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Risk of Spontaneous Preterm Birth in Relation to MaternalDepressive, Anxiety and Stress Symptoms

Sixto E. Sanchez1,2, Gabriella C. Puente3, Guillermo Atencio4,5, Chungfang Qiu6, DavidYanez3, Bizu Gelaye3,7, and Michelle A. Williams3,6,71Universidad San Martin de Porres, Lima, Peru2Department of Obstetrics and Gynecology, Hospital Nacional dos de Mayo, Peru3University of Washington, Multidisciplinary International Research Training Program, Seattle,Washington, USA4Universidad Nacional Mayor de San Marcos, Lima, Peru5Instituto Nacional Materno Perinatal de Lima, Peru6Center for Perinatal Studies, Swedish Medical Center, Seattle, WA, USA7Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA

AbstractObjectiveTo examine the risk of preterm birth (PTB) in relation to maternal psychiatricsymptoms during pregnancy in Peruvian women.

MethodsThis case control study included 479 PTB cases and 480 term controls. In-personinterviews were conducted to assess womens depressive, anxiety and stress symptoms using thePatient Health Questionnaire (PHQ-9) and the Depression Anxiety Stress Scales (DASS-21).Multivariable logistic regression procedures were used to estimate adjusted odds ratios (aOR) and95% confidence intervals (CI).ResultsCompared with women reporting no or minimal depressive symptoms, the aOR (95%CI) for PTB associated with consecutive severity of depressive symptoms based on the PHQ-9assessment method were as follows: mild 2.22 (95% CI 1.643.00) and moderate-severe 3.67(95% CI 2.096.46). The corresponding aORs for mild, moderate, and moderate- severedepressive symptoms based on the DASS-21 assessment were, 1.00 (reference), 3.82 (95% CI1.907.66) and 2.90 (95% CI 1.665.04), respectively. A positive gradient was observed for theodds of PTB with severity of anxiety (ptrend

including cerebral palsy, blindness, cognitive, sensory, learning, and language deficits3.Although the precise etiology of PTB remains elusive, African American race, prior PTB,low maternal pre-pregnancy body mass index, low socioeconomic status, psychosocialstress, genitourinary tract infections, vascular complications, exposure to environmentaltoxins and polymorphisms in candidate genes, particularly those in inflammatory pathways,have been identified as PTB risk factors46.

Increasingly, maternal psychiatric symptoms, particularly symptoms and or diagnoses ofmood and anxiety disorders have been implicated as important PTB risk factors713.Depression, the fourth highest global disease burden in 2000 14, psychosocial stress, anxiety,and common psychiatric symptoms, are known to be elevated during pregnancy 15, 16. Forinstance, point prevalence estimates for major or minor depression range from 6.5% to12.9% for women throughout the pregnancy 17, 18. Notably, investigators have reported thatas many as 14.5% of women experience new depressive symptoms during pregnancy 19.Although data are limited concerning the cumulative incidence of anxiety and stresssymptoms during pregnancy, investigators have noted that these symptoms are prevalentamong reproductive age women in the US 2022.

Evidence linking maternal psychiatric symptoms and diagnoses with PTB risk have beenconflicting, due in part to variations in study methodologies including the diagnostic criteriaand instruments used to define the disorders 9, 23. Despite these methodological limitations,results from recent literature reviews indicate that maternal psychiatric disorders,particularly mood disorders, are important risk factors of PTB 9, 23. For example, Orr andcolleagues, reported that maternal symptoms of anxiety is associated with a 2.7-foldincreased risk (OR=2.73, 95% CI: 1.03, 7.27) of PTB 24. To the best of our knowledge, noinvestigators have evaluated risk of PTB in relation to maternal psychiatric symptomsamong Peruvian women. Given this gap in the literature, we hypothesized that maternaldepressive, anxiety and stress symptoms during pregnancy are associated with increasedPTB risks among low income women in Lima, Peru. We tested our hypothesis in a largecase-control study of 479 PTB cases and 480 term controls.

METHODSStudy population and selection of cases and controls

This case-control study was conducted among women who delivered live births at theHospital Nacional Dos de Mayo, the Instituto Nacional Materno Perinatal de Lima, and theHospital Edgardo Rebagliati Martins in Lima, Peru, from January 2009 through July 2010.This study was approved by the institutional review board of each participating institution.Cases were women with singleton pregnancies who spontaneously delivered beforecompleted 37 weeks of gestation (2236 weeks of gestation). Spontaneous preterm deliverycases were identified by daily monitoring of all new deliveries at postpartum wards ofparticipating hospitals. Of the 515 eligible cases approached, 479 (93%) agreed toparticipate in the study. Controls were women who delivered a singleton infant at term (37weeks of gestation) and were selected from the same hospital of delivery. An eligiblecontrol, delivering immediately after a case patient, was approached and recruited for thestudy. Of the 546 eligible controls approached, 480 (88%) agreed to participate in the study.All participants provided written informed consent.

