NIHR DC Discover

NIHR Signal One type of drug for depression during pregnancy may be linked to a small increase in pre-term births

Published on 9 August 2016

doi: 10.3310/signal-000278

Women who are depressed during pregnancy and who take selective serotonin inhibitors (SSRIs) may be more likely to have a pre-term birth than those who do not take SSRIs. Pre-term birth occurred in 6.8% of women with depression during pregnancy treated with SSRIs compared to 5.8% of depressed women who were treated with talking therapies alone.

However, because this is a review of observational (cohort) studies rather than randomised controlled trials it is not possible to say that SSRIs cause pre-term birth. For example, it is possible that women who had worse depression were more likely to be prescribed SSRIs, and it may have been the greater severity of depression rather than the SSRIs that caused pre-term birth.

The benefits of drugs for depression during pregnancy need to be weighed against potential harms. This information does not suggest a change in practice, but may help the discussion between doctor and patient.

Share your views on the research.

Why was this study needed?

About one in ten women will experience depression during pregnancy. Maternal depression during pregnancy has been associated with an increase in pre-term births, low birth-weight and complications after birth.

Depression during pregnancy can be treated by talking therapies and drug treatments. SSRIs are a class of antidepressant considered to be the safest for use in pregnancy. The class of drugs includes citalopram, sertraline, paroxetine and fluoxetine. Though safe, they are still associated with an increased risk of rare complications including raised blood pressure in the mother, congenital heart defects in the child and miscarriage.

Whether SSRIs are also associated with preterm births independent of the link to depression is unclear. This review was designed to evaluate whether taking SSRIs during pregnancy is associated with an increased risk of pre-term birth.

What did this study do?

This was a systematic review and meta-analysis of eight cohort studies including 1,237,669 pregnant women that measured the incidence of pre-term birth in those with depression who took SSRIs compared to those who didn’t take SSRIs. The control group in five studies were pregnant women without depression; the remaining three studies had control groups of pregnant women with depression but treated with talking therapies alone.

Three studies were from the USA, two from Sweden, two from Canada and one from Denmark. The type of SSRI received varied, and depression was defined differently across studies.

Studies were assessed to be at low risk of bias. However, just three studies adjusted for other influences that may impact on outcomes (confounders), such as maternal age, smoking, and number of previous births. Observational studies can show an association between SSRI exposure and pre-term birth but they cannot prove a direct cause and effect.

What did it find?

  • Pre-term birth was more common in the SSRI group (11.6%) than the control group (5.2%); this remained the case when taking into account confounders (adjusted odds ratio [aOR] 1.24, 95% confidence interval [CI] 1.09 to 1.41).
  • When looking at the three studies in which controls were pregnant women with depression, pre-term birth remained more common in the SSRI group compared to controls. However, the difference between the two groups was reduced (6.8% versus 5.8%; OR 1.17, 95% CI 1.10 to 1.25).
  • There was little difference in risk for women on paroxetine compared to fluoxetine (OR 1.42, 95% CI 0.88 to 2.31).
  • There were no results comparing other SSRIs with each other.

What does current guidance say on this issue?

The 2014 NICE guideline on antenatal and postnatal mental health recommends that SSRIs can be considered for woman with moderate or severe depression in pregnancy. To be considered, the woman must understand the risks associated with antidepressants. She must also have expressed either a preference for drug therapy or declined the option of (or not responded to) talking therapies.

What are the implications?

The results show an association between taking SSRIs in pregnancy and pre-term birth. However, they cannot show that SSRIs cause pre-term birth.

Interpretation is complicated by the fact that depression in pregnancy is itself associated with pre-term birth. It is likely that women who were prescribed SSRIs had more severe depression than those in the control groups, and so it is possible that it was the more severe depression that contributed to pre-term birth rather than the SSRIs.

Other confounders, such as maternal age and smoking, may also have contributed to pre-term birth. Only three of the eight studies accounted for any confounders.

This moderate level evidence from observational studies, is probably sufficient to warrant a caution in the use of SSRIs in pregnancy, something that can be discussed with women. There are likely to be situations when the risk of untreated depression is greater than the small risk of a premature birth and a clinical judgment will be required, one that ideally takes this research into account.

