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Archives of General Psychiatry, 67(10), 2010

A Meta-analysis of Depression during Pregnancy and the Risk of Preterm Birth, Low Birth Weight, and Intrauterine Growth Restriction Nancy K. Grote, Ph.D. Wayne Katon, M.D., Amelia Gavin, Ph.D. Jennifer Melville, M.D. University of Washington

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Archives of General Psychiatry, 67(10), 2010

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  1. A Meta-analysis of Depression during Pregnancy and the Risk of Preterm Birth, Low Birth Weight, and Intrauterine Growth Restriction Nancy K. Grote, Ph.D. Wayne Katon, M.D., Amelia Gavin, Ph.D. Jennifer Melville, M.D. University of Washington Jeffrey A. Bridge, Ph.D. Satish Iyengar, Ph.D. Ohio State University University of Pittsburgh Archives of General Psychiatry, 67(10), 2010

  2. Funding Sources • K23 MH 67595 – Grote - National Institute of Mental Health • K24 MH 069471 – Katon - NIMH • K01 MH 069948 – Bridge -NIMH • KL2RR025015 – Gavin - National Institute of Health • K23 MH070704 – Melville - NIMH \

  3. Adverse Consequences of PTB, LBW, and IUGR • PTB, LBW & IUGR are the leading causes of morbidity, mortality, and neuro-developmental disabilities in infancy and childhood • PTB, LBW, & IUGR also linked with cognitive difficulties and internalizing and externalizing disorders and ADHD in childhood • PTB results in lower rates of reproduction and, for women born preterm, an increased risk of offspring born preterm • Annual economic costs of managing the consequences enormous – for example, the average cost in US of neonatal intensive care unit (NICU) is $3500 a day

  4. Major or Minor Depression during Pregnancy • Prevalence estimates: • 8 -13% for middle-income women in US (Gavin et al., 2005) • 20-25% for poor women of color in US(Hobfall et al., 1995 Siefert et al., 2000) • 20-25% for women in developing countries (Patel et al.,2002; Rahman et al., 2003) • Antenatal depression linked to known risk factors for PTB, LBW, IUGR • Smoking, substance abuse • Poor prenatal practices and prenatal nutrition • Medical problems – hypertension, preeclampsia, gestational diabetes • Antenatal depression directly linked with PTB, LBW, IUGR in some, but not all studies – contradictory results

  5. Possible reasons for inconsistent findings • Study differences in: • Design, methods, sample sizes • Timing, frequency, type of antenatal depression measurement • Misclassification bias in terms of depression or birth outcomes • Target populations; study geographic location • The degree of control over confounding variables, such as previous PTB, substance abuse, anti-depressant medication use, SES or race/ethnicity, medical problems • \11 • \

  6. Objectives • To estimate the risk of PTB, LBW, and IUGR associated with antenatal depression • To examine possible moderators of the association between antenatal depression and PTB, LBW, and IUGR: • Categorical vs. continuous measurement of antenatal depression • Country location: 1) US 2) Developing country (e.g., India, Pakistan, Brazil), 3) European social democracy (i.e., a democratic welfare state that provides universal access to health care) • Socioeconomic status (SES) or black race • \11 • \

  7. MethodsStroup et al., 2000; Moher et al., 1999; Lipsey et al., 2001 • Search strategy: • English and non-English language articles • Databases searched – MEDLINE, PsychINFO, CINAHL, Social Work Abstracts, Social Services Abstracts, Dissertation Abstracts • Study selection – inclusion criteria • January 1980 (advent of DSM-III) – January 2009 • Prospective studies assessing antenatal depression and at least 1 adverse birth outcome: PTB (<37 weeks gestation) LBW (<2500 grams) IUGR (<10th percentile for gestational age as determined by an ultrasound) • Of 862 reviewed studies, 29 US and non-US published studies met inclusion criteria • \11 • \

  8. MethodsStroup et al., 2000; Moher et al., 1999; Lipsey et al., 2001 • Data extraction: by 2 coders and assessed for reliability • Study characteristics – maternal age, year of publication, country location, measure of country income inequality (i.e., Gini coefficient) , sample size and demographics, and timing, frequency, type of antenatal depression measurement (i.e., screening questionnaire or structured psychiatric interview) • Risk factors for adverse birth outcomes controlled for in each study: demographic (e.g., SES), psychiatric (e.g., substance abuse, anxiety disorder or symptoms), medical (e.g., hypertension) • Based on the literature, we designated 4 sets of risk factors as key: 1) smoking/ substance abuse 2) SES or race/ethnicity 3) previous PTB 4) anti-depressant medication use • \11 • \

