetal factors (GA and
stay at the NICU and the number of
Academy of Pediatrics’ classifications small for gestational age [SGA]), in
days on a ventilator or continuous
of neonatal care, Levels II to IV.39 addition to maternal factors, did not
positive airway pressure (CPAP)
Infants with minor neonatal change the OR. The risk was highest
were evaluated by using Mann-
complications may remain in the after exposure to SSRIs during late
Whitney U tests or Kruskal-Wallis
maternity ward (equivalent to Level I pregnancy (adjusted OR: 1.8 [95%
tests. Statistical analyses were
care) and are not included in the SNQ CI: 1.7–1.9]; NNH: 17). Comparison
conducted by using SPSS version
or PRS. Their diagnoses are, however, between late and early SSRI exposure
22 (IBM SPSS Statistics, IBM
registered in the MBR. only yielded an OR of 1.6 (95% CI:
Corporation, Armonk, NY) and Gauss
1.5–1.8) and an NNH of 18, adjusted
(Aptech Systems Inc, Maple Valley,
Statistical Analyses for maternal factors (Supplemental
WA; http://www.aptech.com,version
Table 8).
Odds ratios (ORs) for dichotomous 10).
outcomes, any antidepressant There was a heterogeneity between
use versus no use, the individual Ethics the different antidepressant drug
antidepressant substances versus groups (P = .002) (Supplemental
no use, or late use versus early The study was approved by the Table 8). The risks for treatment at
use only were obtained by using regional ethical review board in Lund the NICU were highest for serotonin
logistic regression analyses. When (dnr. 2013/342-31/5). norepinephrine reuptake inhibitors
so specified in the tables and in and tricyclic antidepressants (ORs:
the text, crude and adjusted ORs 2.7 [95% CI: 2.0–3.5] and 2.6 [95%
are displayed. Prefatory analyses CI: 1.7–3.4], respectively) comparing
RESULTS
were performed to choose the late exposure with early exposure
most efficient way to represent the Table 1 summarizes maternal and and adjusted for maternal factors.
covariates in the analyses (linear, fetal background characteristics
Duration of NICU Care
second-degree polynomial, or for the subcohorts maternal use
division into class variables). In the of SSRIs and no antidepressant The median duration of stay among
final analyses, adjustments were drug use. Corresponding data for infants treated at a NICU was 5 days
made for maternal factors: maternal exposure to other antidepressant for SSRI-exposed infants compared
age (linear continues variable), year drugs are displayed in Supplemental with 7 days for non-exposed (P <
of birth (linear), primiparity (versus Table 7. Pregnant women who used .001). The corresponding figures for
multiparity), maternal smoking SSRIs tended to be older, were term infants only were 4 days and 5
(ordinal scale, 1 = no, 2 = 1–9 to a higher extent smokers, more days, respectively (P < .001). Infants
cigarettes per day, 3 = ≥10 cigarettes often had a BMI >30, and more exposed to other neurotropic drugs
per day), BMI (linear), mother born frequently gave birth by cesarean were excluded from this analysis.
in Sweden (no versus yes), cohabiting delivery. Exposed neonates were
with the child’s father (no versus to a higher extent born moderately Neonatal Morbidity and Treatment
yes), cesarean delivery (yes versus preterm, with birth weight <2500 Table 3 displays diagnoses and
no), any use of mild sedatives (yes g and/or low Apgar scores. The treatments after SSRI use compared
versus no), and maternal use of crude OR in Table 1 indicated with no antidepressant exposure,
other neurotropic drugs (yes versus an increased risk for stillbirth and Table 4 displays exposure to
no).When so specified, adjustments among SSRI-exposed infants. After SSRIs in late versus early pregnancy
were also made for fetal factors: adjustment for maternal factors, the only. An increased frequency of
gestational age (GA) (linear) and association between maternal use of any respiratory disorder (but not
fetal weight for GA and sex (birth antidepressants and stillbirth was no for respiratory distress syndrome)
weight z scores, linear).40 Missing longer statistically significant (OR: was seen, especially after use
data regarding maternal smoking 1.2 [95% confidence interval (CI): of SSRIs during late pregnancy.
and BMI were replaced by the overall 1.0–1.5]; P = .08). Treatment with CPAP was also

