Casper, 2003

Observational study/ retrospective chart study (for outcome of our interest)

N=44

Inclusion: Women who were in treatment in the Women's Wellness

Clinic or with other clinicians and who met DSM-IV criteria

for Major Depressive Disorder during pregnancy were

invited to participate in the follow-up study. They were recruited before or during pregnancy (71%) or after delivery (29%).

Women who were taking SSRIs at referral or started SSRI antidepressant drugs during pregnancy

N=31

Type of SSRI

-sertraling: 48%

-fluoxetine: 23%

-paroxetine: 26%

-fluvoxamine: 3.2% (50mg/day)

Mean daily dose:

-sertraline:

113.2 ± 72.3 mg,

-fluoxetine:

20 ± 11.9 mg,

-paroxetine

17.2 ± 10.1 mg,

Duration:

-entire pregn: 45%

-1st trim: 71%

-3rd trim: 74%

Alle women received supportive psychotherapy

Age: 36.6±3.5

Women who were diagnosed with major depressive disorder in pregnancy and elected not to take

medication

N = 13

Age: 34.9±3.8

Primary outcome: Structural growth and developmental outcome (between 4 and 40 months)

Secondary: Information regarding

delivery and neonatal course were collected from obstetric and neonatal medical records.

- gestational age,

- premature births,

- birth weight and/or

- length (Table II).

- Apgar score 1 minute

-Apgar score 5 minute

- NICU admission

No differences between the groups were observed for:

- gestational age,

- premature births,

- birth weight and/or

- length (Table II).

Drug-exposed children had:

- lower APGAR scores at 1 and 5 minutes than unexposed children.

- a trend for higher NICU admission rate (all used during 3rd trimester)

Reasons for NICU admission included:

- respiratory distress n=6 and

- meconium aspiration n=4

- cardiac murmur n=1

Clearly defined groups: Yes.

Selection bias: No.

Adequate exposure assessment method: Yes

Method of assessing the outcome appropriately: No, chart reviews were used for neonatal outcomes

Impactassessor blinded: No.

Follow-up: chart review

Selective loss to follow up: No

Identification confounders and correction in analysis: Yes

Funding: Not described.

Chambers, 2006

Nested case-control study (n=1213)

Incl: Mothers of children with PPHN.

(Diagnostic criteria for PPHN: GA>34 wks, presentation shortly after birth with severe respiratory failure, and evidence of pulmonary hypertension.). Telephone interview.

Excl: evidence of any cardiac anomaly except for patent ductus arteriosus, patent foramen

ovale, an atrial septal defect, or a single, small, muscular ventricular septal defect.

Setting

Study subjects

from 97 institutions were identified between 1998 and

2003.

Participation rate:

- 69% for cases

- 68% for controls

N=377 children with PPHN

(4.2% of the mothers used SSRI's sometime during pregnancy, 1.1% used other antidepressants)

N=836

(2.9% of the mothers used SSRI's sometime during pregnancy, and 1.6% used other antidepressants)

PPHN (persistent pulmonary hypertension of the newborn)

PPHN was documented either

by a 5 percent or greater gradient between preductal and postductal oxygen saturation or by

echocardiographic evidence.

14 infants with PPHN had been exposed to an SSRI after the completion of the 20th week of gestation (6 in control group)

-> Significant association with PPHN and SSRI use>20 wks gestation: Adjusted odds ratio: 6.1; 95% CI 2.2 to 16.8 (p=0.001)

No significant association for increased risk of PPHN with:

- use of SSRIs <20th week of gestation

- use of non-SSRI antidepressant drugs at any time during pregnancy

Clearly defined groups: yes, although it is unclear whether the patients that were using SSRI's were also using co-medication.

Selection bias: Possibly due to nested case-control design. No other indications for selection bias.

Adequate exposure assessment method: Yes.

Method of assessing the outcome appropriately: Yes.

Impact assessor blinded: Yes, a neonatologist who was blinded to

the history of maternal exposure to medications, reviewed the medical records of all patients with potential PPHN.

Follow-up: adequate

Selective loss to follow up: No, equal in both groups

Identification confounders and correction in analysis: Yes.

Adjustment for maternal diabetes (pregestaional or gestational, with and without treatment), maternal race or ethnic group, body-mass index, smoking, alcohol intake, and use of NSAIDs after week 20.

Funding: Not described

Costei, 2002

Prospective study

N=82

Inclusion:

Cases: women who called Motherisk program about paroxetine exposure

during the third trimester were counseled prospectively between September 1996 and September 1999. Telephone interview after delivery: about the course of pregnancy, delivery, and the neonatal

period, including malformations, developmental milestones, nutrition,

etc. Interviewers did not make any suggestions about

potential adverse outcomes.

Exclusion: women who discontinued paroxetine before the 3rd trimester or those receiving other drugs known to cause withdrawal-type symptoms, such as opioids or benzodiazepines.

3rd-trimester exposure to paroxetine

N=55

2 controle groepen N=52

1) women using paroxetine during the first or second trimester. N=27

2)women using nonteratogenic drugs. N=27

All matched for maternal age, gravity, parity, social drug use,

and non-teratogenic drug use.

Perinatal outcome, not specified in methods section

Of the 55 neonates exposed to paroxetine in

late gestation, 12 had complications necessitating intensive

treatment and prolonged hospitalization.

