and racial disparities in congenital anomaly–related infant deaths. Obstet Gynecol 2015;125:163–9.
Posttraumatic Stress Disorder and Risk of Spontaneous Preterm Birth To the Editor: Approximately 150,000 women, as part of the active component of the U.S. military, deployed to Iraq and Afghanistan between October 1, 2001 and December 31, 2010.1 Although there has been a surge in concerns about mental disorders among female veterans, few data have focused specifically on female deployers.2 Therefore, we read the article by Shaw et al,3 titled “Posttraumatic Stress Disorder and Risk of Spontaneous Preterm Birth,” with interest. We found the results of the study interesting and remarkable. However, we think that mild traumatic brain injury (TBI), which could have an effect on the results of the study, should be emphasized clearly. In military settings, some of the risk factors for postdeployment posttraumatic stress disorder (PTSD) mirror those in the general population; others (eg, mild TBI) are specific to military experiences, such as combat experience.4 The exact proportion of troops who have mild TBI is not known, although it has been reported to be as high as 18%. The case definition of mild TBI that is being adopted by the new Department of Defense and Department of Veterans Affairs screening programs is consistent with national surveillance definitions. However, the use of this definition for clinical screening weeks or months after concussive events has not been evaluated. The definition may not be sufficiently specific for the combat environment, where acute signs of concussion, such as alteration of mental status (eg, being dazed or confused), may overlap with symptoms of PTSD. More than 40% of soldiers with injuries associated with loss of consciousness met the criteria for PTSD.5 The prevalence of neurologic deficits associated with combat-related mild TBI and the relationships among neurologic deficits, PTSD, and number of episodes of mild TBI are unknown.5 Maternal cognitive (eg, involving attention, concentration, perception, memory) and behavioral deficits (eg, irritability, quickness, disinhi-
988
Letters
bition, and emotional lability) may be the cause of spontaneous preterm delivery in patients with PTSD who have mild TBI. As a result, we think that increased risk of preterm birth in patients with PTSD (deployment-related, distinct from sexual trauma–related) may be a result of not patients with mild TBI excluding from the study. Financial Disclosure: The authors did not report any potential conflicts of interest.
Barbaros Ozdemir, MD Cemil Celik, MD Taner Oznur, MD Gulhane Military Medical Faculty, Ankara, Turkey
REFERENCES 1. Armed Forces Health Surveillance Center (AFHSC). Health of women after wartime deployments: correlates of risk for selected medical conditions among females after initial and repeat deployments to Afghanistan and Iraq, active component, U.S. Armed Forces. MSMR 2012;19:2–10. 2. Seelig AD, Jacobson IG, Smith B, Hooper TI, Gackstetter GD, Ryan MA, et al. Prospective evaluation of mental health and deployment experience among women in the US military. Am J Epidemiol 2012;176:135–45. 3. Shaw JG, Asch SM, Kimerling R, Frayne SM, Shaw KA, Phibbs CS. Posttraumatic stress disorder and risk of spontaneous preterm birth. Obstet Gynecol 2014;124:1111–119. 4. Crum-Cianflone NF, Jacobson I. Gender differences of postdeployment posttraumatic stress disorder among service members and veterans of the Iraq and Afghanistan conflicts. Epidemiol Rev 2014;36:5–18. 5. Hoge CW, McGurk D, Thomas JL, Cox AL, Engel CC, Castro CA. Mild traumatic brain injury in U.S. soldiers returning from Iraq. N Engl J Med 2008;358:453–63.
