Hum. Reprod. Advance Access originally published online on December 13, 2006
Human Reproduction 2007 22(3):878-884; doi:10.1093/humrep/del450
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Psychiatric outcomes following medical and surgical abortion
1 Department of Psychiatry 2 Department of Obstetrics, Gynecology and Reproductive Sciences and the Magee-Womens Research Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA 3 Department of Psychiatry, University of Massachusetts Medical School and UMassMemorial HealthCare, Worcester, MA, USA 4 Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA 5 Medical and Laboratory Directory, Planned Parenthood of Western Pennsylvania, Pittsburgh, PA, USA
6 To whom correspondence should be addressed at: Department of Psychiatry, Women's Behavioral HealthCARE, University of Pittsburgh, 3811 O'Hara Street, Oxford 410, Pittsburgh, PA 15213, USA. Tel: +1412 246 5248; Fax: +1412 246 6960; E-mail: sitdk{at}upmc.edu
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Abstract |
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BACKGROUND: Hypercortisolaemia is associated with certain depressive disorders. Mifepristone has possible antidepressant properties related to its anti-glucocorticoid activity. To explore the possible mood effects of mifepristone, we examined the mood outcomes after surgical and medical (mifepristone–misoprostol) abortion. The objectives were to determine post-abortion depression risk, evaluate risk factors for post-abortion depression and to explore the relationship between cortisol and depression.
METHODS: We enrolled 47 surgical and 31 medical abortion patients. Women were assessed pre-abortion and 1 month post-abortion with the Edinburgh Postnatal Depression Scale (EPDS) and salivary cortisol levels. RESULTS: Pre-abortion, 36% (17/47) of surgical and 35% (11/31) of medical patients had high depression risk (EPDS 
10; (
2 = 0.31, df = 1, P = 0.58). At follow-up, 17% (7/42) of surgical and 21% (5/24) of medical patients had an EPDS 10 (2 = 0.18, df = 1, P = 0.67). The decline post-abortion in the women with EPDS 10 was significant (P = 0.01). Women with past psychiatric history (Fisher's exact P = 0.05) or anxiety disorders (Fisher's exact P = 0.005) had elevated risk for post-abortion depression. Change in cortisol levels was not correlated with change in EPDS (r = 0.10, P = 0.28).
CONCLUSIONS: Most patients experienced post-abortion mood improvement. Mifepristone did not offer additional antidepressant effects. The lack of correlation between cortisol and depression could represent hypersuppression of the hypothalamic-pituitary-adrenal (HPA) axis or insufficient mifepristone dose to alter HPA axis activity.
Key words: biomarker/depression/mifepristone/salivary cortisol
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Background and significance |
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One in five American women of childbearing age undergoes abortion (Henshaw et al., 1991
). Women develop post-abortion depression at a rate of 9–20% (Urquhart and Templeton, 1991; Major et al., 2000), which is comparable to the rates of depression in childbearing aged women in the general population of 20% (Blazer et al., 1994), post-partum of 10–15% (O'Hara and Swain, 1996) and post-miscarriage of 22–51% (Garel et al., 1992; Neugebauer et al., 1992). Factors that contributed to post-abortion psychiatric morbidity were a biological predisposition, psychosocial stress and complicated grief reactions. Using quality of life measures in surgical and medical abortion patients, investigators detected equal improvement in emotional function 1 month post-abortion compared to pre-abortion (Westhoff et al., 2003). Earlier reports on psychiatric morbidity post-abortion were difficult to interpret due to the use of non-validated, non-standardized symptom scale instruments. In other instances, researchers interviewed women shortly (1–2 weeks) post-abortion and likely detected early adjustment to a stressful life event rather than psychiatric morbidity.
Severe forms of depression, particularly psychotic depression, are linked to chronic hypercortisolaemia. This is based on evidence of cortisol non-suppression on the dexamethasone suppression test (DST) (Rothschild et al., 1982; Kumar et al., 1986), elevated 24-h urinary-free cortisol (Anton, 1987) and blunted adrenocorticotrophic hormone response to exogenous corticotropin-releasing hormone (Gold et al., 1986). Mifepristone, an antiprogestin agent utilized primarily for abortion, also blocks central glucocorticoid (GC) receptors in the amygdala and hippocampus. Belanoff et al. (2002) postulated that these anti-glucocorticoid effects could reset and normalize hypothalamic-pituitary-adrenal (HPA) axis activity in depressed patients to restore euthymic mood. In a small open-label study, mifepristone appeared to lessen psychotic and depressive symptoms in patients with psychotic depression, although the effects were not statistically significant (Belanoff et al., 2002). Therefore, mifepristone may have novel psychotropic properties related to its biological actions on GC receptors (Gold et al., 2002; Flores et al., 2006). Within 2 weeks of receiving a single 200 mg dose of mifepristone [the typical dose in abortion regimens (American College of Obstetrics and Gynecology, 2005)], a compensatory increase in serum corticotropin and cortisol was observed, followed by normalization of GC bioactivity (Heikinheimo et al., 2003). This finding suggested that even one dose of mifepristone exerted measurable effects on GC receptor activity that could impact mood symptoms.