The most prevalent clinical picture was:

- respiratory distress (n=9),

- followed by hypoglycemia (n=2),

- jaundice (n=1).

The symptoms disappeared within 1 to 2 weeks.

In the comparison group, only 3 infants experienced complications

(P=.03). In logistic regression, only 3rd trimester exposure to paroxetine was associated with neonatal distress (odds ratio, 9.53; 95% confidence interval, 1.14-79.3).

Clearly defined groups: Yes.

Selection bias: possible, only the women calling for information could be recruited

Adequate exposure assessment method: yes

Method of assessing the outcome appropriately: No, telephone interview creates risk of bias

Impactassessor blinded: Not reported, but unlikely

Follow-up: September 1996- September 1999. Unclear when the phone interview took place ("after delivery")

Selective loss to follow up: Not reported

Identification confounders and correction in analysis: adequate: prematurity, maternal smoking, alcohol, cesarean delivery.

Funding: no evident conflict of interest

Davis, 2007

Retrospective cohort study

N=1602

Inclusion: female members older than 15 years of age who were admitted to a hospital between

January 1, 1996 and December 31, 2000 for delivery

of an infant and were continuously enrolled with

prescription drug coverage for 1 year prior to the

admission. Follow up available up to 30 days postpartum. Automated database.

Controls: infants born to mothers who were not prescribed

antidepressants at any time during pregnancy, but who

might have had other medications prescribed

N=874

(out of original data set of 99419 pregnancies)

N= 75219

- preterm birth

- fetal distress

- respiratory distress syndrome

- endocrine and metabolic disturbances

- temperature regulation disorders

- convulsions

- prolonged hospitalization

And many other outcome measures as described in table 2

Infants exposed to SSRIs in utero showed a

significant increase in risk for preterm delivery. The

overall risk for preterm delivery among exposed

infants was 9.4% (166/1768), compared to 6.6%

(5268/79 759) among infants unexposed to SSRIs (RR

1.45; 95%CI 1.25, 1.68).

Fullterm infants exposed to SSRIs during the third trimester showed a significant increase in risk for several conditions evident in the perinatal period, including:

- fetal distress (RR 6.00; 95%CI 1.88, 19.18),

- respiratory distress syndrome (RR 1.97; 95%CI 1.65, 2.35),

- endocrine and metabolic disturbances (RR 1.61; 95%CI 1.15, 2.27), - temperature regulation disorders (RR 1.56; 95%CI 1.06, 2.31),

- convulsions (RR 2.60; 95%CI 1.16, 5.84), and

- prolonged hospitalization (RR 2.22; 95%CI 1.70, 2.90)(Table 2).

Clearly defined groups: No, no patient characteristics reported

Selection bias: possible due to restrospective study design

Adequate exposure assessment method: No, the administrative datasets provided information on prescriptions, but not on whether the medication

was actually taken by the mother

Method of assessing the outcome appropriately: Unclear

Impactassessor blinded: No, possible diagnostic bias-> clinicians might be more

likely to diagnose conditions in the infant known to be associated with the medications if they knew the mother had been exposed.

Follow-up: up to 30 days postpartum, high percentage loss to follow up (35%)

Selective loss to follow up: Possibly

Identification confounders and correction in analysis: no, since there was no information in the automated database on e.g. race and substance (ab)use.

Funding: No conflict of interest

Dubnov Raz, 2008

Prospective cohort study

N=104

Between January 2000 and December 2005, we collected data on all of the

newborns born at a single tertiary care hospital. Electrocardiograms of infants exposed

to selective serotonin-reuptake inhibitor antidepressants in utero were compared

with those of healthy control newborns matched on gestational age. The

tracings were interpreted by a pediatric cardiologist who was unaware of the drug

exposure.

N=52

newborns exposed to selective serotonin-reuptake inhibitor

antidepressants in the immediate antepartum period

N= 52

matched control subjects

QT interval on ECG

The tracings were interpreted by a pediatric cardiologist who was unaware of the drug exposure.

The time from delivery to first ECG ranged from 3 to 96 hours postpartum. ECGs were performed on days 1, 2, 3, and 4 in 22%, 18%, 10%, and 2% in the SSRI group, respectively, and in 8%, 12%, 20%, and 12% in the control group, respectively.

No association between

the age at which the ECG was performed (in hours) and

the QTc interval

The mean QTc was significantly longer in the group of newborns exposed to antidepressants as compared with control subjects (409 ± 42 vs 392 ±29 milliseconds).

Five (10%) newborns exposed to selective serotonin-reuptake inhibitor antidepressants had a markedly prolonged QTc interval (>460 milliseconds) compared with none of the unexposed newborns. The longest QTc interval observed among exposed newborns was 543 milliseconds. All of the drug-associated repolarization abnormalities normalized in subsequent electrocardiographic tracings.

Clearly defined groups: Yes.

Selection bias: no

Adequate exposure assessment method: yes

Method of assessing the outcome appropriately: Yes

Impactassessor blinded: yes

Follow-up: adequate

Selective loss to follow up: not reported

Identification confounders and correction in analysis: There is no mentioning of alcohol or tobacco use.

Funding: no conflict of interest

Other: neonates with Apgar scores <7 (either 1 or 5 minutes) were excluded

Heikkinen, 2002

Prospective cohort study

N=21

Inclusion: pregnant women using citalopram (cases) or who were not taking any medication (matched controls).