Data collection and analytical variable specificationAfter obtaining informed consent, enrolled participants were asked to take part in a 45-minute in-person interview in which trained research personnel used a standardized,structured Spanish-language questionnaire to elicit information regarding maternal socio-

Sanchez et al. Page 2

J Reprod Med. Author manuscript; available in PMC 2014 January 01.

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demographic, lifestyle habits, medical and reproductive histories. Participants labor anddelivery medical records and prenatal medical records were also reviewed by trainedresearch fellows (obstetricians) who used a standardized abstraction form. Informationabstracted from medical records included participants medical and reproductive histories,blood pressure values, pregnancy complications and condition of the newborn.

The diagnosis of preterm delivery was made using the American College of Obstetriciansand Gynecologists (ACOG) guidelines 25. Gestational age was based on the date of the lastmenstrual period and was confirmed by an ultrasound examination before 20 weeks. Usingdetailed information collected from medical records, we categorized preterm delivery casesaccording to the three pathophysiological groups previously described (i.e., spontaneouspreterm labor and delivery and preterm premature rupture of membranes) 26. Spontaneouspreterm labor and delivery cases were comprised of women whose medical recordsindicated a physician diagnosis of spontaneous labor onset (with intact fetal membranes) anddelivery prior to the completion of 37 weeks gestation. Preterm premature rupture ofmembranes cases were comprised of women whose medical records indicated a physiciandiagnosis of rupture of fetal membranes (prior to the onset of labor) and delivery prior to thecompletion of 37 weeks gestation. Women who delivered prior to 37 completed weeks ofgestation as a result of medical intervention were not eligible for this study. We alsocategorized preterm delivery cases according to gestational age at delivery (i.e., verypreterm delivery, defined as delivery prior to the completion of 34 weeks gestation;moderate preterm delivery, defined as delivery between 34 and 36 weeks gestation).

Information collected during the interviews included maternal age, marital status,employment status during pregnancy, medical history, and smoking and alcoholconsumption during pregnancy. We used the Patient Health Questionaire-9 (PHQ-9) toassess participants experience of depression or depressive symptoms during pregnancy. Theinstrument has been demonstrated to be a reliable tool for assessing recent psychosocialstressors among obstetrics-gynecology patients 27 and in Spanish-speaking women 28. In arecent validation study of the PHQ-9 questionnaire, the authors concluded that theinstrument is a reliable and valid measure of depression severity and a useful clinical andresearch tool 29. The PHQ-9 scale includes nine items, and choices for responses were (a)never; (b) several weeks over the pregnancy; (c) more than half the pregnancy; or (d) nearlythe whole pregnancy. The PHQ-9 total score is the sum of scores for the nine items for eachwoman, and ranged from 027. We categorized participants as exhibiting minimal (PHQ-9score 04), mild (PHQ-9 score 59), and moderate-severe (PHQ-9 score 10) depressivesymptoms.

Maternal depressive, anxiety and stress levels were also characterized using the DepressionAnxiety Stress Scales (DASS-21) instrument. The DASS-21 is a 21-item instrumentdesigned to measure the 3 negative affective states of depression, anxiety, and stress. Thedepression scale assessed dysphoria, hopelessness, devaluation of life, self-deprecation, lackof interest or involvement, anhedonia, and inertia. The anxiety scale assessed autonomicarousal, situational anxiety, and subjective experience of anxious affect. The stress scaleassessed difficulty relaxing, nervous arousal, and being easily upset or agitated, irritable, orover-reactive and impatience 30, 31. The psychometric properties of the English and Spanishversions of DASS-21 have been extensively evaluated, and there is evidence for theconvergent and discriminative validity of data obtained with the instrument31, 32. Brown etal. 32 reported that patients meeting the criteria for major depression, based on the DSM-III-R and using a structured interview, had a mean score of 25.3 (SD10.24) on the DASSdepression scale. Using previously suggested cutoff scores 30, 31, participants werecategorized as exhibiting normal (DASS score

exhibiting normal (DASS score

(Table 2). The corresponding aORs for mild and moderate-severe depressive symptomsbased on the DASS-21 assessment were (aOR=3.82, 93%; 1.907.66) and (aOR=2.90; 95%CI 1.665.04), respectively. Strong positive and statistically significant associations of PTBcategorized by sub-type (SPTL or PPROM) or severity of preterm birth (

have formal diagnostic examinations. As a result, some misclassification is possible.However, both the PHQ-9 and DASS-21 have been shown to have good-to-excellentpsychometric properties when compared with the Structured Clinical Interview for DSM-IVmood disorder module 28, 29, 31. As well, the findings from both sets of analyses areconsistent with each other, providing some robustness to the study. Lastly, although weadjusted for multiple confounding factors, as with all observational studies, we cannotexclude the possibility of some residual confounding.