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PEDIATRICS Volume 138, number 5, November 2016 3
TABLE 1 Background Characteristics of the Study Population: Maternal Use of SSRIs Versus No Antidepressant Drug Use During Pregnancy
Characteristic SSRI Without Other SSRI + Other Total SSRI Use (n No Antidepressant Total SSRI Versus No Antidepressant
Neurotropic Drugs (n Neurotropic Drugsa = 17 736) Use (n = 718 533) Use
= 12 516) (n = 5220)
% % % % OR 95% CI
Maternal characteristics
Year of child’s birth
2005–2008 33.7 35.9 34.2 42.0 0.7 0.7–0.7
2009–2012 66.3 64.1 65.8 58.0 1.4 1.4–1.4
Maternal age, y
<20 1.8 1.7 1.8 1.7 1.1 1.0–1.2
≥35 26.1 26.6 26.3 21.5 1.3 1.2–1.3
Parity
Primipara 46.2 45.4 45.8 45.3 1.0 1.0–1.0
Multipara 53.8 54.6 54.2 54.7 1.0 1.0–1.0
BMI
<18.5b 2.3 2.4 2.3 2.4 1.0 0.9–1.1
>30b 16.1 20.8 17.6 12.1 1.6 1.5–1.6
Missing 7.6 8.9 8.1 8.5 0.9 0.9–1.0
Maternal smokingb 11.8 17.9 14.1 6.4 2.4 2.3–2.5
Missing 3.7 4.2 3.9 4.7 0.8 0.8–0.9
Maternal country of birth
Sweden 88.2 83.9 87.0 76.0 2.1 2.0–2.2
Other Nordic 1.6 1.8 1.7 2.0 0.8 0.7–0.9
Non-Nordic 10.2 14.3 11.3 20.6 0.5 0.5–0.5
Not living with father of child 9.5 14.5 11.1 5.8 2.0 1.9–2.1
Maternal disease
Diabetes 0.8 1.1 0.9 0.5 1.7 1.4–2.0
Gestational diabetes 1.3 1.6 1.5 1.1 1.3 1.2–1.5
Hypothyroidism 3.0 3.1 3.1 1.6 2.0 1.8–2.2
Essential hypertension 0.4 0.8 0.5 0.4 1.4 1.1–1.7
Severe preeclampsia 1.2 1.1 1.2 0.9 1.3 1.2–1.5
Crohn’s disease 0.4 0.6 0.5 0.2 2.0 1.6–2.5
Use of neurotropic drugsc
Opioids (N02A) — 35.6 12.7 5.1 2.7 2.6–2.8
Antiepileptics (N03A) — 4.3 3.0 0.4 7.8 7.1–8.6
Psycholeptics (N05) — 57.7 19.0 1.4 17.0 16.3–17.8
Centrally acting sympathomimetics (N06BA) — 2.3 1.1 0.1 11.8 10.1–13.9
Use of mild sedativesd 21.0 39.2 27.5 3.5 10.5 10.2–10.9
Cesarean delivery 20.8 25.3 22.4 16.5 1.5 1.4–1.5
Infant characteristics
Male sex 51.3 51.7 51.5 51.2 1.0 1.0–1.0
GA, wk
<32 0.9 1.1 1.0 1.2 0.8 0.7–1.0
32–36 2.7 3.1 2.9 1.9 1.6 1.4–1.7
37–41 88.6 88.0 88.2 88.0 1.0 1.0–1.1
≥42 4.8 3.4 4.3 6.7 0.6 0.6–0.7
Birth weight
<2500 g 4.2 5.2 4.6 3.2 1.5 1.4–1.6
SGA 2.4 2.9 2.6 2.3 1.1 1.0–1.2
LGA 4.3 4.7 4.5 4.0 1.1 1.0–1.2
Apgar score <7 at 5 min 2.7 2.6 2.7 1.3 2.2 2.0–2.4
Birth defects (weeded)e
Total 2.2 2.3 2.2 2.2 1.0 0.9–1.2
Heart malformation 0.8 0.7 0.8 0.8 1.0 0.9–1.2
Perinatal deathf 0.5 0.7 0.5 0.4 1.2 1.0–1.5
Stillbirth 0.4 0.6 0.5 0.3 1.4 1.1–1.7
Neonatal deathg 0.1 0.2 0.1 0.1 1.0 0.7–1.5
LGA, large for gestational age.
a Opioids (N02A), antiepileptics (N03A), psycholeptics (N05), and centrally acting sympathomimetics (N06BA).
b Percentages were based on records with valid information.
c Anatomical Therapeutic Chemical classification system codes given within parentheses.
d Alimemazine, propiomazine, promethazine, and hydroxyzine.
e Birth defects (weeded), malformations defined as International Classification of Diseases, 10th Revision, diagnoses beginning with Q, excluding the following minor conditions:

preauricular appendix, patent ductus arteriosus in a preterm infant, single umbilical artery, tongue tie, undescended testicle, hip dislocation/subluxation, and nevus.
f Stillbirth and death within 7 days from birth.
g Death within 28 days after birth.

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4 NÖRBY et al
TABLE 2 Admission to NICU Among Infants Exposed to SSRIs Compared With Infants Not Exposed to Antidepressant Drugs During Pregnancy
Exposure Group Crude Adjusted for Maternal Factors, Adjusted for Maternal and
a Including Use of Other Fetal Factorsc
Neurotropic Drugsb
Total NICU % OR 95% CI OR 95% CI OR 95% CI
No antidepressant 718 533 59 210 8.2 1.0 Ref 1.0 Ref 1.0 Ref
SSRI, any use 17 736 2437 13.7 1.8 1.7–1.9 1.5 1.4–1.5 1.5 1.4–1.5
SSRI, early use onlyd 8636 936 10.8 1.4 1.3–1.4 1.1 1.0–1.2* 1.2 1.1–1.2
SSRI, late usee 9100 1501 16.5 2.2 2.1–2.3 1.8 1.7–1.9 1.7 1.6–1.8
Exposure information acquired from self-reported use in early pregnancy or any prescription during pregnancy or 1 month before. ORs were obtained by using multiple logistic regression
analyses.
a Maternal age, year of birth, primiparity (versus multiparity), maternal smoking, BMI, mother born in Sweden, cohabiting with the child’s father, cesarean delivery, and any use of mild

sedatives during pregnancy.

b Opioids (N02A), antiepileptics (N03A), psycholeptics (N05), and centrally acting sympathomimetics (N06BA).
c GA and fetal weight for GA and sex (birth weight z scores).
d Exposure 1 month before and during pregnancy but not for the last 90 days of the pregnancy.
e Drugs dispensed during the last 90 days of the pregnancy with or without use during early pregnancy.
* Statistically significant (P < .05).