Assessment:

- Pregnancy: 3 checks (physical and US examinations and bloodsamples)

-Delivery: Standardized investigation

-Early puerperium. Standardized investigation

-Follow-up until 1 year: standardized (breastmilk, plasma and examination)

Pregnant women taking citalopram

N=11

Indication for citalopram: depression (n=6), or panic disorder (n=5)

Dose: 20-40 mg a day

No significant difference between groups in characteristics except 2 patients in the citalopram group had a habit of light alcohol use during pregnancy

Pregnant women who were not taking any medication

N=10

Control group was prospectively matched for confounding obstetric characteristics (age, gravidity, parity, and time and mode of delivery) at time of delivery.

1 of 11 controls dropped out due to protocol violation

Primary: plasma and breast milk concentrations of citalopram and metabolites

Secondary outcomes:

Neonatal outcomes:

-birth weight,

-Apgar score,

-umbilical artery pH,

-body temperature and

-physical examination

1 year follow up:

-development of the infant assessed by pediatrician and physiotherapist (outcome "normal" or "abnormal")

No significant differences in neonatal outcomes (or at 1 year follow up) between groups:

Clearly defined groups: No, recruitment procedure unclear.

Selection bias: Possible.Unclear how many women were initially approached

Adequate exposure assessment method: yes

Method of assessing the outcome appropriately: unclear

Impactassessor blinded: Not described

Follow-up: yes

Selective loss to follow-up: unlikely (one drop out in control group)

Identification confounders and correction in analysis: yes

Financiering: Not mentioned!

Other:

-small sample size

-secondary outcome measurement

Kallen, 2008

Prospective study

N=831.324

N=7587 SSRI exposure

N=506 PPHN

N=11 PPHN and SSRI exposure

Swedish Medical Birth Register

for the years 1997-2005

Co-medication?

Mothers of

7587 infants reported the use of SSRI drugs in early pregnancy, 39% were citalopram, 31% sertraline, 15%

fluoxetine, 13% paroxetine and 2% fluvoxamine or escitalopram.

Persistent pulmonary hypertension in the neonate (PPHN)

The following variables were

studied: year of birth, maternal age in completed years, parity (first-born infant is born in parity 1), maternal smoking (unknown, none, <10 cigarettes per day, <10 cigarettes per day), maternal diabetes, maternal pre-pregnancy BMI (unknown, <19.8, 19.8-25.9, >26), gestational duration (completed weeks).

N=506 PPHN, out of N=831.324 infants. N=11 PPHN and SSRI exposure.

Adjusting for putative confounders and year of birth, an association between maternal use of SSRI and PPHN in births after 34 completed weeks was identified with a RR 2.4, 95% CI 1.2-4.3 when based on women who reported the drug use in early pregnancy. When a subgroup of the women were studied who also had prescriptions for SSRI from the antenatal care later in pregnancy, the RR 3.6, 95% CI 1.2-8.3.

Clearly defined groups: Yes.

Selection bias: No randomisation or blinding

Adequate exposure assessment method: Yes. But no information about co-medication used. But cause of the prospective design, confounding medication should be reported when used.

Method of assessing the outcome appropriately: Yes.

Impactassessor blinded: No.

Follow-up: 1997-2005

Selective loss to follow up: Not described.

Identification confounders and correction in analysis: In the present study, we first analyzed various exposures which could appear as confounders in the study of the relationship between

PPHN and SSRI and then studied that relationship with consideration to those confounders. Putative confounders were studied: an increased risk for PPHN was indicated for high maternal age, for first parity, for maternal BMI, and possibly for maternal smoking.

Funding: Not described.

Kieler, 2011

Prospective population based cohort study

Denmark, Finland, Iceland, Norway, Sweden 1996-2007

N=1.618.255

Aim: To assess whether maternal use of selective serotonin

reuptake inhibitors (SSRIs) increases the risk of persistent pulmonary

hypertension in the newborn, and whether such an effect might differ

between specific SSRIs.

Inclusion criteria:

All singletons born after 231 gestational days (33 weeks) between 1996 and 2007. Only births were included from

the years when prescription data were available.

Exclusion criteria:

Exposed to SSRIs

< 8 weeks only:

-Any SSRI: N=17053

-Fluoxetine: N=3899

-Citalopram:

N=6816

-Paroxetine:

N=2293

-Sertraline:

N=3396

-Fluvoxamine:

N=278

-Escitalopram:

N=2510

≥ 20 weeks:

-Any SSRI:

N=11014

-Fluoxetine:

N=3315

-Citalopram:

N=3294

-Paroxetine:

N=1281

-Sertraline:

N=2843

-Fluvoxamine:

N=112

- Escitalopram:

N=557

Not exposed to SSRIs

Risks of PPHN of the newborn associated with early and late exposure to SSRIs during pregnancy.

Adjusted for important maternal and pregnancy characteristics.

Demographics:

Information on PPHN of the newborn, level of delivery, maternal smoking, BMI in early pregnancy, year of birth, mode of delivery, gestational age at birth, birth weight, meconium aspiration, and maternal diseases recorded

during pregnancy.

(Maternal diseases included epilepsy, malignancies, rheumatoid arthritis, juvenile arthritis, and arthritis in connection with psoriasis or inflammatory bowel disease, inflammatory bowel disease, systemic lupus erythematosus, and hypertension or pre-eclampsia).