Posttraumatic Stress Disorder and Risk of Spontaneous Preterm Birth To the Editor: I congratulate the authors for their research in this important area and also give recognition to these patients who are serving our country.1 I am concerned, however, with the lack of information on antidepressant use in this study. Serotonin is a crucial neurotransmitter and
cell-signaling molecule that plays an essential role in fetal formation and pregnancy development. Most antidepressants disrupt this serotonin system. It should come as no surprise, then, that animal studies show pregnancy complications with antidepressant exposure. Human studies also show complications—including preterm birth. Three solid metaanalyses all conclude that antidepressant use is associated with preterm birth.2–4 Of the 41 studies included in our review,4 39 showed increased preterm birth rates in the medication group. There are no randomized controlled trials, so confounding by indication is a concern. However, when the mechanism is plausible (serotonin system disruption) and animal and human data align, it is highly likely that the increased preterm birth rates are due to a direct chemical (ie, drug) effect and not simply confounding by indication. Are the authors arguing that: 1) serotonin is not crucial, 2) the antidepressants do not alter the serotonin system, or 3) the antidepressants do disrupt the crucial serotonin system but somehow do not affect pregnancy outcomes? The issue is essential: if posttraumatic stress disorder causes preterm birth, some might conclude that the best way to address this would be with antidepressants. However, if, in fact, the medications are causing the increase, drug treatment might be exactly the wrong approach. History is informative here. For years, conventional wisdom in obstetrics suggested that the increase in poor outcomes seen in the pregnancies of women with epilepsy was due to the underlying epilepsy and not the medications.5 We now know this was incorrect. These medications are chemicals that freely cross the placenta into the fetus. They alter important biological systems and have pregnancy effects. A study on mental health issues such as posttraumatic stress disorder that does not fully account for medication effects is limited and may lead to drawing incorrect conclusions and suggested solutions. Financial Disclosure: The author did not report any potential conflicts of interest.
Adam C. Urato, MD Tufts University School of Medicine, Boston, Massachusetts; Division of Maternal-Fetal Medicine, Tufts Medical Center, Boston, Massachusetts; and MetroWest Medical Center, Framingham, Massachusetts
OBSTETRICS & GYNECOLOGY
Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
REFERENCES 1. Shaw JG, Asch SM, Kimerling R, Frayne SM, Shaw KA, Phibbs CS. Posttraumatic stress disorder and risk of spontaneous preterm birth. Obstet Gynecol 2014;124:1111–9. 2. Ross LE, Grigoriadis S, Mamisashvili L, Vonderporten EH, Roerecke M, Rehm J, et al. Selected pregnancy and delivery outcomes after exposure to antidepressant medication: a systematic review and metaanalysis. JAMA Psychiatry 2013;70:436–43. 3. Huang H, Coleman S, Bridge JA, Yonkers K, Katon W. A meta-analysis of the relationship between antidepressant use in pregnancy and the risk of preterm birth and low birth weight. Gen Hosp Psychiatry 2014;3613–8. 4. Huybrechts KF, Sanghani RS, Avorn J, Urato AC. Preterm birth and antidepressant medication use during pregnancy: a systematic review and meta-analysis. PLoS One 2014;9:e92778. 5. Speidel BD, Meadow SR. Maternal epilepsy and abnormalities of the fetus and newborn. Lancet 1972;2:839–43.
In Reply: We appreciate Dr. Urato highlighting the uncertainty around the risk-benefit of antidepressant use in pregnancy, and we agree that prospective study of outcomes of posttraumatic stress disorder (PTSD) treatment in pregnancy is needed—with specific attention paid not only to medications, but also to the effective psychotherapies at the core of treatment recommendations for PTSD.1 Although we could not comprehensively adjust for serotoninaltering medications, several observations argue against the suggestion that increased risk of spontaneous preterm birth seen with PTSD may be attributed
primarily to antidepressant use. First, in contrast to what we observed for active PTSD, an active diagnosis of depression was not independently associated with risk of preterm birth in our cohort; yet pharmacy data confirmed, as expected, antidepressant prescription was more common in the latter.2 If antidepressants were the basis for the PTSD–preterm association, we would reasonably expect to observe a similar or stronger (confounded) association between clinically diagnosed depression and preterm birth in our cohort. Second, although our pharmacy and pregnancy data did not permit the desired level of detail to adjust for dose or trimester-specific exposure to antidepressants, we performed several posthoc analyses to account for both broad and restrictive definitions of antidepressant exposure—eg, testing our model by adding a covariate for any prescription of antidepressants in the antenatal period and, at the other extreme, examining our adjusted model within only the subpopulation of women with numerous (six or more) antidepressant refills in the antenatal period to see whether the PTSD–preterm relationship persisted even within a universally medicated population. Throughout these sensitivity tests, we consistently found active PTSD’s association to be robust, with effect size remaining of similar magnitude (adjusted odds ratio 1.25–1.60). In reply to Ozdemir et al’s concerns, highlighting the overlap of deployment traumatic brain injury and postdeployment PTSD, it should be clarified that both the majority of our cohort (69%) and the majority of our active PTSD cases (55%) were among nondeployed veterans. Further, we tested restricting
our analysis to the subpopulation of nondeployed veterans and found that the association of PTSD and preterm birth remained similar and robust, making it implausible that deployment-specific risks explain the association. Financial Disclosure: The authors did not report any potential conflicts of interest.