more frequent for infants exposed (171 of 2051) for nonexposed infants increased risk of admission to
to SSRIs. The median treatment (OR: 0.4 [95% CI: 0.1–1.2]).The the NICU in all groups exposed to
time with CPAP was 2 days for need for ventilator treatment among antidepressant drugs, with the highest
both exposed and nonexposed children with PPHN was significantly proportion of neonatal care after
infants. Ventilator treatment was less in infants exposed to SSRIs (47% exposure to serotonin norepinephrine
slightly more common in infants reuptake inhibitors or tricyclic
[42 of 89]) than among nonexposed
born to mothers who used SSRIs antidepressants in late pregnancy.
infants (62% [1267 of 2051]; OR:
during late pregnancy compared Because the median duration of NICU
with early pregnancy only. The 0.6 [95% CI: 0.4–0.9]). When GA was stay for the SSRI-exposed infants was
median time on a ventilator was 3 adjusted for, no difference between ∼1 week (just slightly shorter than
days for SSRI-exposed infants and the need for ventilator treatment that for the nonexposed infants), we
4 days for nonexposed infants (P was indicated (OR: 0.9 [95% CI: believe that they were admitted due
value for difference: .16). Analysis 0.5–1.4]). Exposure to SSRIs did to substantial neonatal problems
of neonatal morbidity according to not affect the median length of stay and not only as a precaution. This
GA for late SSRI use versus early in the NICU, which was 11 days for theory is supported by the fact that
SSRI use revealed that the ORs for term infants with PPHN (P = .7 for CPAP treatment was more common
respiratory disorders were more difference in exposed/nonexposed) than in nonexposed infants, and
pronounced in term infants than and 63 days for preterm infants with ventilator treatment more frequent,
in preterm infants (Supplemental after exposure during late pregnancy
PPHN (P = .5).
Tables 9 and 10). compared with early pregnancy only.
An increased occurrence of
hypoglycemia, CNS symptoms, and Some earlier reports suggested that
PPHN was more common both when
feeding difficulties after maternal severity of maternal depression
comparing SSRI exposure versus
use of SSRIs was also reported per se is of greater importance
nonexposure (OR: 1.3 [95% CI: 1.0–
(Table 3 and 4). than the drug effects.24,25 Untreated
1.6]; P = .03) and treatment during
late versus early pregnancy (OR: 2.1 depression and anxiety disorders
[95% CI: 1.3–3.2]) (Tables 3 and 4). have been linked to similar outcomes
DISCUSSION as treatment with antidepressant
The corresponding NNH was 285
comparing late and early exposure, Poor neonatal adaptation is well agents (eg, neonatal adaptation
adjusted for maternal factors. described as a consequence of difficulties, preterm birth, SGA).41–45
maternal use of antidepressant drugs We found increased odds for
Restricting the analysis to term
during pregnancy.1–5,7–15,17,33 Our admission to the NICU after exposure
infants, the OR for PPHN, SSRI late
study adds information concerning to antidepressants during late
exposure versus early exposure, was the need for neonatal care associated pregnancy compared with exposure
2.6 (95% CI: 1.4–4.8), and the NNH with antidepressant exposure; for during early pregnancy only. This
was 322. The mortality rate among SSRIs, it provides detailed data finding was an attempt to account for
infants with PPHN was 3.4% (3 of 89) on morbidity as well as neonatal the underlying psychiatric condition,
for SSRI-exposed infants and 8.3% interventions. We observed an and the clearly increased risk after

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PEDIATRICS Volume 138, number 5, November 2016 5
6
TABLE 3 Neonatal Morbidity Among Infants Exposed to SSRIs Compared With No Antidepressant Drug Exposure During Pregnancy
Outcome Any SSRI (n = 17 736) No Antidepressants (n = 718 533) Crude Adjusted for Maternala Factors, Adjusted for Fetalc and Maternal
Including Use of Other Neurotropic Factors, Including Use of Other
Drugsb Neurotropic Drugs
n % n % OR 95% CI OR 95% CI OR 95% CI
Any respiratory disorder 1 019 5.7 20 922 2.9 2.0 1.9–2.2 1.6 1.5–1.7 1.6 1.5–1.7
RDS 127 0.7 3744 0.5 1.4 1.2–1.6 1.0 0.8–1.2 1.0 0.8–1.2
Transient tachypnea/other respiratory 819 4.6 15 860 2.2 2.1 2.0–2.3 1.7 1.6–1.9 1.7 1.6–1.9
disease
PPHN 89 0.5 2051 0.3 1.8 1.4–2.1 1.3 1.0–1.6* 1.3 1.0–1.7*
MAS 42 0.2 969 0.1 1.8 1.3–2.4 1.6 1.1–2.1 1.8 1.3–2.4
Ventilator treatment 140 0.8 3849 0.5 1.5 1.2–1.8 1.1 1.0–1.4 1.2 1.0–1.4
CPAP 749 4.2 15 690 2.2 2.0 1.8–2.1 1.5 1.4–1.6 1.5 1.4–1.7
Hypoglycemia 701 4.0 17 439 2.4 1.6 1.5–1.8 1.3 1.2–1.4 1.3 1.2–1.4
Hyperbilirubinemia 918 5.2 32 481 4.5 1.1 1.1–1.2 1.0 1.0–1.1 1.0 0.9–1.1
CNS-related disorders 94 0.5 2082 0.3 1.8 1.5–2.2 1.5 1.2–1.9 1.5 1.2–1.8
Intracranial hemorrhage 52 0.3 1897 0.3 1.1 0.8–1.5 0.9 0.7–1.2 0.9 0.7–1.2
Feeding difficulties 227 1.3 6777 0.9 1.4 1.2–1.6 1.0 0.9–1.2 1.0 0.9–1.2
Treated PDA 50 0.3 1362 0.2 1.5 1.1–2.0 1.2 0.9–1.6 1.3 1.0–1.8
Verified infections 91 0.5 2539 0.4 1.4 1.2–1.8 1.2 1.0–1.5 1.2 1.0–1.6
ORs were obtained by using multiple logistic regression analyses. MAS, meconium aspiration syndrome; PDA, patent ductus arteriosus; RDS, respiratory distress syndrome.
a Maternal age, year of birth, primiparity (versus multiparity), maternal smoking, BMI, mother born in Sweden, cohabiting with the child’s father, cesarean delivery, and any use of mild sedatives during pregnancy.
b Opioids (N02A), antiepileptics (N03A), psycholeptics (N05), and centrally acting sympathomimetics (N06BA).
c GA and fetal weight for GA and sex (birth weight z scores).
* Statistically significant (P < .05).