Information on the mothers' admissions to hospital for a psychiatric diagnosis during the 10 years before giving birth and identified women who had filled prescriptions for antidepressants, antidiabetes drugs, or non-steroidal anti-inflammatory drugs from three months before the start of pregnancy until delivery.

Around 30 000 women had used SSRIs during pregnancy and

11 014 had been dispensed an SSRI later than gestational week 20.

Exposure to SSRIs in late pregnancy was associated with an increased risk of persistent pulmonary hypertension in the newborn: 33 of 11014 exposed infants (absolute risk 3 per 1000 liveborn infants compared with the background incidence of 1.2 per 1000); adjusted odds ratio 2.1 (95% CI 1.5 to 3.0). The increased risks of persistent pulmonary hypertension in the newborn for each of the specific SSRIs (sertraline, citalopram, paroxetine, and fluoxetine) were of similar magnitude. Filling a prescription with SSRIs before gestational week 8 yielded slightly increased risks: AOR 1.4 (95% CI 1.0 to 2.0).

Exposure to SSRIs in gestational week 20 or later and the risk for PPHN of the newborn (N not exposed vs N exposed (per 1000):

- Any SSRI: 1899 (1.2) vs 33 (3.0), AOR 2.1; 95% CI 1.5-3.0

- Fluoxetine: 1952 (1.2) vs 9 (2.7), AOR 2.0; 95% CI 1.0-3.8

- Citalopram: 1936 (1.2) vs 11 (3.3), AOR 2.3; 95% CI 1.2-4.1

- Paroxetine: 1959 (1.2) vs 5 (3.9), AOR 2.8; 95% CI 1.2-6.7

- Sertraline: 1949 (1.2) vs 10 (3.5), AOR 2.3; 95% CI 1.3-4.4

- Escitalopram: 1966 (1.2) vs 1 (1.8), AOR 1.3; 95% CI 0.2-9.5

Clearly defined groups: Yes.

Selection bias: No. Population based. Clearly defined inclusion criteria. Possible misclassification bias exposure medication in pregnancy. Not everyone takes the prescribed medication and some people use more than one antidepressive. But no large effects were expected.

Adequate exposure assessment method: Yes. Power analysis.

Method of assessing the outcome appropriately: Yes.

Impact assessor blinded: No.

Follow-up: 1996-2007

Selective loss to follow up: Not described.

Identification confounders and correction in analysis: Yes. Adjusted for maternal age, dispensed non-steroidal anti-inflammatory drugs and antidiabetes drugs, pre-eclampsia, chronic diseases during pregnancy, country of birth, birth year, level of delivery hospital, and birth order.

Funding: Not described.

Kulin, 1998

Prospective controlled cohort study

N= 534

Inclusion criteria:

All women who contacted 1 of 9 participating

Teratology Information Service centers

regarding exposure to fluvoxamine, paroxetine, and sertraline during the first trimester of pregnancy for depression.

Exclusion criteria: women who, in addition to being exposed to a new SSRI, were also

exposed to a known human teratogen or

drugs of uncertain teratogenicity.

N= 267

Use of:

Sertraline N=147

Paroxetine N=97

Fluvoxamine N=26

(dosage also described)

2 women used paroxetine and sertraline and 1 women used sertraline and fluoxetine.

N= 267

Controls were randomly selected

from the total group of women counseled

and followed by the Mother risk Program

after exposure to agents proven to be nonteratogenic (eg,dentalx-rays,acetaminophen).

Primary outcome: the rates of major malformations, (defined as structural or functional anomalies that have significant medical or social consequences)

Secondary outcome:

-Birthweight

-Gestational age at birth

Pregnancy outcome did not differ between the groups,

With similar rates of major malformations, spontaneous and elective abortions and stillbirth, and similar mean birth weight and gestational age. The RR for major malformations among SSRI-exposed neonates was 1.06 (95% CI, 0.43-2.62)

Demographics:

Women exposed to an SSRI were significantly less likely to be primigravid and significantly more likely to smoke cigarettes and to have had a previous therapeutic abortion than the 267control women These trends were homogeneousamongthe3SSRIs

Correction for smoking did not change the outcome.

Clearly defined groups: Yes.

Selection bias: No. But no (blind) randomisation. Clearly described inclusion and exclusions.

Adequate exposure assessment method: No blindness to exposure.

Method of assessing the outcome appropriately: Yes.

Impactassessor blinded: No.

Follow-up: Fixed times for interviewing no data pronounced when the study started and ended.

Selective loss to follow up: No loss to follow up.

Identification confounders and correction in analysis: No description if they corrected for (all) confounders. But they did a correction for smoking.

Funding: Not described.

Laine, 2003

Controlled prospective cohort study

N=40

Inclusion: enrollment between January 1, 1997, and August 31, 2000. The patients were referred to the study clinic by primary care physicians.

N=20

SSRIs:

-citalopram (20- to 40-mg/d; n=10)

- fluoxetine(n=10) during their pregnancy and lactation.

Indication:

-depression(n=10) -panic disorder

(n=10).

Comedication:

-1 patient concomitant thyroxin for hypothyroidism,

-3 patients had occasional

use of benzodiazepines

N=20 healthy control women

(healthy women who were not taking

psychotropic medication were prospectively and individually

matched for confounding obstetric characteristics (age, gravidity,

parity, duration of pregnancy, and time and mode of

delivery) at the time of delivery.