  9. Methods • Methodologic quality assessment(adapted from Downs & Black, 1998) : • 2 investigators rated each observational study on 6 components: 1) size of sample 2) the representativeness of the sample 3) whether sample demographics were clearly described 4) reliability and validity of the antenatal depression measure used 5) whether the study controlled for risk factors, esp. key ones 6) whether the study response rate (i.e., those who declined to enter) and the study attrition rate were reported and controlled for statistically • 3 levels of quality (adequate, somewhat adequate, not adequate) • Composite quality score (total score range, 0-12)

  10. Methods - Data Analysis • Relative risks (RRs) used as the measure of the association between antenatal depression and PTB, LBW, IUGR • We weighted each study-specific RR by the inverse of its variance to compute a pooled RR using random effects models • A 2-tailed P <.05 was used to determine statistical significance • Heterogeneity of effect size was assessed using the Cochran QX2 statistic (P <.10) and the I2 statistic ( a transformation of the Cochran Q) • A significant X2 statistic suggests that the pooled RR for a birth outcome is not a unitary effect and that the variation in effect sizes is caused by the influence of potential moderator variables, rather than random error • \11 • \

  11. Methods – Data Analysis • For each pooled RR birth outcome where heterogeneity was present, random-effects meta-regression analyses and moderator analyses were used to examine whether 6 potential moderators explained the variability in effect sizes: • Study country location – US, developing country, social democracy • Country rating of income inquality (i.e., gini coefficient) • Sample SES • Sample race (eg., black or white), controlling for sample SES • Study methodologic quality • Categorical vs. continuous depression measurement • Sensitivity analyses used for studies that measured antenatal depression and antenatal SSRI use to compare birth outcomes for depressed women treated and not treated with SSRIs • \11 • \

  12. Methods – Data Analysis • Publication bias assessment: • Assesses the possible influence of studies not published due to insignificant findings • Visual inspection of a funnel plot to assess asymmetry and a regression procedure to measure funnel plot asymmetry • Trim-and-fill method by Duval and Tweedie (2000) used to adjust for potential publication bias in the pooled estimate (i.e., RR) • Assesses asymmetry in the funnel plot, suggesting possible publication bias • Imputes the number of suspected missing studies • Recalculates the adjusted effect size estimate for the RR

  13. Presentation of Results • Flowchart of independent studies included in meta-analysis: • Overall significant effect of antenatal depression on risk for PTB, LBW • Significant effect of 3 moderators: • Categorical vs. continuous depression • County location of the study • Low vs. middle and upper SES in US studies • \11 • \

  14. Identification of Independent Studies for Inclusion in Meta-Analysis Databases searched: MEDLINE (592) PsycINFO (27) CINAHL (106) Social Work Abstracts (63) Social Services Abstracts (73) Dissertation Abstracts International (1) TOTAL: 862 citations 808 Articles were excluded based on inclusion criteria (i.e., 1980-present, prospective design, empirical measures of variables of interest, data not reported in a previous study) 54 Articles were retrieved 3 Were identified from references of retrieved reports 57 articles were retrieved for more detailed evaluation 28 articles were excluded: 13 Had incomplete or no data reported on outcomes of interest examined in meta- analysis 5 Had no data reported on how antenatal depression was measured 3 Had antenatal depression measured during postpartum period 2 Had mixed retrospective and prospective design 5 Had studies in which the same data were reported in a previous paper Final set of independent studies included: 57 - 28 = 29 studies total

  15. OverallEffect of Antenatal Depression on Risk for PTB, LBW, and IUGR and Effect by Type of Depression Measurement Note: Categorical vs. continuous difference in PTB p=001; in LBW P<.001, and in IUGR p=.04 Heterogeneity among studies significantly reduced

  16. Effect of Antenatal Depression on Risk of LBW and IUGR by Country Location of Study Note: Developing nation vs. US at least p<.05; Developing nation vs. social dem. at least p<.05 ; US vs. social dem, NS Heterogeneity among US studies significantly reduced or eliminated.

  17. Effect of Categorically – defined Antenatal Depression on the Risk of PTB in the US by Socioeconomic Status Note: Depressed women of lower SES tended to be more at risk for PTB (p=.05) than those of middle-upper SES

  18. Additional Results • The following variables were not significant moderators of the links between antenatal depression and PTB, LBW, or IUGR: • Income inequality, study quality, type of depression severity measurement (e.g., CES-D vs. BDI), the use of adjusted vs. non-adjusted effect sizes, race (controlled for SES) in US studies, type of IUGR measurement • In the 5 studies of PTB that examined both antenatal depression and antenatal SSRI use, the summary RR was comparable for depressed women treated and not treated with SSRIs – approaching 2 times the risk • The risk estimates for PTB and LBW associated with categorically-defined antenatal depression were robust to the effects of publication bias • \11 • \