In a phase II trial of mifepristone treatment for unipolar psychotic depression, antidepressant responses occurred with doses of 50, 600 and 1200 mg daily for 7 days (Belanoff et al., 2002). Significant reductions in depression and psychosis were observed only at the middle and higher doses. The investigators found that 8/19 subjects (42%) achieved >50% reduction in the Hamilton Depression Rating Scale (HAM-D) at the 600 and 1200 mg doses of mifepristone (Belanoff et al., 2002). In a separate study, researchers treated psychotically depressed patients with mifepristone 200 mg three times daily for 1 week. At week 4, they detected >50% reduction in the 21-item HAM-D in 18/20 subjects and full remission (HAM-D <8) in 11/18 subjects who persisted during 8 weeks of follow-up (Simpson et al., 2005).
This study was performed to explore whether mifepristone offered beneficial mood effects in women from the general population, by comparing the mood outcomes of women after first trimester surgical and medical abortion. The study objectives were to compare the risk for depression after first trimester surgical and medical abortion, identify risk factors for post-abortion depression, and investigate the relationship between salivary cortisol levels and depression severity.
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Materials and methods |
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The research protocol and consent procedures were approved by the Institutional Review Boards of the University of Pittsburgh and complied with the standards in the Declaration of Helsinki for Medical Research involving Human Subjects. Subjects were recruited from Planned Parenthood of Western Pennsylvania and Magee Womens Hospital Family Planning Research Clinic in Pittsburgh, PA, from 2003 to 2004. Women between 18 and 45 years and <9 weeks gestation were approached about this study, after they had confirmed their decision to have an abortion. All surgical abortions were performed by vacuum aspiration. All medical abortion patients received mifepristone 200 mg followed 6–48 h later by misoprostol 800 µg vaginally (ACOG, 2005). Women were excluded from the study post-enrolment if they became pregnant again during the follow-up period.
Assessments were scheduled for immediately pre-procedure and 1 month post-abortion. We collected demographic data and information on past and current psychiatric and medical history. We assessed mood symptoms with the Edinburgh Postnatal Depression Scale (EPDS) (Cox et al., 1987) and we measured cortisol levels from salivary samples. We chose the EPDS because it had been validated extensively as a self-report screening tool for post-partum depression (Cox et al., 1987; Eberhard-Gran et al., 2001) and antenatal depression (Murray and Carothers, 1990). Cox et al. (1996) subsequently confirmed the validity of the EPDS in non-post-partum patients and detected a sensitivity of 88% and specificity of 71% with the cutoff of EPDS 10. In our study, the clinician who assessed the mood remained blinded to the subjects' procedure choice at all evaluations. Subjects with scores on the EPDS 10 were deemed at high risk for depression (Peindl et al., 2004). We referred any subject with safety concerns, such as imminent thoughts to harm herself or others, to urgent psychiatric care; they were retained in the study.
We chose salivary cortisol because it offered a convenient sampling method and an accurate and valid measure of free cortisol that closely correlated with serum and plasma levels pre-and post-DST (Edwards et al., 2001; normal values 1–25 nmol/l). All saliva samples were collected in the morning 4 h post-awakening. Saliva production was induced by asking the subject to chew gum or suck on a candy. Five millilitres of saliva were deposited into a plastic container, and samples were stored in a freezer at –70°C, prior to laboratory assay testing.
The solid phase, 125I radioimmunoassay for salivary cortisol was a modified version of Diagnostic Products Corporation's plasma cortisol method. Since salivary cortisol levels are significantly lower than plasma levels, the calibrators of the standard curve were diluted 1:10 in water. The range of the standard curve was 0.1–5.0 µg/dl or 2.76–138 nmol/l. The limit of detection for the method was 0.1 µg/dl. The test required 200 µl of sample for each replicate. Samples were tested in duplicate. Those duplicates with a coefficient of variation (CV) that exceed 5.0% were retested. At the University of Pittsburgh, the mean intra-assay CV was 0.90% (range 0.00–4.68%); the inter-assay CV ranged from 11.07% CV (mean = 0.28 µg/dl) to 9.14% CV (mean = 3.13 µg/dl).