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infants only.

be excluded.
drug treatment.

Similar to previous studies,

we found a higher frequency
of respiratory disorders, CNS

Primarily in term infants, we

growth restriction. In fact, all

reported mortality rates up to

respiratory distress syndrome.

and PPHN,28–30,46 a potentially

for GA and SGA, indicating that

life-threatening condition with

restricting the analysis to term

confirmed the earlier described

in the subcohort of term infants

considered. In the present SSRI-

to antidepressants and neonatal

overall impact of SSRI use in late

among term infants. Because the
estimates remained and were, in
via preterm birth or intrauterine

than in the total cohort. Thus, the

and SSRI-exposed infants were at

the NNH was nevertheless higher

the association between exposure

among preterm than term infants,

absolute risk for PPHN was higher
varied between the drug exposure

pregnancy on PPHN rates is larger

NICU in exposed infants compared

The rate of admissions to the NICU

differences in underlying maternal

with nonexposed infants remained

early SSRI use, was significant only

psychiatric conditions between the

use of SSRIs but no increased risk of

association between SSRI exposure

if both term and preterm births are

suggests a true association with the

largely unchanged after adjustment

The higher risk of admittance to the

most cases, more pronounced when

morbidity is not primarily mediated

groups. This finding might be due to

10%.47 The OR for PPHN, late versus

exposed cohort with PPHN, neonatal

antidepressant use in late pregnancy

groups, but a drug class effect cannot

difficulties3,4,9,14,17,20–22 after maternal

increased risk of being born preterm,

symptoms, hypoglycemia, and feeding

NÖRBY et al
 TABLE 4 Neonatal Morbidity Among Infants Exposed to SSRIs During Late Pregnancy Compared With Exposure During Early Pregnancy Only
Outcome SSRI, Late Usea (n = 9100) SSRI, Early Use Onlyb (n = Crude Adjusted for Maternalc Factors, Adjusted for Fetale and Maternal
8636) Including Use of Other Neurotropic Factors, Including Use of Other
Drugsd Neurotropic Drugs
n % n % OR 95% CI OR 95% CI OR 95% CI
Any respiratory disorder 649 7.1 370 4.3 1.7 1.5–2.0 1.6 1.4–1.9 1.4 1.2–1.6
RDS 64 0.7 63 0.7 1.0 0.7–1.4 1.0 0.7–1.4 0.5 0.3–0.9
Transient tachypnea/other 536 5.9 283 3.3 1.8 1.6–2.1 1.7 1.5–2.0 1.6 1.4–1.8
respiratory distress
PPHN 60 0.7 29 0.3 2.0 1.3–3.0 2.1 1.3–3.2 1.7 1.1–2.8
MAS 26 0.3 16 0.2 1.5 0.8–2.9 1.6 0.8–3.0 1.9 1.0–3.6
Ventilator treatment 85 0.9 55 0.6 1.4 1.0–2.1* 1.5 1.1–2.1 1.1 0.8–1.7
CPAP 480 5.3 269 3.1 1.7 1.5–2.0 1.7 1.4–2.0 1.4 1.2–1.7
Hypoglycemia 427 4.7 274 3.2 1.5 1.3–1.8 1.5 1.3–1.7 1.3 1.1–1.6

