This meta-analysis showed that depression during pregnancy, regardless of the type of antenatal depression measurement (ie, categorical or continuous), is associated with modest but statistically significant risks of PTB and LBW. Furthermore, the estimates of risk for PTB and LBW from categorically defined antenatal depression appear resilient to the effects of publication bias. Sensitivity analyses showed that the magnitude of RR for these adverse birth outcomes was consistent within the set of 20 studies examining PTB and the set of 11 studies investigating LBW. Although the sizes of the significant RRs for PTB and LBW posed by antenatal depression are modest, the test of relevance in our study is not statistical significance but public health significance. That is, given the prevalence of antenatal depression in a population of pregnant women, what will be the likely burden of PTB or LBW for their infants? Thus, a relatively small effect size magnified by a large population base can have a considerable and noteworthy effect on public health.
We also found evidence that the type of depression measurement (categorical vs continuous) moderated the strength of the associations between antenatal depression and PTB, LBW, and IUGR, thereby eliminating or reducing the heterogeneity associated with these findings. Results for categorical measures of antenatal depression revealed that having major depression or clinically significant depressive symptoms significantly increased the RR of PTB by 39%, the risk of LBW by 49%, and the risk of IUGR by 45%. As expected, continuous measures of antenatal depression showed a similar albeit weaker pattern, indicating that every 1-point increase in depression severity was associated with a 3% significantly increased risk of PTB and nonsignificantly increased risks of LBW (4%) and IUGR (2%). To place the categorical results for antenatal depression in context, we note that smoking was observed to have a dose-dependent relationship with PTB,106,107
with smoking more than 10 cigarettes a day shown to increase the likelihood of PTB between 33 and 36 weeks by 40% and of PTB at 32 weeks or less by 60%. Furthermore, in a cohort analysis of a large, ethnically diverse population,11
substance use disorders were associated with a 2.4-fold higher risk of PTB and a 3.7-fold higher risk of LBW, and black race increased the likelihood of PTB by 60% and of LBW by 2-fold. Thus, the magnitude of risk for PTB and LBW posed by antenatal depression is comparable to the risk of smoking 10 or more cigarettes a day for PTB but is relatively modest contrasted to the greater risks of black race and substance abuse associated with PTB and LBW.
Moderator analyses for country location revealed that the RR of delivering an infant with LBW or IUGR was higher among women from developing countries who experienced antenatal depression than their counterparts in the United States or social democracies. Moreover, in US studies, categorically defined antenatal depression tended to be associated with an elevated risk of PTB in women of predominantly lower SES but not in women of middle- or upper-income status. Pregnant women of lower SES in the United States are also twice as likely to experience antenatal major and minor depression as are women from middle- to upper-income strata.20–22
Whereas cross-cultural variability in the prevalence of perinatal depression certainly exists,29
estimates of the prevalence of perinatal depression in several developing countries27,28
are similar to the higher depression rates in pregnant US women of lower SES. Thus, many socioeconomically disadvantaged childbearing women in developing countries and in the United States experience a double-barreled threat: an increased risk of becoming depressed during their pregnancies and an increased likelihood of experiencing adverse birth outcomes once they have antenatal depression. Depressed pregnant women living near or below poverty levels are subject to large amounts of acute and chronic stress, such as living in unsafe neighborhoods, experiencing racial/ethnic or economic discrimination, and confronting food inadequacy in their households.22,108,109
At the same time, despite Medicaid or other public insurance coverage during pregnancy, their mental health problems are seldom accurately diagnosed and they often lack access to specialty mental health services.110–112
Several potential direct and indirect causal pathways through which antenatal depression leads to adverse pregnancy outcomes have been proposed. One possibility is that prenatal stress or depression during pregnancy might promote adverse birth outcomes through the dysregulation of the hypothalamic-pituitary-adrenocortical axis, stimulating the release of stress hormones, such as cortisol and catecholamines. These biological changes may result in placental hypofusion and consequent restriction of oxygen and nutrients to the fetus, leading to fetal growth restriction and/or precipitation of PTB.113–117
Other mechanisms include the possibility that antenatal depression might compromise immune system functioning,118
which in turn may lead to a reproductive tract infection triggering PTB.117
The harmful public health effect of antenatal depression on birth outcomes is further heightened by evidence that depression during pregnancy is associated with risky but modifiable health practices, such as poor nutrition and hygiene, lack of motivation to obtain prenatal care or to follow medical recommendations, and smoking and/or alcohol and substance abuse, all of which adversely affect pregnancy outcomes.11,33,85,119
Clearly, pregnancy is an important time to universally screen women for depression, especially those who are socioeconomically disadvantaged, and to improve their timely access to evidence-based prenatal and mental health services.120
Improved accuracy of diagnosis and treatment of antenatal depression combined with education about harmful but potentially modifiable lifestyle practices could lead to decreased rates of PTB and LBW.
