Preterm birth is a leading cause of infant morbidity and mortality.1 In the United States 12% of deliveries are preterm, and roughly half are spontaneous as opposed to medically indicated.2 Although certain risk factors for spontaneous preterm birth have been clearly identified, including demographic characteristics, substance use, and multiple gestations, the etiology remains poorly understood; efforts to reduce the preterm birth rate have made little progress over the past two decades.1–4 A growing number of studies suggest a role for psychosocial factors such as maternal stress5–7 and depression.8–10 However, the effect of posttraumatic stress disorder (PTSD) remains unclear.
Posttraumatic stress disorder is a complex of disruptive symptoms arising from a traumatic experience (eg, violence, disaster). Its prevalence varies substantially between populations based on exposure.11 U.S. surveys show women affected at higher rates than men, and estimate lifetime prevalence of PTSD among females to be 10–14%.12,13
Posttraumatic stress disorder could affect preterm delivery directly through biological pathways or indirectly through risky health behaviors and poor self-care (eg, attendance to medical care, nutrition, and sleep). Previous studies have been limited by inadequate sample size, heterogeneity in diagnostic criteria, and generalizability concerns.14–23
We examined whether PTSD is associated with spontaneous preterm birth by evaluating deliveries covered by the Veterans Health Administration. With standardized mandatory PTSD screening,24 a high PTSD prevalence (13–21% in reproductive-aged women),25,26 and centralized national data, the Veterans Health Administration provides an ideal setting in which to examine the association between PTSD and preterm birth in a cohort of unprecedented size.
MATERIALS AND METHODS
Using data from national clinical and administrative databases for Veterans Health Administration-based (nonobstetric) care and outsourced (obstetric) Veterans Health Administration care, we conducted a retrospective cohort analysis of all Veterans Health Administration-reimbursed deliveries in fiscal years 2000–2012 and evaluated associations between antepartum PTSD and spontaneous preterm delivery: 16,477 deliveries were identified using a validated algorithm.27 Our main Veterans Health Administration data set is derived from standardized hospital discharge abstracts, entered by professional coders, and diagnosis data from such discharge abstracts have previously been shown to be reliably coded.28 We excluded 102 women without Veterans Health Administration encounters before delivery (and thus without antecedent Veterans Health Administration PTSD screening or clinical data) and 41 additional deliveries resulting from irreconcilable data.
Our primary outcome was spontaneous preterm birth. Spontaneous cases were deemed most relevant to evaluating the direct contribution of PTSD to premature delivery. Cases were identified by International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) diagnosis code 644.2 “spontaneous onset of delivery before 37 weeks” in the delivery claim, which in external validation corresponds to a median gestational age of 35 weeks (see Appendix 1, available online at http://links.lww.com/AOG/A571, for a description of validation).
The Veterans Health Administration routinely screens for PTSD within its primary care system,29 and prior Veterans Health Administration studies confirm the reliability of ICD-9-CM 309.81 to identify PTSD.30,31 We used Veterans Health Administration encounters from 1997 to 2012 (ensuring a minimum 3-year look-back for our cohort, which begins with deliveries in 2000) to identify PTSD in any encounter before delivery. For each delivery, we further distinguished two mutually exclusive categories of PTSD status in pregnancy: “active PTSD” and “historical PTSD.” This distinction was invoked based on prior research that observed poorer birth outcomes in women with current PTSD symptoms during pregnancy, not past (recovered) PTSD.32 We categorized as “active PTSD” those cases in which a PTSD diagnosis was documented in any encounter(s) within 365 days before the day of delivery, presuming these represented pregnancies with clinically relevant PTSD symptoms in the prenatal period; PTSD cases not meeting this criterion were labeled “historical PTSD.” In choosing a 1-year window to define active PTSD, we aimed to maximize overlap with the pregnancy and ensure likelihood of a Veterans Health Administration encounter for all participants in that time period. (A more restrictive 9-month window was explored in a sensitivity analysis.) By our inclusion criteria, all women had Veterans Health Administration encounters before delivery, and more than 99% had an encounter within 1 year before delivery and thus the opportunity for active PTSD to be documented.