Citation and Funding

Eke AC, Saccone G, Berghella V. Selective serotonin reuptake inhibitor (SSRI) use during pregnancy and risk of preterm birth: a systematic review and meta-analysis. BJOG. 2016. [Epub ahead of print].

No funding information was provided for this study.

Bibliography

NICE. Antenatal and postnatal mental health: clinical management and service guidance. CG192. National Institute for Health and Care Excellence: London; 2014.

Wadhwa PD, Entringer S, Buss C, Lu MC. The contribution of maternal stress to preterm birth: issues and considerations. Clin Perinatol. 2011;38(3):351-84.

Why was this study needed?

About one in ten women will experience depression during pregnancy. Maternal depression during pregnancy has been associated with an increase in pre-term births, low birth-weight and complications after birth.

Depression during pregnancy can be treated by talking therapies and drug treatments. SSRIs are a class of antidepressant considered to be the safest for use in pregnancy. The class of drugs includes citalopram, sertraline, paroxetine and fluoxetine. Though safe, they are still associated with an increased risk of rare complications including raised blood pressure in the mother, congenital heart defects in the child and miscarriage.

Whether SSRIs are also associated with preterm births independent of the link to depression is unclear. This review was designed to evaluate whether taking SSRIs during pregnancy is associated with an increased risk of pre-term birth.

What did this study do?

This was a systematic review and meta-analysis of eight cohort studies including 1,237,669 pregnant women that measured the incidence of pre-term birth in those with depression who took SSRIs compared to those who didn’t take SSRIs. The control group in five studies were pregnant women without depression; the remaining three studies had control groups of pregnant women with depression but treated with talking therapies alone.

Three studies were from the USA, two from Sweden, two from Canada and one from Denmark. The type of SSRI received varied, and depression was defined differently across studies.

Studies were assessed to be at low risk of bias. However, just three studies adjusted for other influences that may impact on outcomes (confounders), such as maternal age, smoking, and number of previous births. Observational studies can show an association between SSRI exposure and pre-term birth but they cannot prove a direct cause and effect.

What did it find?

  • Pre-term birth was more common in the SSRI group (11.6%) than the control group (5.2%); this remained the case when taking into account confounders (adjusted odds ratio [aOR] 1.24, 95% confidence interval [CI] 1.09 to 1.41).
  • When looking at the three studies in which controls were pregnant women with depression, pre-term birth remained more common in the SSRI group compared to controls. However, the difference between the two groups was reduced (6.8% versus 5.8%; OR 1.17, 95% CI 1.10 to 1.25).
  • There was little difference in risk for women on paroxetine compared to fluoxetine (OR 1.42, 95% CI 0.88 to 2.31).
  • There were no results comparing other SSRIs with each other.

What does current guidance say on this issue?

The 2014 NICE guideline on antenatal and postnatal mental health recommends that SSRIs can be considered for woman with moderate or severe depression in pregnancy. To be considered, the woman must understand the risks associated with antidepressants. She must also have expressed either a preference for drug therapy or declined the option of (or not responded to) talking therapies.

What are the implications?

The results show an association between taking SSRIs in pregnancy and pre-term birth. However, they cannot show that SSRIs cause pre-term birth.

Interpretation is complicated by the fact that depression in pregnancy is itself associated with pre-term birth. It is likely that women who were prescribed SSRIs had more severe depression than those in the control groups, and so it is possible that it was the more severe depression that contributed to pre-term birth rather than the SSRIs.

Other confounders, such as maternal age and smoking, may also have contributed to pre-term birth. Only three of the eight studies accounted for any confounders.

This moderate level evidence from observational studies, is probably sufficient to warrant a caution in the use of SSRIs in pregnancy, something that can be discussed with women. There are likely to be situations when the risk of untreated depression is greater than the small risk of a premature birth and a clinical judgment will be required, one that ideally takes this research into account.

Citation and Funding

Eke AC, Saccone G, Berghella V. Selective serotonin reuptake inhibitor (SSRI) use during pregnancy and risk of preterm birth: a systematic review and meta-analysis. BJOG. 2016. [Epub ahead of print].