Associations between depression and increased odds of PTB are biologically plausible.Psychiatric disorders have been associated with hypothalamic-pituitary-adrenal (HPA) axishyperactivity34. Maternal depression, for example, is thought to activate the mothers HPAaxis and, in turn, is regulated by peptides derived from the activated HPA axis. Depressionmay cause an increase in the release of corticotropin-releasing hormone (CRH) from theplacenta via the actions of catecholamines and cortisol 3540. Smith and colleaguesexamined the relationships between mood changes, obstetric experience, and alterations inplasma cortisol, beta-endorphin, and CRH36. Plasma levels of these hormones were obtainedthroughout pregnancy, at delivery, and postpartum. Smith and colleagues reported that theprevalence of mood disturbances found in the late antenatal period was higher than the levelfound in the postnatal period; the prevalence correlated with hormone levels, which peakedin late pregnancy and fell postpartum36. These data suggest a role for CRH and the HPAaxis in the relationship between antenatal mood states and obstetric events. Depression maybe mediated by an altered excretion of vasoactive hormones and other neuroendocrinetransmitters. This may in turn cause vasoconstriction and uterine artery resistance and,therefore, premature labor39. Available evidence also implicates pro-inflammatory cytokinesin the pathogenesis of psychiatric disorders, particularly major depression. The stresshormones may facilitate inflammation through induction of interleukins (IL) such as IL-1,IL-6, tumor necrosis factor-alpha, and C-reactive protein production 41 and contribute to thepathogenesis of PTB 42.

Our results, combined with those reported by others, suggest that the risk of PTB isincreased in women experiencing psychological stress and symptoms of mood and anxietydisorders during pregnancy. Additional efforts are required to carefully characterize thesequelae of psychiatric illnesses among pregnant women. Longitudinal studies, withprospective assessment of clinical and sub-clinical psychiatric illnesses in ethnically andracially diverse populations are warranted. Efforts to screen and treat affected women maymodify risks of PTB and possibly other associated disorders.

AcknowledgmentsThis research was supported by awards from the National Institutes of Health (NIH), National Institute of MinorityHealth and Health Disparities (T37-MD-001449) and the Eunice Kennedy Shriver Institute of Child Health andHuman Development (R01-HD-059835). The NIH had no further role in study design; in the collection, analysisand interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. Theauthors wish to thank the staff of the Hospital Nacional dos de Mayo, Instituto Especializado Materno Perinatal,and Hospital Edgardo Rebagliati Martins for their technical assistance with this research.

References1. Beck S, Wojdyla D, Say L, Betran AP, Merialdi M, Requejo JH, Rubens C, Menon R, Van Look

PF. The worldwide incidence of preterm birth: a systematic review of maternal mortality andmorbidity. Bulletin of the World Health Organization. 2010; 88(1):3138. [PubMed: 20428351]

2. Lawn JE, Wilczynska-Ketende K, Cousens SN. Estimating the causes of 4 million neonatal deathsin the year 2000. International journal of epidemiology. 2006; 35 (3):706718. [PubMed:16556647]



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3. Allen MC. Neurodevelopmental outcomes of preterm infants. Current opinion in neurology. 2008;21(2):123128. [PubMed: 18317268]

4. Behrman, RE. Preterm Birth: Causes, Consequences, and Prevention. Behrman, RE.; Butler, AS.,editors. Washington (DC): 2007.

5. Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth.Lancet. 2008; 371(9606):7584. [PubMed: 18177778]

6. Muglia LJ, Katz M. The enigma of spontaneous preterm birth. The New England journal ofmedicine. 2010; 362(6):529535. [PubMed: 20147718]

7. Bansil P, Kuklina EV, Meikle SF, Posner SF, Kourtis AP, Ellington SR, Jamieson DJ. Maternal andfetal outcomes among women with depression. J Womens Health (Larchmt). 2010; 19(2):329334.[PubMed: 20095906]

8. de Paz NC, Sanchez SE, Huaman LE, Chang GD, Pacora PN, Garcia PJ, Ananth CV, Qiu C,Williams MA. Risk of placental abruption in relation to maternal depressive, anxiety and stresssymptoms. Journal of affective disorders. 2011; 130(12):280284. [PubMed: 20692040]

9. Grote NK, Bridge JA, Gavin AR, Melville JL, Iyengar S, Katon WJ. A meta-analysis of depressionduring pregnancy and the risk of preterm birth, low birth weight, and intrauterine growth restriction.Archives of general psychiatry. 2010; 67(10):10121024. [PubMed: 20921117]

10. Hobel CJ, Goldstein A, Barrett ES. Psychosocial stress and pregnancy outcome. Clinical obstetricsand gynecology. 2008; 51(2):333348. [PubMed: 18463464]

11. Phillips GS, Wise LA, Rich-Edwards JW, Stampfer MJ, Rosenberg L. Prepregnancy depressivesymptoms and preterm birth in the Black Womens Health Study. Annals of epidemiology. 2010;20(1):815. [PubMed: 20006271]

12. Qiu C, Williams MA, Calderon-Margalit R, Cripe SM, Sorensen TK. Preeclampsia risk in relationto maternal mood and anxiety disorders diagnosed before or during early pregnancy. Americanjournal of hypertension. 2009; 22(4):397402. [PubMed: 19197246]

13. Suri R, Altshuler L, Hellemann G, Burt VK, Aquino A, Mintz J. Effects of antenatal depressionand antidepressant treatment on gestational age at birth and risk of preterm birth. The Americanjournal of psychiatry. 2007; 164(8):12061213. [PubMed: 17671283]

14. Meyer C. Depressive disorders were the fourth leading cause of global disease burden in the year2000. Evidence-based mental health. 2004; 7(4):123. [PubMed: 15504811]

15. Parkitny L, McAuley J. The Depression Anxiety Stress Scale (DASS). Journal of physiotherapy.2010; 56(3):204. [PubMed: 20795931]

16. Ruiz RJ, Fullerton JT. The measurement of stress in pregnancy. Nursing & health sciences. 1999;1(1):1925. [PubMed: 10894648]

17. Bennett HA, Einarson A, Taddio A, Koren G, Einarson TR. Prevalence of depression duringpregnancy: systematic review. Obstetrics and gynecology. 2004; 103(4):698709. [PubMed:15051562]

18. Gavin NI, Gaynes BN, Lohr KN, Meltzer-Brody S, Gartlehner G, Swinson T. Perinatal depression:a systematic review of prevalence and incidence. Obstetrics and gynecology. 2005; 106(5 Pt 1):10711083. [PubMed: 16260528]

19. Gaynes BN, Gavin N, Meltzer-Brody S, Lohr KN, Swinson T, Gartlehner G, Brody S, Miller WC.Perinatal depression: prevalence, screening accuracy, and screening outcomes. Evid Rep TechnolAssess (Summ). 2005; (119):18. [PubMed: 15760246]

20. Faisal-Cury A, Rossi Menezes P. Prevalence of anxiety and depression during pregnancy in aprivate setting sample. Archives of womens mental health. 2007; 10(1):2532.

21. Lee AM, Lam SK, Sze Mun Lau SM, Chong CS, Chui HW, Fong DY. Prevalence, course, and riskfactors for antenatal anxiety and depression. Obstetrics and gynecology. 2007; 110(5):11021112.[PubMed: 17978126]

22. Woods SM, Melville JL, Guo Y, Fan MY, Gavin A. Psychosocial stress during pregnancy.American journal of obstetrics and gynecology. 2010; 202(1):61 e6167. [PubMed: 19766975]

23. Alder J, Fink N, Bitzer J, Hosli I, Holzgreve W. Depression and anxiety during pregnancy: a riskfactor for obstetric, fetal and neonatal outcome? A critical review of the literature. The journal ofmaternal-fetal & neonatal medicine: the official journal of the European Association of Perinatal



NIH


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Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society ofPerinatal Obstet. 2007; 20(3):189209.