We collected data on two potential trauma exposures, military sexual trauma and recent military deployment, both associated with high rates of PTSD within the Veterans Health Administration.25,33 Mandatory one-time screening for military sexual trauma has been in place since 2002 through a brief validated instrument33 (see Appendix 1, http://links.lww.com/AOG/A571, for screening questions). We used the Department of Defense Roster34 to identify veterans with recent deployment in support of operations in Afghanistan or Iraq.
We obtained demographic covariates from Veterans Health Administration administrative data, including maternal age, race, and marital status. We identified obstetric risk factors including twins or higher-order gestations and prior cesarean delivery from obstetric hospitalizations using validated ICD-9-CM codes.35,36 We extracted medical comorbidities from previously developed Veterans Health Administration chronic condition data sets.37 Specifically, we recorded those conditions that were both prevalent in our cohort (2% or more) and have been suggested as risk factors for preterm birth3: hypertension, diabetes, and asthma.
To identify mental health diagnoses other than PTSD, we used a modified version38 of the Agency for Healthcare Research and Quality Clinical Classifications Software's categories of mental illness.39 Applying the same criteria as for PTSD, we created three-level indicator variables (active, historical, none) for the most prevalent disorders. We identified active drug and alcohol abuse and tobacco dependence in the antenatal period by the presence of diagnostic codes in Veterans Health Administration encounters within 1 year before delivery or within reimbursed prenatal encounters (where screening for substances should be standard of care) to maximize sensitivity.
Delivery was our unit of analysis and we used statistical methods accounting for repeated measures adjusting effect estimates to take into account a within-person correlation for women with repeat deliveries in our cohort. We performed unadjusted χ2 bivariate analysis, then performed adjusted multivariate logistic regression (SAS 9.2) using generalized estimating equations modeling (clustered by individual) to determine adjusted odds ratio (OR) of spontaneous preterm delivery by PTSD status as a three-level predictor comparing “active PTSD” and “historical PTSD” with none.
We performed regressions in an iterative (additive) fashion, exploring demographic and obstetric factors, and potential trauma (military sexual trauma, deployment) as possible confounders. For parsimony, covariates were only retained in subsequent models if they altered the β coefficient of the primary predictor, active PTSD, by 10% or more. All models were adjusted for multiple gestations given their undisputed association with spontaneous preterm birth. Our resulting primary model adjusted for age, race, multiple gestation, and deployment history. We examined interaction terms for PTSD*military sexual trauma and PTSD*deployment history. We explored three possible explanatory pathways: preselected chronic comorbidities (hypertension, diabetes, asthma), behavioral risks (drug, alcohol, or tobacco use), and other mental health disorders frequently codiagnosed with PTSD (those disorders with prevalence 2% or more in our cohort). We did not include these as confounders in our primary analysis because they could arguably represent intermediate steps in the causal pathway (ie, if the pathophysiology of chronic PTSD predisposes women to the selected comorbidities). In evaluating the potential explanatory role of codiagnosed mental health conditions, we placed these variables in regression models, both alongside PTSD and in place of PTSD. Lastly, we tested our model assumptions in a series of sensitivity analyses, including models restricted to first deliveries or singleton deliveries, models adjusted for obstetric history (eg, prior spontaneous preterm birth, excluding multiples), and models applying more restrictive timeframes (see Appendix 2, available online at http://links.lww.com/AOG/A571, for a detailed description).
This research was approved by Stanford University's institutional review board as part of the Women's Health Evaluation Initiative.
The cohort included 16,334 deliveries among 14,047 women. There were 1,248 (7.6%) spontaneous preterm deliveries. Of the 16,334 deliveries, 3,049 (19%) were to women who carried an antepartum diagnosis of PTSD, two thirds of whom (1,921 [12%]) had active PTSD. Nearly one third of the deliveries (4,948) were to women with recent deployment (Afghanistan or Iraq); 3,568 (23%) deliveries were to women reporting a history of military sexual trauma.