Jonathan G. Shaw, MD, MS Steven M. Asch, MD, MPH Susan M. Frayne, MD, MPH Ciaran S. Phibbs, PhD Department of Veterans Affairs, Palo Alto Healthcare System, Palo Alto, California; and Stanford University School of Medicine, Stanford, California Rachel Kimerling, PhD Department of Veterans Affairs, Palo Alto Healthcare System, Palo Alto, California Kate A. Shaw, MD, MS Stanford University School of Medicine, Stanford, California
REFERENCES 1. Department of Veterans Affairs, Department of Defense. VA/DoD clinical practice guideline for the management of post-traumatic stress. Version 2.0–2010. Available at: http://www.healthquality. va.gov/guidelines/MH/ptsd/cpg_PTSDFULL-201011612.pdf. Retrieved January 5, 2015. 2. Shaw JG, Asch SM, Kimerling R, Frayne SM, Shaw KA, Phibbs CS. Posttraumatic stress disorder and risk of spontaneous preterm birth. Obstet Gynecol 2014;124:1111–119.
VOL. 125, NO. 4, APRIL 2015
Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Letters
989
Posttraumatic Stress Disorder and Risk of Spontaneous Preterm Birth To the Editor: Approximately 150,000 women, as part of the active component of the U.S. military, deployed to Iraq and Afghanistan between October 1, 2001 and December 31, 2010.1 Although there has been a surge in concerns about mental disorders among female veterans, few data have focused specifically on female deployers.2 Therefore, we read the article by Shaw et al,3 titled “Posttraumatic Stress Disorder and Risk of Spontaneous Preterm Birth,” with interest. We found the results of the study interesting and remarkable. However, we think that mild traumatic brain injury (TBI), which could have an effect on the results of the study, should be emphasized clearly. In military settings, some of the risk factors for postdeployment posttraumatic stress disorder (PTSD) mirror those in the general population; others (eg, mild TBI) are specific to military experiences, such as combat experience.4 The exact proportion of troops who have mild TBI is not known, although it has been reported to be as high as 18%. The case definition of mild TBI that is being adopted by the new Department of Defense and Department of Veterans Affairs screening programs is consistent with national surveillance definitions. However, the use of this definition for clinical screening weeks or months after concussive events has not been evaluated. The definition may not be sufficiently specific for the combat environment, where acute signs of concussion, such as alteration of mental status (eg, being dazed or confused), may overlap with symptoms of PTSD. More than 40% of soldiers with injuries associated with loss of consciousness met the criteria for PTSD.5 The prevalence of neurologic deficits associated with combat-related mild TBI and the relationships among neurologic deficits, PTSD, and number of episodes of mild TBI are unknown.5 Maternal cognitive (eg, involving attention, concentration, perception, memory) and behavioral deficits (eg, irritability, quickness, disinhi-
988
Letters
bition, and emotional lability) may be the cause of spontaneous preterm delivery in patients with PTSD who have mild TBI. As a result, we think that increased risk of preterm birth in patients with PTSD (deployment-related, distinct from sexual trauma–related) may be a result of not patients with mild TBI excluding from the study. Financial Disclosure: The authors did not report any potential conflicts of interest.