24. Orr ST, Reiter JP, Blazer DG, James SA. Maternal prenatal pregnancy-related anxiety andspontaneous preterm birth in Baltimore, Maryland. Psychosomatic medicine. 2007; 69 (6):566570. [PubMed: 17636150]

25. ACOG. ACOG technical bulletin. Preterm labor. Number 206--June 1995 (Replaces No. 133,October 1989). International journal of gynaecology and obstetrics: the official organ of theInternational Federation of Gynaecology and Obstetrics. 1995; 50(3):303313. [PubMed:8543120]

26. Williams MA, Mittendorf R, Stubblefield PG, Lieberman E, Schoenbaum SC, Monson RR.Cigarettes, coffee, and preterm premature rupture of the membranes. American journal ofepidemiology. 1992; 135(8):895903. [PubMed: 1585902]

27. Spitzer RL, Williams JB, Kroenke K, Hornyak R, McMurray J. Validity and utility of the PRIME-MD patient health questionnaire in assessment of 3000 obstetric-gynecologic patients: the PRIME-MD Patient Health Questionnaire Obstetrics-Gynecology Study. American journal of obstetricsand gynecology. 2000; 183(3):759769. [PubMed: 10992206]

28. Wulsin L, Somoza E, Heck J. The Feasibility of Using the Spanish PHQ-9 to Screen forDepression in Primary Care in Honduras. Primary care companion to the Journal of clinicalpsychiatry. 2002; 4(5):191195.

29. Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure.Journal of general internal medicine. 2001; 16(9):606613. [PubMed: 11556941]

30. Lovibond PF. Long-term stability of depression, anxiety, and stress syndromes. Journal ofabnormal psychology. 1998; 107(3):520526. [PubMed: 9715586]

31. Lovibond PF, Lovibond SH. The structure of negative emotional states: comparison of theDepression Anxiety Stress Scales (DASS) with the Beck Depression and Anxiety Inventories.Behaviour research and therapy. 1995; 33(3):335343. [PubMed: 7726811]

32. Brown TA, Chorpita BF, Korotitsch W, Barlow DH. Psychometric properties of the DepressionAnxiety Stress Scales (DASS) in clinical samples. Behaviour research and therapy. 1997; 35(1):7989. [PubMed: 9009048]

33. Rothman, KJ.; Greenland, S. Modern epidemiology. Philadelphia: Lippincott-Raven; 1998.34. Chrousos GP, Torpy DJ, Gold PW. Interactions between the hypothalamic-pituitary-adrenal axis

and the female reproductive system: clinical implications. Annals of internal medicine. 1998;129(3):229240. [PubMed: 9696732]

35. Paarlberg KM, Vingerhoets AJ, Passchier J, Dekker GA, Van Geijn HP. Psychosocial factors andpregnancy outcome: a review with emphasis on methodological issues. Journal of psychosomaticresearch. 1995; 39(5):563595. [PubMed: 7490693]

36. Smith R, Cubis J, Brinsmead M, Lewin T, Singh B, Owens P, Chan EC, Hall C, Adler R, LovelockM, et al. Mood changes, obstetric experience and alterations in plasma cortisol, beta-endorphinand corticotrophin releasing hormone during pregnancy and the puerperium. Journal ofpsychosomatic research. 1990; 34(1):5369. [PubMed: 2138227]

37. Guendelman S, Kosa JL, Pearl M, Graham S, Kharrazi M. Exploring the relationship of second-trimester corticotropin releasing hormone, chronic stress and preterm delivery. The journal ofmaternal-fetal & neonatal medicine: the official journal of the European Association of PerinatalMedicine, the Federation of Asia and Oceania Perinatal Societies, the International Society ofPerinatal Obstet. 2008; 21(11):788795.

38. Holzman C, Senagore P, Tian Y, Bullen B, Devos E, Leece C, Zanella A, Fink G, Rahbar MH,Sapkal A. Maternal catecholamine levels in midpregnancy and risk of preterm delivery. Americanjournal of epidemiology. 2009; 170(8):10141024. [PubMed: 19741043]

39. Sandman CA, Wadhwa PD, Chicz-DeMet A, Dunkel-Schetter C, Porto M. Maternal stress, HPAactivity, and fetal/infant outcome. Annals of the New York Academy of Sciences. 1997; 814:266275. [PubMed: 9160976]

40. Wadhwa PD, Dunkel-Schetter C, Chicz-DeMet A, Porto M, Sandman CA. Prenatal psychosocialfactors and the neuroendocrine axis in human pregnancy. Psychosomatic medicine. 1996; 58(5):432446. [PubMed: 8902895]



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41. Elenkov IJ, Iezzoni DG, Daly A, Harris AG, Chrousos GP. Cytokine dysregulation, inflammationand well-being. Neuroimmunomodulation. 2005; 12(5):255269. [PubMed: 16166805]

42. Christian LM, Franco A, Iams JD, Sheridan J, Glaser R. Depressive symptoms predict exaggeratedinflammatory responses to an in vivo immune challenge among pregnant women. Brain, behavior,and immunity. 2010; 24(1):4953.



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Tabl

e 1

Soci

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Ni Hms 464721

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