Only age remained statistically different between groups.

Clinical examination and specific assessment of serotonergic symptoms during the first 4 days of life and at the ages of 2 weeks and 2 months.

There was a statistically significant (P=.008,

V=15, n=20 for both groups), 4-fold difference in the

serotonergic symptom score during the first 4 days of life

between the SSRI group and the control group. The SSRIexposed

infants had significantly lower cord blood 5-hydroxyindoleacetic

acid (5-HIAA) concentrations (P=.02, t31=2.57) compared with the control group. A significant inverse correlation (rs=−0.66, P=.007, n=15) was seen between the serotonergic symptom score and the

umbilical vein 5-HIAA concentrations in the SSRIexposed

but not the control infants.

Clearly defined groups: Yes.

Selection bias: possible, unclear whether recruitment was consecutive

Adequate exposure assessment method: yes

Method of assessing the outcome appropriately: Yes

Impactassessor blinded: The assessment was designed to be blinded but this blinding was not completely sustained in this clinical setting, which may somewhat affect the results

Follow-up: +

Selective loss to follow up: not reported

Identification confounders and correction in analysis: 2 (10%) of the women in the SSRI group had a habit of occasional light alcohol use during pregnancy compared with none in the control group.

Funding: no evident conflict of interest

Levinson-Castiel, 2006

Cohort study

(n=120)

2002- 2004

Setting: Tertiary center

Incl: full-term infants with prolonged exposure to SSRIs during the entire pregnancy or at least during the third trimester

Excl: known or probable exposure to other medications, illicit drugs, or alcohol, which could have contributed

to a NAS, congenital anomalies or conditions affecting

the central nervous system.

N=60

37paroxetine (10-40 mg)

12 fluoxetine (20-60 mg)

8 citalopram

(10-40 mg)

2 venlafaxine

( 37.5-75 mg)

1 sertraline

( 25 mg).

N=60

healthy non-SSRI-exposed neonates born to healthy

mothers within the last 2 months of the study were matched for sex, gestational age (±1 week), birth

weight (±100 g), and mode of delivery.

Neonatal abstinence syndrome (NAS)

Measured by the Finnegan score.

- Severe NAS: A score ≥8 at 1 or more assessments

- Mild NAS: a score of 4 to 7 in at least 2 examinations

Of the 60 neonates exposed to SSRIs in utero,

8 showed severe and 10 showed mild symptoms of a neonatal

abstinence syndrome. All nonexposed neonates had

a normal Finnegan score. In neonates who developed severe

symptoms, the maximum mean daily Finnegan scores

were recorded within 2 days after birth, although maximum

individual scores were recorded as long as 4 days

after birth.

Clearly defined groups: yes, women with co-medication were excluded.

Selection bias: -

Adequate exposure assessment method: Yes

Method of assessing the outcome appropriately: Yes

Impact assessor blinded:

Follow-up: adequate

Selective loss to follow up:

Identification confounders and correction in analysis: Yes.

Adjustment for maternal diabetes (pregestaional or gestational, with and without treatment), maternal race or ethnic group, body-mass index, smoking, alcohol intake, and use of NSAIDs after week 20.

Funding: Not described

Possible recall bias because of study design.

Malm, 2005

Prospective cohort study (Finland)

N=1782

Inclusion:

Singleton pregnancies

Exclusion:

Not described

N=1398

SSRI use 1st, second or/and third trimester: Citalopram, fluoxetine, paroxetine, sertraline, fluvoxamine, combination.

NB more than twice as many

tobacco smokers in the cohort of women with SSRI

N=1782

No SSRI use 1st, second or/and third trimester

Primary outcomes:

- Major malformations

- Preterm birth

- SGA

- LBW

- NICU stay

- Apgar score

SSRI intake separately reported for each trimester

SGA (adjusted):

OR=2.4, 95% CI 1.1-5.3 -> continues exposure vs only exposure in first trimester.

Apgar score (adjusted): OR=1.6, 95% CI 1.0-2.4 -> third trimester SSRI intake.

NICU: Adjusted OR 1.6 (1.1-2.2)

Other outcomes show no significant effect.

Clearly defined groups: Yes.

Selection bias: Not certain. But only one inclusion criteria and no exclusion criteria described.

Adequate exposure assessment method: Yes. But no information about dosage of the medication. No information about co-medication.

Method of assessing the outcome appropriately: Yes.

Impactassessor blinded: No.

Follow-up: 1996-2001

Selective loss to follow up: Not described.

Identification confounders and correction in analysis: They did a correction for confounders.

Funding: Not described.

Nulman, 2002

Prospective cohort study

N=40

Inclusion:

Cases: Women who contacted Mother Risk program regarding fluoxetine exposure and diagnosed with major depression. Included women using other psychotropic meds,

alcohol or smokers. Recruitment during first trimester.

Exclusion: Discontinuation of antidepressant,

exposure to more than one antidepressant

or known teratogen, major medical

conditions that may adversely affect fetal

outcome, depressive symptoms

N=40

Fluoxetine use in pregnancy (for depression)

N=36

no history of psychiatric d/o

or depressive symptoms. No exposure to

any drug, chemical, radiation, or

infection known to affect fetus adversely (other medication allowed)

CES-D scale<16

Primary: long term neonatal developmental outcomes (chapter long term effects)

Secondary

-birth weight

- GA at birth

- head circumference

No significant difference in BW, GA or head circumference at birth

The children in the fluoxetine group were significantly younger than those in the comparison group.