Reducing the rates of these adverse birth outcomes is a critically important public health issue. During childhood, PTB is associated with an increased risk of mortality3
; adverse medical outcomes4,121–123
including respiratory distress syndrome, cerebral palsy, chronic lung disease, vision and hearing loss, and neurodevelopmental disabilities; cognitive difficulties124
; and psychiatric problems,124
such as internalizing and externalizing behaviors and attention-deficit/hyperactivity disorder. Long-term consequences of PTB in adulthood include diminished rates of reproduction and, for women born preterm, an increased risk of next-generation PTB, fetal stillbirth, and infant mortality.3
Pernicious child and adult outcomes related to LBW125–133
reflect patterns similar to that of PTB. Furthermore, in the United States, the annual economic costs of medically managing the consequences of these adverse birth outcomes are enormous.140,141
For example, approximately 75% of admissions to the neonatal intensive care unit are related to prematurity.142
Daily neonatal intensive care unit costs in the United States exceed $3500 per infant, and it is not unusual for costs to reach $1 million for a prolonged stay.142
A strength of our meta-analysis is that our search included US and non-US English-language studies, as well as a study in French that was translated into English by an expert. Thus, the 29 studies included in our meta-analysis came from 12 non-US countries, indicating significant international representation. Our meta-analysis also included studies that varied in the extent to which they controlled for confounding factors related to PTB, LBW, and IUGR. For example, one-third of the studies (n=10) controlled for SSRI use31,57,62,67,68
or reported that SSRI use was unlikely in their sample.34,36,51,64,66
An increasing number of women with depression are prescribed antidepressant medications during pregnancy.143
These medications, especially SSRIs, have been significantly linked with LBW in some49,92,93,144
but not all studies.145–147
Wisner et al68
recently found that infants who were continuously exposed to either SSRIs or major depression throughout the 3 trimesters of pregnancy were more likely to be born preterm than were infants with partial or no exposure. Differentiating between the effects of depression or depressive symptoms and the effects of antidepressants on birth outcomes is challenging because (1) researchers typically investigate the effects of one without controlling adequately for the other; (2) use of antidepressants during pregnancy occurs at different times, dosages, and durations; (3) recognition and treatment of depression by the physician is often associated with depression severity and persistence; and (4) depression is also associated with the use of additional prescription and nonprescription medications148
and other potential confounders, such as smoking or substance use disorders.
Finally, prior evidence has shown that key variables in addition to depression, such as substance use or abuse, race/ethnicity or SES, and previous PTB, are strongly and consistently predictive of negative birth outcomes. Most of the studies in our meta-analysis (80%) controlled for at least 2 of these key predictors, but few controlled for all of them. In addition, most of the studies did not control for stressful life events and other psychiatric comorbidities of depression, such as antenatal anxiety, which has been linked with adverse birth outcomes in some studies.6
A recent meta-analysis of anxiety symptoms and birth outcomes, however, did not show evidence of this association.149
Only 5 of 29 studies in our meta-analysis assessed major depression during pregnancy by using diagnostic criteria adhering to or compatible with the Diagnostic and Statistical Manual of Mental Disorders
Most studies used relatively short screening tools to evaluate levels of depressive symptoms and to set cutoff scores for describing clinically significant depressive symptoms. Although categorizing depressive symptom levels may be related to the diagnosis of clinically significant depression, it is not a substitute nor may it be as accurate as a structured interview. Finally, although we found possible publication bias, the findings of an elevated risk of PTB and LBW associated with categorically defined depression remained robust to trim-and-fill analyses that corrected for this bias.
Limitations of the studies reviewed suggest the need for a large prospective epidemiological study to simultaneously evaluate the RRs during pregnancy of depression, SSRI use, smoking, substance use disorders, key sociodemographic variables, obstetric/medical variables, and important behavioral health practices, including engagement in adequate prenatal and medical care and nutrition. Multiple assessments of major and minor antenatal depression should be performed, using criteria from the Diagnostic and Statistical Manual of Mental Disorders
(Fourth Edition) as well as measures assessing depression severity. The RRs of anxiety disorders and anxiety severity should also be assessed because these psycho-pathologic conditions typically accompany depression and were found to be related in some, but not all, studies to adverse birth outcomes. Ideally, this future study would prospectively gather data during the prepregnancy, pregnancy, and postpartum periods, considering that a broader perspective on a woman’s health status may be necessary to better understand the risk factors associated with harmful birth outcomes.58,151,152
Our overall pattern of findings in this meta-analysis highlights the salient public health risk of PTB and LBW posed by antenatal depression, particularly for socioeconomically disadvantaged women in developing countries and in the United States. Furthermore, mounting evidence from this meta-analysis and other sources68
suggests that untreated major depression during pregnancy is as likely to lead to poor birth outcomes as is treatment with SSRIs. An important implication of these findings is that pregnant women should be universally screened for depression and provided guideline-level treatment before childbirth. Given that untreated antenatal depression is the most robust predictor of postpartum depression and has additional serious adverse consequences for infant and child development beyond harmful birth outcomes, women and their obstetrics professionals will need to weigh the costs and benefits of treating antenatal depression pharmacologically, especially when treatment with evidence-based psychotherapy is not available or desired.