Table 1 presents descriptive characteristics by PTSD status. Those with active PTSD were significantly more likely to have been deployed (45%) than were those with historical (32%) or no PTSD (28%). Those with active and historical PTSD were more likely to report military sexual trauma (57% and 46%) than those without PTSD (16%) and carried a significantly higher burden of active comorbid mental health, drug-, and alcohol-related diagnoses (P<.001 for all). The unadjusted proportion of spontaneous preterm birth (Table 1) was significantly higher in those with active PTSD (9.2%) than those with historical (8.0%) or no PTSD (7.4%) (P=.02).
In our primary adjusted model (Table 2), active PTSD remained associated with spontaneous preterm delivery (adjusted OR 1.35 [1.14–1.61]), whereas historical PTSD's association was nonsignificant (adjusted OR 1.06 [0.84–1.34]).
Although deployment history was associated with a lower risk of spontaneous preterm birth, adjusted OR 0.71 (0.61–0.81)—consistent with our expectation that the selection process for deployment results in a subpopulation of healthier, lower-risk individuals (the “healthy warrior effect”)40—we found no statistical support for our a priori hypothesis that deployment modifies the effect of PTSD (P=.42 for interaction term active PTSD*deployment added to our base model). In contrast, military sexual trauma showed no association with spontaneous preterm birth (unadjusted OR 1.08 [0.94–1.24]; adjusted OR 0.99 [0.84–1.15]; see Appendix 3, available online at http://links.lww.com/AOG/A571, Table A1). However, as shown in Table 3, when the interaction of military sexual trauma and PTSD was explored, we observed that those with both active PTSD and military sexual trauma carried the greatest, and most significant, risk (adjusted OR 1.43 [1.15–1.77]), although the interaction term was not statistically significant (P=.25 for interaction term active PTSD*military sexual trauma).
In analysis of possible explanatory pathways (Table 4; see Appendix 3, http://links.lww.com/AOG/A571, Table A2 for full details), adjusting for comorbid hypertension, diabetes, and asthma, made little difference—suggesting that the higher prevalence of these chronic conditions observed in PTSD-affected women did not explain the increased risk of spontaneous preterm birth. Only hypertension was a significant predictor of spontaneous preterm birth (adjusted OR 1.75 [1.43–2.13]) and its addition to the model did not significantly change the effect of active PTSD (from adjusted OR 1.35 to adjusted OR 1.33 [1.12–1.59]). Adjusting for drug, alcohol, and tobacco use mildly attenuated the independent risk estimate for active PTSD (adjusted OR 1.29 [1.08–1.55]); among the three substance categories, only active drug dependence or abuse was itself a significant predictor (adjusted OR 1.38 [1.03–1.85]). Lastly, adjusting for co-occurring psychiatric disorders, we found no evidence that an alternative comorbid mental health condition better explained the effect observed—no other active mental disorder was predictive of spontaneous preterm birth at a statistically significant level and, when all were included in the model, the effect of active PTSD, independent of co-occurring mental disorders, remained similar and significant (adjusted OR 1.30 [1.07–1.58]). Numerous additional sensitivity analyses of our model were explored—including adjusting for prior spontaneous preterm birth, restricting cohort to first deliveries, reinclusion of dropped demographic covariates, and alternative timeframes and definitions for active PTSD—and the effect size for active PTSD remained robust (Table 5; see Appendix 3, http://links.lww.com/AOG/A571, Tables A3–A5 for full details).
We analyzed an unprecedented14–23 number of parturients with active PTSD (nearly 2,000) within a health care system that routinely screens for PTSD and affirmed it is associated with increased risk of spontaneous preterm delivery—a finding robust to adjustment for other known risk factors. The 35% increased odds of spontaneous preterm delivery in those with active PTSD is clinically relevant (two excess preterm births per 100 affected deliveries) and on par with risks such as advanced maternal age (older than 35 years)41 and, within our cohort, only slightly smaller than the well-established risk factor of African American race.