  19. Important Findings • Significant overall effect of antenatal depression on PTB & LBW • Stronger effect for studies of categorically-defined antenatal depression: 39% increased risk of PTB 49% increased risk of LBW 45% increased risk of IUGR • To place these categorical results in context -- the magnitude of risk for PTB posed by antenatal depression is comparable to the risk of smoking 10 or more cigarettes a day the magnitude of risk for PTB and LBW posed by antenatal depression is modest compared to the greater risk of black race or substance abuse (2 to 3 times higher risk) • \11 • \

  20. Important Findings • Salient public health risk of PTB and LBW posed by antenatal depression – this reflects a modest effect size multiplied by a large population base, esp. of poor, pregnant, depressed women • Pregnant women in developing countries are at 2 times higher risk for depression and, once depressed, at 2 times higher risk for LBW & IUGR vs. those in the US & social democracies • Pregnant women of low SES in the US are at 2 times higher risk for depression and, once depressed, at 69% increased risk for PTB vs. those of middle or upper SES (13%) • Poor, pregnant, depressed women in developing countries & US are seldom accurately diagnosed & lack access to m.h. services • \11 • \

  21. King County • US has pockets of the country where health conditions mirror those of developing countries – African Americans and native Americans have almost double the infant mortality rate as that for whites • Of the 15 largest counties in the US: • King County ranks second in terms of ratio of percent in poverty of adults of color relative to white, non Hispanic adults – 2000-2005 average • King County ranks first in terms of ratio of percent of uninsured adults of color relative to white, non Hispanic adults – 2000-2005 average

  22. Budget cuts • Maternity Support Services Program (First Steps Program in WA state since 1989) pregnant woman on Medicaid meets with a public health nurse, social worker, and nutritionist – 20,000 pregnant women on Medicaid in King County annually • Retrospective, population-based cohort study of women on Medicaid who participated in MSS vs. those who did not (1999-2002; Arima et al., 2009) • MSS has been found to reduce low birth weight babies across the entire state and to reduce low birth weight and preterm birth babies for Hispanic participants across the entire state

  23. Important Findings • Untreated antenatal depression is as important a risk factor (if not more important) for PTB as is antenatal use of SSRIs • Similarly, Wisner et al. found that infants who were continuously exposed to SSRIs or untreated depression during the 3 trimesters of pregnancy were more at risk for PTB than were infants with partial or no exposure (American Journal of Psychiatry, 2009) • Many studies examining the risks of PTB, LBW, IUGR associated with antenatal SSRI use do not control for length of SSRI exposure, whether SSRIs taken, untreated antenatal depression, depression severity, or other potential confounders (e.g., smoking or substance use, previous PTB or LBW) • \11 • \

  24. Figure 2. Possible Explanations of the Links between Antenatal Depression and the Increased Risk of Adverse Birth Outcomes Dys-regulation of HPA axis Maternal Antenatal Depression ▪ Release of stress hormones PTB LBW IUGR Increased Morbidity, Mortality, Dev. Disabilities in Infancy & Childhood Reproductive problems in adulthood Poor prenatal practices: • ▪ Poor nutrition & hygiene • ▪ Lack of motivation for prenatal care • ▪ Smoking/substance abuse Impaired immune system • Reproductive tract infection Direct effect

  25. Limitations • 80% of the studies in the meta-analysis controlled for at least 2 key control variables, but few controlled for all of them • Most of the studies in the meta-analysis did not control for antenatal anxiety or stressful life events (but see Littleton et al., 2007) • Most of the studies did not use a structured psychiatric interview to assess for major depression • Next steps -- the need for a prospective, epidemiological study that uses diagnostic and severity measures of depression and controls for SSRI use, smoking, substance abuse, anxiety, maternal age, race/ethnicity, SES, obstetrical/medical problems, BMI, and behavioral health practices • \11 • \

  26. Implications • To decrease rates of PTB & LBW, pregnancy is an opportune time • To universally and accurately screen women for depression, especially those who are socio-economically disadvantaged • To educate pregnant women about harmful, but potentially modifiable life style practices (e.g., smoking, substance use, poor nutrition) • To provide timely access to prenatal care and specialty mental health services • \11 • \

  27. Implications for treatment of antenatal depression • Given that untreated antenatal depression is as likely to lead to poor birth outcomes as is antenatal use of SSRIs • Given that untreated antenatal depression is the most robust predictor of postpartum depression which leads to additional harmful consequences for infant and child development • Women and their OB providers will need to weigh the costs and benefits of anti-depressant medication use for treating antenatal depression, especially when treatment with evidence-based psychotherapy is not available or desired • \11 • \

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