Clearly defined groups:Yes

Selectionbias: Unclear how many women were initially approached

Method ng adequaat: yes

Adequate exposure assessment method: yes

Impactassessor blinded : yes

Follow-up: yes

Selective loss to follow-up: Unclear

Identification confounders and correction in analysis: yes, many possible confounders were taken into account

Financiering: no evident conflict of interest

Other:

-small sample size

-secondary outcome measurement

Oberlander, 2004

Prospective cohort study

N=51

Inclusion:

Cases: consecutive prospective recruitment during pregnancy of women with 2nd and 3rd trimester exposure to single-agent SSRI from 1996-2000

Controls: recruitment postpartum. Criteria: no mental illness, term birth, no psychotropic medication, no NICU admission

Single agent SSRI

N=25

Dose at delivery (mean/day):

Paroxetine 22.2 (10-40mg)

Fluoxetine 21.3 (10-30mg)

Sertraline 81.3 (50-150)

(second group SSRI and clonazepam N=18 not included for our guideline)

Control

N=23

1) gestational age at birth

2) growth parameters at birth

3) Apgar score (1 and 5 minute)

4) evidence of transient neonatal symptoms suggesting altered adaptation in the newborn period (jitteriness, respiratory difficulty, hypoglycemia, lethargy, weak or absent cry, or desaturation on feeding)

5) presence of major anomalies

6) admission for observational unit or special care nursery

7) duration of hospital stay

4) Transient neonatal symptoms in SSRI group 25% (7/28; fluoxetine N=3, paroxetine N=3, sertraline N=1), control group 9% (2/23)

-Respiratory distress was the most prominent symptom

- Length of prenatal SSRI exposure or maternal dose did not vary between infants with and without poor adaptation

-Differences in drug levels between SSRI and control infants were not significant (p=0.08).

-BSDI assessment at 2 and 8 months of age: no significant difference

Clearly defined groups: Yes

Selection bias: controls with NICU admission were excluded. Consecutive recruitment.

Adequate exposure assessment method: Yes

Method of assessing the outcome appropriately: Yes

Impactassessor blinded: partially

Follow-up: Unclear. Seems like there was no standard follow up appointment. Patients reported with symptoms.

Selective loss to follow up: possible although follow up of early neonatal symptoms is short and therefore unlikely to be missed.

Identification confounders and correction in analysis: No

Funding: No evident conflict of interest

Oberlander, 2006

Retrospective cohort study

N=107877

Data from the British Columbia Linked Health Database between April 1, 1997, and March 31, 2002 (all registered live births in Britsh Columbia)

2 groups:

1) The SSRI group: neonates of depressed mothers with SSRI prescription >49 after conception, no other psychiatric medication.

N= 1451

2) Depression only group (no medication)

N=14234

3) Nonexposed control group

N=92192

- birth weight (grams and incidence of birth weight <p10),

- percentage born <37 weeks,

- length of hospitalstay >3 days

- incidence of adverse neonatal symptoms (RDS, jaundice, convulsions, or feeding difficulties).

Birth weight and GA for SSRI exposed infants (group 1) were significantly less than for non-exposed infants of depressed mothers (group 2), as was the proportion of infants born at less than 37 weeks (95% confidence interval [CI], −1 to −64, −0.25 to −0.45, and −0.009 to −0.04, respectively), although differences in the incidence of birth weight <p10 for GA were not significant.

An increased proportion of SE-D infants had:

- neonatal respiratory distress (13.9% vs 7.8%),

- jaundice (9.4% vs 7.5%),

- feeding problems (3.9% vs 2.4%)

Compared with DE infants (95% CI of difference, 0.042-

0.079, 0.003-0.334, and 0.005-0.025, respectively).

Controlled for variables that reflect the severity of illness, the apparent effects of SSRIs generally disappeared, except the effect on RDS remained large and significant, and birthweight <p10.

Clearly defined groups: yes

Selection bias: not likely

Adequate exposure assessment method: Yes.

Method of assessing the outcome appropriately: Yes.

Impact assessor blinded: No, retrospective design

Follow-up: number patients with incomplete information not reported, but seems adequate.

Selective loss to follow up: unlikely

Identification confounders and correction in analysis: Yes. Propensity score matching was used to eliminate bias due to confounders.

Funding: no evident conflict of interest

Pastuszak, 1993

Prospective patient controlled study

Inclustion:

All women that contacted one of the TIS during pregnancy.

There were no differences in any of the characteristics of the women using fluoxetine across the four participating centers.

Fluoxetine use in 1st trimester of pregnancy

(mean daily dose of 25.8mg range 10-80mg)

N= 128

1. nonteratogen medication users (NTC) N=128

2. Tricyclic antidepressants users(TC) N= 74

Telephone interview 8-12 months after the expected date of delivery.

Primary outcomes:

- Major congenital anomalies

- Weight gain (mother)

- Gestational age with delivery

- Birth weight

- Type of delivery

-miscarraige

No statistic significance between the groups for major congenital anomalies, gestational age with delivery, birth weight and type of delivery.

There was a tendency for a higher percentage of miscarriages in the 128 fluoxetine patients compared with the NTC group, but it did not reach statistical significance 14.8% vs 7.8%, RR 1.9, 95% CI 0.92-3.92.