PEDIATRICS Volume 138, number 5, November 2016

Hyperbilirubinemia 481 5.3 437 5.1 1.0 0.9–1.2 1.0 0.9–1.2 0.8 0.6–0.9
CNS-related disorders 65 0.7 29 0.3 2.1 1.4–3.3 2.0 1.3–3.1 1.9 1.2–3.0
Intracranial hemorrhage 30 0.3 22 0.3 1.3 0.7–2.2 1.3 0.7–2.3 1.0 0.6–1.8
Feeding difficulties 147 1.6 80 0.9 1.8 1.3–2.3 1.7 1.3–2.3 1.4 1.1–1.9
Treated PDA 31 0.3 19 0.2 1.6 0.9–2.7 1.6 0.9–3.0 1.0 0.5–2.1
Verified infections 50 0.5 41 0.5 1.2 0.8–1.8 1.1 0.7–1.7 0.8 0.5–1.3
ORs were obtained by using multiple logistic regression analyses. MAS, meconium aspiration syndrome; PDA, patent ductus arteriosus; RDS, respiratory distress syndrome.
a Drugs dispensed during the last 90 days of the pregnancy with or without use during early pregnancy.
b Exposure 1 month before and during pregnancy but not for the last 90 days of the pregnancy.
c Maternal age, year of birth, primiparity (versus multiparity), maternal smoking, BMI, mother born in Sweden, cohabiting with the child’s father, cesarean delivery, and any use of mild sedatives during pregnancy.
d Opioids (N02A), antiepileptics (N03A), psycholeptics (N05), and centrally acting sympathomimetics (N06BA).
e GA and fetal weight for GA and sex (birth weight z scores).
* Statistically significant (P < .05).

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of a large, population-based,

information on alcohol or illicit

the results. Alcohol is, however,

diagnoses.37 We could adjust for
were not significantly different

for GA, the need for ventilatory

closely associated with smoking,

combined with severe neonatal

of illicit drug use among pregnant

have less severe symptoms than

MD, PhD, written communication,

not differ between SSRI-exposed

It is likely that the real exposure is

PDR only provides information on
other infants with this condition.
PPHN versus nonexposed infants

with high coverage of data35,48 and

mortality was 3%, which is lower

BMI, family situation, and cesarean

sparse data exist regarding the rate

detailed information on the infants’
(which is probably more common
than previously reported.28 In our

and adjustment for smoking did not

drug use, which might have affected
between exposed and nonexposed

2016). Another limitation is that the

the region during 2014 had ongoing
study, the neonatal mortality rates

prospectively collected study cohort

only 8 women continued their abuse

in SSRI-exposed infants) and PPHN

the 29 166 women who gave birth in

the treatment is obviously unknown.

infants with PPNH. To some extent,

different conditions: isolated PPHN

The present study had the advantage

drugs that have been dispensed from

illicit drug use during pregnancy, and
support and length of NICU stay did

and nonexposed infants with PPHN.