No funding information was provided for this study.

Bibliography

NICE. Antenatal and postnatal mental health: clinical management and service guidance. CG192. National Institute for Health and Care Excellence: London; 2014.

Wadhwa PD, Entringer S, Buss C, Lu MC. The contribution of maternal stress to preterm birth: issues and considerations. Clin Perinatol. 2011;38(3):351-84.

Selective serotonin reuptake inhibitor (SSRI) use during pregnancy and risk of preterm birth: a systematic review and meta-analysis

Published on 31 May 2016

Eke, A.,Saccone, G.,Berghella, V.

Bjog , 2016

BACKGROUND: Depression is a prevalent condition in pregnancy affecting about 10% of women. Maternal depression has been associated with an increase in preterm births (PTB), low birthweight and fetal growth restriction, and postnatal complications. Available treatments for depressive disorders are psychotherapeutic interventions and antidepressant medications including selective serotonin inhibitors (SSRIs). SSRI use during pregnancy has been associated with several fetal and neonatal complications; so far, however, the risk of PTB in women using SSRIs during pregnancy is still a subject of debate. OBJECTIVE: To evaluate the risk of preterm birth (PTB) in cases of exposure to SSRIs during pregnancy. SEARCH STRATEGY: Electronic databases (MEDLINE, Scopus, ClinicalTrials.gov, the PROSPERO International Prospective Register of Systematic Reviews, EMBASE and the Cochrane Central Register of Controlled Trials) were searched from their inception until May 2015 with the use of a combination of the following text words 'depression', 'pregnancy', 'exposure', 'antidepressant', 'SSRI', 'selective serotonin reuptake inhibitor', 'preterm birth', 'small for gestational age' and 'prematurity'. SELECTION CRITERIA: We included studies evaluating the effect of SSRIs exposure in utero and pregnancy outcomes. All cohort and case-control studies were eligible to be included if they reported the incidence of PTB after any exposure to SSRIs and had a comparison group of unexposed pregnant women. Studies without a control group were excluded. DATA COLLECTION AND ANALYSIS: The primary outcome was the incidence of PTB <37 weeks. Subgroup analysis of studies in which controls were defined as women with depression but without SSRI exposure during pregnancy were planned. MAIN RESULTS: Eight studies (1 237 669 women) were included: 93 982 in the exposure group and 1 143 687 in the control group. After adjusting for confounders, the incidence of PTB was significantly higher in the group of women treated with SSRIs compared with controls (i.e. both women with depression but without SSRI exposure and women without depression) (adjusted OR (aOR) 1.24, 95% CI 1.09-1.41). In the subgroup analysis of studies in which controls were defined as women with depression but without SSRI exposure during pregnancy, an increased risk of PTB (6.8 versus 5.8%; OR 1.17, 95% CI 1.10-1.25) in the SSRI group was found compared with controls (i.e. depressed women treated with psychotherapy alone). CONCLUSIONS: Women who received SSRIs during pregnancy had a significantly higher risk of developing PTB compared with controls. This higher risk remained significant even when comparing depressed women on SSRI with women not on SSRI. TWEETABLE ABSTRACT: Selective serotonin reuptake inhibitors may be associated with preterm birth.

The full list of confounders adjusted for were:

  • Maternal age (three studies)
  • Smoking (three studies)
  • Parity (two studies)
  • Pre-pregnancy counselling (one study)
  • Race (one study)
  • Education (one study)

Expert commentary

This study shows that using SSRIs during pregnancy is associated with a small increase in preterm birth.

Antenatal depression is associated with preterm birth, whether or not women take medication, so the only relevant control group is the smaller subgroup analysis (still quite large at 97,303). Women taking antidepressants in pregnancy probably have more severe depression, unclear from the data given. Anxiety is also linked to pre-term birth and another indication for SSRIs, not considered by the authors. Finally, the gestation at which preterm birth occurred is not stated. The clinical relevance of this study is hard to judge.

Dr Judy Shakespeare, GP and RCGP Clinical Champion in Perinatal Mental Health