Barbaros Ozdemir, MD Cemil Celik, MD Taner Oznur, MD Gulhane Military Medical Faculty, Ankara, Turkey
REFERENCES 1. Armed Forces Health Surveillance Center (AFHSC). Health of women after wartime deployments: correlates of risk for selected medical conditions among females after initial and repeat deployments to Afghanistan and Iraq, active component, U.S. Armed Forces. MSMR 2012;19:2–10. 2. Seelig AD, Jacobson IG, Smith B, Hooper TI, Gackstetter GD, Ryan MA, et al. Prospective evaluation of mental health and deployment experience among women in the US military. Am J Epidemiol 2012;176:135–45. 3. Shaw JG, Asch SM, Kimerling R, Frayne SM, Shaw KA, Phibbs CS. Posttraumatic stress disorder and risk of spontaneous preterm birth. Obstet Gynecol 2014;124:1111–119. 4. Crum-Cianflone NF, Jacobson I. Gender differences of postdeployment posttraumatic stress disorder among service members and veterans of the Iraq and Afghanistan conflicts. Epidemiol Rev 2014;36:5–18. 5. Hoge CW, McGurk D, Thomas JL, Cox AL, Engel CC, Castro CA. Mild traumatic brain injury in U.S. soldiers returning from Iraq. N Engl J Med 2008;358:453–63.
Posttraumatic Stress Disorder and Risk of Spontaneous Preterm Birth To the Editor: I congratulate the authors for their research in this important area and also give recognition to these patients who are serving our country.1 I am concerned, however, with the lack of information on antidepressant use in this study. Serotonin is a crucial neurotransmitter and
cell-signaling molecule that plays an essential role in fetal formation and pregnancy development. Most antidepressants disrupt this serotonin system. It should come as no surprise, then, that animal studies show pregnancy complications with antidepressant exposure. Human studies also show complications—including preterm birth. Three solid metaanalyses all conclude that antidepressant use is associated with preterm birth.2–4 Of the 41 studies included in our review,4 39 showed increased preterm birth rates in the medication group. There are no randomized controlled trials, so confounding by indication is a concern. However, when the mechanism is plausible (serotonin system disruption) and animal and human data align, it is highly likely that the increased preterm birth rates are due to a direct chemical (ie, drug) effect and not simply confounding by indication. Are the authors arguing that: 1) serotonin is not crucial, 2) the antidepressants do not alter the serotonin system, or 3) the antidepressants do disrupt the crucial serotonin system but somehow do not affect pregnancy outcomes? The issue is essential: if posttraumatic stress disorder causes preterm birth, some might conclude that the best way to address this would be with antidepressants. However, if, in fact, the medications are causing the increase, drug treatment might be exactly the wrong approach. History is informative here. For years, conventional wisdom in obstetrics suggested that the increase in poor outcomes seen in the pregnancies of women with epilepsy was due to the underlying epilepsy and not the medications.5 We now know this was incorrect. These medications are chemicals that freely cross the placenta into the fetus. They alter important biological systems and have pregnancy effects. A study on mental health issues such as posttraumatic stress disorder that does not fully account for medication effects is limited and may lead to drawing incorrect conclusions and suggested solutions. Financial Disclosure: The author did not report any potential conflicts of interest.