Clearly defined groups: Yes.

Selection bias: No. But each fluoxetine user was only age-matched to two controls. No exclusion criteria.

Adequate exposure assessment method: Yes. Also dosage info.

Method of assessing the outcome appropriately: Yes. Telephone interview. Clearly described outcomes.

Follow-up: Telephone interview 8-12 months after the expected date of delivery.

Selective loss to follow up: No loss to follow up.

Identification confounders and correction in analysis: Maternal characteristics (obstetric histerory, ethanol and sigarette use) were also compared. But they did no correction for confounders.

Funding: Not described.

Rampono, 2009

Prospective observational study

N=57

Inclusion: mothers

treated with antidepressants during pregnancy, and untreated

controls were recruited opportunistically (18 - 32 weeks of pregnancy)

Exclusion: known substance abusers, use of other medication known to alter infant behaviour

NB Mothers who delivered infants

prematurely, or with congenital anomalies were withdrawn

from the study.

N=27 SSRI

Citalopram N=9

Escilatopram N=8

Sertraline N=6

Fluoxetine N=2

Fluvoxamine N=1

Paroxetine N=1

Dose in mg; median (IQR):

Cital. 20(20-30)

Escil. 20(10-28)

Sertr. 50(44-100)

Fluox. 30

Fluvox. 150

Parox 40

(Another group of women using SNRI's was analysed, not included for this guideline; n=11)

N=30

Untreated

Antenatal EPDS>11 in control group 28%

(vs 58% in SSRI group)

- Medication intolerance/ withdrawal ( Finnegan neonatal abstinence scoring system)

- Neonatal behavior (day 3 using the fully validated Brazelton Neonatal Behavioral Assessment Scale)

- Restlessness, myoclonus, hyper-reflexia, tremor, rigidity, sweating

and hyperthermia (all measured with Neonatal serotonin score on 0 - 3 scale)

- Neonatal abstinence scores were signifi cantly higher (p < 0.05) in exposed infants than controls on day 1.

- Brazelton scores for habituation, social-interactive, motor and autonomic clusters, and serotonin scores were significantly greater (p < 0.05) in exposed infants.

- Neonates born to control mothers were delivered at later median

(IQR) gestational age than those born to mothers in the cases (data not shown)

- There were no significant differences between cases and controls for obstetric outcomes (labour, presentation or delivery mode) or for neonatal outcomes (Apgar scores, need for resuscitation, gender, birth weight, or head circumference).

Clearly defined groups: yes

Selection bias: possible, opportunistic recruitment

Adequate exposure assessment method: Yes

Method of assessing the outcome appropriately: Yes

Impactassessor blinded: Yes

Follow-up: up to 3 days postpartum.

Selective loss to follow up: -. High loss to follow up:19 mother-infant pairs.

Identification confounders and correction in analysis: Characteristics are reported (smoking, alcohol etc), unreported whether differences are statistically significant (alcohol use controls vs SSRI = 11 vs 22%). No correction.

Funding: no conflict of interest

Sanz, 2005

Retrospective database analysis

Spontaneously reported cases of suspected adverse drug reactions (ADRs) in 72 countries to the WHO Drug

Monitoring Centre

Causality assessment by the national centres

102 cases of SSRI use and suspected adverse drug reactions

Dose: of

paroxetine was reported only in 13 cases and ranged

from 10 mg to 50 mg per day (mode 20 mg per day).

-

Neonatal withdrawal syndrome

A total of 102 cases (reported up to the second quarter of

2003, from 11 different countries) of SSRI use associated

with either neonatal convulsions or withdrawal

syndrome were identified. Paroxetine was the most

commonly reported SSRI with these ADRs. Cases were

also reported for fluoxetine, sertraline, and citalopram (not for other)

Retrospective analysis

No control group

Describing data

No information on women's characteristics and possible confounders

Causality not sure

Co-medication: Of the 51 cases of neonatal withdrawal syndrome associated with paroxetine, 43 were exposed only to this compound, and in eight there were other concomitant pharmacological treatments

Funding: No conflict of interest

Sivojelezova, 2005

Prospective patient controlled study

N=396

Inclusion:

The women were recruited from the cohort of pregnant women or women planning pregnancy who contacted the Motherisk Program from 1999 to 2002 inquiring about the safety of citalopram and other medications in pregnancy

Exclusion criteria:

Exposure to a known teratogen or a xenobiotic with undetermined safety in pregnancy. Premature infants and infants

exhibiting intrauterine growth retardation.

Citalopram use N=132

Only mother-infant pairs with medication exposure during the period of organogenesis were included.

Maternal characteristics not statistically different from the disease match comparison except for smoking-> significant difference in comparison with the non exposed group.

1. Disease-matched Group (other SSRI use) N=132

2. Non teratogen group N=132

Telephone follow-up interview

Risk of adverse pregnancy outcome, birth defects and neonatal complications.

(Major malformations

were defined as structural and/or functional anomalies that have to be corrected surgically or that

may alter the social acceptability of the individual.)

Although the rate of perinatal complications following third-trimester exposure to citalopram did not differ statistically from that of the unexposed group of women, there was a 4-fold increased risk of need for the NICU (relative risk, 4.2 [95% CI 1.71-10.26])

Clearly defined groups: Yes.