known confounders such as smoking,

substantially alter the estimates. Only

throughout the pregnancy (I. Sarman,

illness.47 However, after adjustment

report from the Stockholm area, 31 of

delivery. The registries do not contain
use of other drugs with similar effects,
with PPHN may be partly comparing

the pharmacies, and the compliance to

Therefore, our results do not suggest
that SSRI-exposed infants with PPHN

women in Sweden. According to a local

comparing SSRI-exposed infants with

7
lower but this outcome would only ethical reasons but for moderate primarily among term infants. The
slightly affect the calculated risks. disease, it might be feasible.49 individual risk for neonatal illness
Furthermore, the timing of drug When assessing an infant prenatally linked to antidepressant drug
intake was approximated from the exposed to antidepressant treatment was moderate, and it
dates the drugs were dispensed. Some drugs, one should be particularly must be carefully weighed
women might have lowered their aware of respiratory disorders, against the potentially negative
dose before conception or during the hypoglycemia, feeding difficulties, consequences for both the
pregnancy and therefore did not need and CNS symptoms. However, it woman and her child that
a refill of drugs after the expected 3 is important to note that the risk untreated psychiatric conditions
months. This approach could have led increase for severe disease is small could entail.
to misclassification of the exposure in the individual case. The majority
group, which may result in an (85%) of exposed infants do not have
underestimation of ORs. problems requiring neonatal care. ABBREVIATIONS
The main drawback with this study The overall amount of admissions
CI: confidence interval
and other observational studies is to neonatal care associated with
CNS: central nervous system
the difficulty of adjusting for the antidepressant exposure might be
CPAP: continuous positive airway
mothers’ psychiatric illness. We substantial. If ∼4% are treated in
pressure
tried to account for the underlying a population of 100 000 pregnant
GA: gestational age
psychiatric condition by comparing women, ∼145 extra admissions to the
MBR: Medical Birth Register
exposure during late pregnancy with NICU could be expected.
NNH: number needed to harm
exposure during early pregnancy only,
OR: odds ratio
but considerable residual confounding
CONCLUSIONS PDR: Prescribed Drug Register
might exist. It is reasonable to
PPHN: persistent pulmonary
assume that women who continued Maternal use of antidepressant
hypertension of the
their medication during the entire drugs during pregnancy was
newborn
pregnancy have a more severe associated with an increased risk
PRS: Perinatal Revision South
psychiatric condition than women that the newborn child would need
Register
who discontinued treatment. treatment at a NICU. The association
RDS: respiratory distress
Randomized, placebo-controlled remained after adjustment for
syndrome
studies would be valuable for premature birth and SGA, factors
SGA: small for gestational age
determining to what extent neonatal that are known to be linked to
SNQ: Swedish Neonatal Quality
outcomes are due to drug treatment maternal depression and anxiety.
Register
or to the pregnant woman’s mental The study confirms previous
SSRI: selective serotonin
condition. In severe depression, this findings of an increased risk of
reuptake inhibitor
approach would not be possible for PPHN after SSRI exposure,

Address correspondence to Ulrika Nörby, MSc Pharm, Department of E-health and Strategic IT, Health and Medical Care Administration, Stockholm County Council,
PO Box 17533, SE-118 91 Stockholm, Sweden. E-mail: ulrika.norby@sll.se
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright © 2016 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: The study was partly financed by the Department of E-health and Strategic IT, Health and Medical Care Administration, Stockholm County Council. Drs Forsberg
and Wide were partly supported by grants from the Swedish Research Council (2011-3440 and 2012-3466) and the Stockholm County Council (ALF project 532069).
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

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10 NÖRBY et al
 Neonatal Morbidity After Maternal Use of Antidepressant Drugs During
Pregnancy
Ulrika Nörby, Lisa Forsberg, Katarina Wide, Gunnar Sjörs, Birger Winbladh and
Karin Källén
Pediatrics 2016;138;; originally published online October 25, 2016;
DOI: 10.1542/peds.2016-0181
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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

publication, it has been published continuously since 1948. PEDIATRICS is owned, published,
and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk
Grove Village, Illinois, 60007. Copyright © 2016 by the American Academy of Pediatrics. All
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 Neonatal Morbidity After Maternal Use of Antidepressant Drugs During
Pregnancy
Ulrika Nörby, Lisa Forsberg, Katarina Wide, Gunnar Sjörs, Birger Winbladh and
Karin Källén
Pediatrics 2016;138;; originally published online October 25, 2016;
DOI: 10.1542/peds.2016-0181

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
/content/138/5/e20160181.full.html

PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

publication, it has been published continuously since 1948. PEDIATRICS is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2016 by the American Academy
of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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