Our findings build on suggestive previous studies too small to detect this association.14–23 We benefit from a design that confirms PTSD temporally preceded the delivery, adding support for a causal relationship. The Veterans Health Administration has mandatory PTSD screening, using a validated instrument24 built into the electronic medical record,42 and our reliance on clinician-entered encounter diagnoses is supported by prior Veterans Health Administration studies confirming the ICD-9-CM diagnosis reliably predicts PTSD.30,31
Several limitations are noteworthy. First, we were unable to measure degree of prematurity and do not account for medically indicated (eg, induced) preterm births; however, the preterm births that we focused on—spontaneous—disproportionately account for very preterm births3 and are most relevant to understanding the role stress plays in early-onset delivery. Second, deployment and military sexual trauma were the only two trauma exposures examined; neither demonstrated significant interaction with PTSD, but they are unlikely the only sources of PTSD in our sample, and we cannot comment on the role of premilitary trauma. Third, the generalizability of our findings to non-Veterans Health Administration populations is uncertain. However, the association is not unique to combat veterans because the majority of our cohort was nondeployed. The spontaneous preterm birthrate in our cohort (7.6%) is similar to the 8.1% observed nationally43; the 12% prevalence of active PTSD in our veteran cohort is disturbingly high but comparable to the 7–14% reported in populations receiving maternity care in urban, public-payer clinics.32,44 Military women experience diverse traumas, yet their most common antecedent of PTSD remains sexual trauma45—the same as for women in the general population.46
Although we cannot rule out unmeasured or residual confounding, the robustness of our findings to adjustments for known risk factors is reassuring. The stark difference observed for active compared with historical PTSD suggests we are not confounded by the shared, unobserved, sociodemographic characteristics predisposing these mothers to PTSD. One potential confounder is antidepressant use. Although prior observation links antidepressants to preterm birth,47 it remains uncertain whether the effect is from antidepressants or the underlying depression9; adjusting for antidepressant use may introduce additional confounding (by indication) rather than resolving it.48 Given this, and limitations of Veterans Health Administration pharmacy data, we did not adjust for psychiatric medication use. However, post hoc analysis confirms that women with active antenatal depression were more likely prescribed antidepressants than women with active PTSD. If antidepressant use explained the increased spontaneous preterm risk associated with PTSD, we would see equal or greater increased risk among the more than 3,500 deliveries to women with active depression; but, in our cohort, we detected no such signal—thus, it is improbable that antidepressant use is the pathway from PTSD to spontaneous preterm birth.
Our study adds to the nascent understanding of the relationship between stress and preterm labor, suggesting the abnormal stress response imparted by PTSD49 might contribute to premature delivery. It also identifies PTSD-affected patients as an important clinical population in which to focus efforts to elucidate, and hopefully interrupt, the pathway from stress to preterm birth. Plausible biologic mechanisms associating PTSD with spontaneous preterm birth include neuroendocrine, inflammatory, and cardiovascular alterations—all of which have been implicated in our incomplete understanding of premature labor.3 Among the indirect mechanisms that we could examine, drug abuse and hypertension only slightly attenuated the relationship between active PTSD and spontaneous preterm delivery, suggesting direct effects over and above these factors.
Identifying PTSD-affected pregnancies as high risk is clinically important and widely relevant. One in 20 U.S. pregnancies is likely in women affected by PTSD12 and one in five among women veterans returning from military duty in Iraq and Afghanistan.26
Regardless of setting or population, obstetric and primary care providers will inevitably find themselves caring for women with active PTSD in pregnancy and preconception and need to be aware of it as a risk factor. Brief, effective screening tools for PTSD exist24 and could feasibly be included in prenatal care, especially in populations with high prevalence. Our study highlights the importance of ensuring women with PTSD are connected to appropriate mental health care in the prenatal period not only to address stress dysregulation, but also the potential maladaptive behaviors that too often accompany untreated PTSD, and raises hope that appropriate treatment will not only improve maternal well-being, but may well improve infant outcomes. If future clinical trials determine that PTSD treatment reduces risk for preterm delivery, we will have a blueprint for how to prevent the invisible wounds of trauma from extending into the next generation.
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