Selection bias: Selection criteria not clearly described. Selection and measurement method was clearly described. Groups were matched for maternal age and gestational age. But other demographic matches/differences were not described. NB. Premature infants and infants exhibiting intrauterine growth retardation were excluded.

Adequate exposure assessment method: Yes.

Method of assessing the outcome appropriately: Yes.

Impactassessor blinded: No.

Follow-up: 1999-2002, fixed intervals for follow up

Selective loss to follow up:

Not described.

Identification confounders and correction in analysis: No correction for smoking. The exposure group had significant more smokers.

Funding: Not described.

Suri, 2004

Prospective cohort study

N=62

Inclusion: outpatient women between the ages of 18 and 45 in the first

trimester of pregnancy with either a history of major depressive

disorder or no psychiatric history (for the control group).

Exclusion: presence of psychotic symptoms, use of medications that are known to adversely affect the fetus, use of other psychotropic medications, presence of suicidality,

and use of alcohol, cigarettes, or substances while pregnant.

Study entry: Structured Clinical Interview for DSM-IV

Pregnancy: Subjects were then followed once in each trimester with administration of the

Center for Epidemiologic Studies Depression Scale (CES-D)

(cut-off 16). The presence or absence of active major or minor depression was confirmed with the SCID-Mood Module and

Research Diagnostic Criteria (RDC)

respectively.

Group 2: Depressed no fluoxetine

(N=18)

Group 3: Depressed

Fluoxetine (N=28)

Majority are

Caucasian, well-educated subjects

of high socioeconomic status

Dose: mean dose fluoxetine was 30.98 ±15.67 mg and the mean duration of fluoxetine exposure

was 29.82 ±10.14 weeks

Group 1: Controls (N=16)

Primary outcomes: infant gestational age, birth weight, Apgar score, and admission to the

neonatal intensive care unit.

Analyzable data were available for 62 women. No significant

differences were found in outcome variables between those

women with exposure to medication and=or prenatal depressed mood and those women without a history of depression.

Clearly defined groups: Yes.

Selection bias: not likely although it was not reported whether recruitment was consecutive

Adequate exposure assessment method: Yes

Method of assessing the outcome appropriately: Not clearly reported

Impactassessor blinded: Not reported

Follow-up: September 1996- September 1999

Selective loss to follow up: Unlikely, 62/64.

Identification confounders and correction in analysis: Women with alcohol use and women smoking were excluded.

Funding: by a grant from Eli Lilly and Company.

(=farmaceutisch bedrijf!)

Toh, 2009

Retrospective cohort study

Inclusion criteria:

Women with non-malformed infants.

Exclusion criteria: Women who used both SSRIs and non-SSRI antidepressants (n = 18), and those who initiated antidepressive medications

during pregnancy (n = 47

N= 5961

N=251

Discontinuers SSRI (Stopped before end of first trimester) SSRI N=106)

Continuers SSRI (N=86)

Other antidepressants non-SSRI (N=59)

(separate analysis)

N=5710

Outcomes:

-Preterm delivery (<37 weeks)

-SGA (birth weight

<10th percentile)

Preterm delivery:

Only SSRI users (controls N=415)

- SSRI whole group AOR 1.12, 95% CI 0.64-1.95(cases N=17)

- Discontinue SSRI AOR 1.01, 95% CI 0.64-1.95 (cases N=8)

- Continue SSRI AOR 1.27, 95% CI 0.59-2.76 (cases N=9)

SGA:

Only SSRI users (controls N=408)

- SSRI whole group AOR 1.68, 95% CI 1.03-2.74 (cases N=21)

- Discontinue SSRI AOR 0.81, 95% CI 0.35-1.90 (cases N=6)

- Continue SSRI AOR 3.01, 95% CI 1.65-5.47 (cases N=15)

Clearly defined groups:Yes

Selection bias:

Adequate exposure assessment method: Yes. But no information available about distribution of SSRI separately.

Method of assessing the outcome appropriately: Telephone interview -> Recall bias possible -> underreporting SSRI use.

Impactassessor blinded: No.

Follow-up: 1998 and 2008

Selective loss to follow up: Not described.

Identification confounders and correction in analysis: Yes.

Funding: Not described.

Wen, 2006

Retrospective cohort study

Population of Canadian province of Saskatchewan.

N=972

Poly + Monotherapie SSRI's:

Citalopram N=13

Fluoxetine N=533

Fluvoxamine N=121

Paroxetine N=325

Sertraline N=226

Monotherapie SSRI:

Citalopram N=1

Fluoxetine N=440

Fluvoxamine N=83

Paroxetine N=238

Sertraline N=169

N=3878 (matched by the year of infant birth, type of institute at birth and mother postal code)

Maternal/pregnancy outcomes:

- Preeclampsia

- Urinary infection

- Gestational diabetes mellitus

-Placental previa

-Placental abruption

Neonatal outcomes:

- Low birth weight

- Preterm birth

- Fetal/infant death

- Seizures

- Sepsis

- Major and minor structural anomalies

Maternal/pregnancy outcomes:

-Preeclampsia AOR 1.20, 95% CI 0.90-1.61

-Urinary Infection AOR 1.53, 95% CI 0.76-3.09

-Gestational diabetes Mellitus AOR 1.31, 95% CI 0.86-2.01

-Placental previa AOR 1.20, 95% CI 0.55-2.60 (N <10)

-Placental abruption &a