Adam C. Urato, MD Tufts University School of Medicine, Boston, Massachusetts; Division of Maternal-Fetal Medicine, Tufts Medical Center, Boston, Massachusetts; and MetroWest Medical Center, Framingham, Massachusetts
OBSTETRICS & GYNECOLOGY
Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
REFERENCES 1. Shaw JG, Asch SM, Kimerling R, Frayne SM, Shaw KA, Phibbs CS. Posttraumatic stress disorder and risk of spontaneous preterm birth. Obstet Gynecol 2014;124:1111–9. 2. Ross LE, Grigoriadis S, Mamisashvili L, Vonderporten EH, Roerecke M, Rehm J, et al. Selected pregnancy and delivery outcomes after exposure to antidepressant medication: a systematic review and metaanalysis. JAMA Psychiatry 2013;70:436–43. 3. Huang H, Coleman S, Bridge JA, Yonkers K, Katon W. A meta-analysis of the relationship between antidepressant use in pregnancy and the risk of preterm birth and low birth weight. Gen Hosp Psychiatry 2014;3613–8. 4. Huybrechts KF, Sanghani RS, Avorn J, Urato AC. Preterm birth and antidepressant medication use during pregnancy: a systematic review and meta-analysis. PLoS One 2014;9:e92778. 5. Speidel BD, Meadow SR. Maternal epilepsy and abnormalities of the fetus and newborn. Lancet 1972;2:839–43.
In Reply: We appreciate Dr. Urato highlighting the uncertainty around the risk-benefit of antidepressant use in pregnancy, and we agree that prospective study of outcomes of posttraumatic stress disorder (PTSD) treatment in pregnancy is needed—with specific attention paid not only to medications, but also to the effective psychotherapies at the core of treatment recommendations for PTSD.1 Although we could not comprehensively adjust for serotoninaltering medications, several observations argue against the suggestion that increased risk of spontaneous preterm birth seen with PTSD may be attributed
primarily to antidepressant use. First, in contrast to what we observed for active PTSD, an active diagnosis of depression was not independently associated with risk of preterm birth in our cohort; yet pharmacy data confirmed, as expected, antidepressant prescription was more common in the latter.2 If antidepressants were the basis for the PTSD–preterm association, we would reasonably expect to observe a similar or stronger (confounded) association between clinically diagnosed depression and preterm birth in our cohort. Second, although our pharmacy and pregnancy data did not permit the desired level of detail to adjust for dose or trimester-specific exposure to antidepressants, we performed several posthoc analyses to account for both broad and restrictive definitions of antidepressant exposure—eg, testing our model by adding a covariate for any prescription of antidepressants in the antenatal period and, at the other extreme, examining our adjusted model within only the subpopulation of women with numerous (six or more) antidepressant refills in the antenatal period to see whether the PTSD–preterm relationship persisted even within a universally medicated population. Throughout these sensitivity tests, we consistently found active PTSD’s association to be robust, with effect size remaining of similar magnitude (adjusted odds ratio 1.25–1.60). In reply to Ozdemir et al’s concerns, highlighting the overlap of deployment traumatic brain injury and postdeployment PTSD, it should be clarified that both the majority of our cohort (69%) and the majority of our active PTSD cases (55%) were among nondeployed veterans. Further, we tested restricting
our analysis to the subpopulation of nondeployed veterans and found that the association of PTSD and preterm birth remained similar and robust, making it implausible that deployment-specific risks explain the association. Financial Disclosure: The authors did not report any potential conflicts of interest.
Jonathan G. Shaw, MD, MS Steven M. Asch, MD, MPH Susan M. Frayne, MD, MPH Ciaran S. Phibbs, PhD Department of Veterans Affairs, Palo Alto Healthcare System, Palo Alto, California; and Stanford University School of Medicine, Stanford, California Rachel Kimerling, PhD Department of Veterans Affairs, Palo Alto Healthcare System, Palo Alto, California Kate A. Shaw, MD, MS Stanford University School of Medicine, Stanford, California
REFERENCES 1. Department of Veterans Affairs, Department of Defense. VA/DoD clinical practice guideline for the management of post-traumatic stress. Version 2.0–2010. Available at: http://www.healthquality. va.gov/guidelines/MH/ptsd/cpg_PTSDFULL-201011612.pdf. Retrieved January 5, 2015. 2. Shaw JG, Asch SM, Kimerling R, Frayne SM, Shaw KA, Phibbs CS. Posttraumatic stress disorder and risk of spontaneous preterm birth. Obstet Gynecol 2014;124:1111–119.
VOL. 125, NO. 4, APRIL 2015
Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Letters
989