We estimated a sample size of 64 women, with equal numbers of surgical and medical patients, to detect a difference in the change in proportion with EPDS 10 from baseline to follow-up of 20–25% between procedure groups, if the proportion that changed was 0–35% (power = 0.80, two-tailed 
= 0.05). This sample also would allow us to estimate the proportion of women with EPDS 10 at 30 ± 10% (power = 0.80, two-tailed = 0.05) and detect differences and change in the continuous measures of mood (EPDS) and salivary cortisol levels from baseline to follow-up between procedure groups, with a moderate effect size of 
0.46 (Cohen, 1992; power = 0.80; two-tailed = 0.05). This detectable change translates into 2–3 points on the EPDS and 2–3 nmol/l for cortisol values (standard deviation = 5–6). To account for women who would not complete the follow-up evaluation, we increased the sample size by 25% to 80 women.
The primary outcome measures were the EPDS scores, percentage with an EPDS 10 and salivary cortisol levels (nmol/l). First, we used 2 tests to compare the demographic characteristics of the surgical and medical procedure groups. Then we used non-parametric tests to compare women with an EPDS > 10 and women with an EPDS < 10 and to investigate characteristics associated with high depression risk (EPDS 10). We used mixed effect logistics regression to investigate change between baseline and follow-up, in the dichotomized mood scores (EPDS 10). We used parametric tests to compare the differences in EPDS and cortisol levels between procedure groups at baseline and follow-up.
Since the actual follow-up occurred 14–60 days post-abortion, we used mixed effect linear regression to explore change (baseline to follow-up) in EPDS scores and change in cortisol levels over time (days to follow-up). In these regressions, we considered the EPDS scores, cortisol levels and time as continuous variables. We tested the interaction of procedure group x time to explore for possible differences between procedure groups in the change in EPDS or cortisol levels over time. All regressions initially included age and race to test their effects on the outcome measures.
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Results |
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Seventy-eight women were enrolled of whom 47 had a surgical abortion and 31 had a medical abortion (Table I). At the pre-abortion evaluation, 36% (17/47) of surgical and 35% (11/31) of medical patients scored an EPDS
10 (2 = 0.31, df = 1, P = 0.58). There were no significant differences between procedure groups in the mean EPDS scores (surgical 8.04 ± 5.93; medical 8.74 ± 5.55)(t = –0.52, df = 76, P = 0.60) or mean cortisol levels (surgical 7.70 ± 3.53 nmol/l; medical 8.66 ± 4.68 nmol/l)(t = –1.01, df = 75, P = 0.32).
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At follow-up, 66 (85%) of subjects completed the mood questionnaire (EPDS) by phone call or mail-in self-report; 48 women (62%) returned a repeat saliva sample. There were no differences between procedure groups in the percentage of women with follow-up EPDS (P = 0.53) and cortisol levels (P = 0.74). In the post-abortion assessment, 17% (7/42) of surgical and 21% (5/24) medical patients scored an EPDS
10 (2 = 0.18, df = 1, P = 0.67). The mean EPDS of the surgical (5.24 ± 6.02) and medical (6.25 ± 5.39) groups were not significantly different (z = 0.59, P = 0.56). The overall reduction in the percentage of women with EPDS 10 (McNemar's 2 = 5.26, df = 1, exact P = 0.03) and the reduction in mean EPDS by 2.68 (z = 3.48, P < 0.001) were significant. The predictors for elevated depression risk (EPDS 10) at follow-up were past psychiatric history (Fisher's exact P = 0.05) and anxiety disorders (Fisher's exact P = 0.005). At follow-up, the mean cortisol levels of the surgical (9.86 ± 6.85 nmol/l) and medical groups (6.13 ± 3.89 nmol/l) were not significantly different (t = 2.15, df = 46, P = 0.04). However, the change in cortisol levels between baseline and follow-up was significant in the medical but not in the surgical group (z = –2.17, df = 1, P = 0.03).
In the mixed-effect linear regressions, we detected a significant decrease in EPDS scores over time (days) to follow-up (
2 = 6.31, P = 0.001) with no significant difference with the procedure group (surgical or medical abortion) (2 = 0.22, P = 0.63). The interaction between procedure group and time to follow-up was not predictive of the change in EPDS (2 = 0.01, P = 0.96) (Table II). In contrast, the interaction between procedure group and time to follow-up was a significant predictor of change in cortisol levels (2 = 4.72, P = 0.03). Among medical patients, there was a significant decrease in cortisol levels over the days of follow-up that was not detected in the surgical patients (Table II; Figure 1). The procedure (2 = 0.31, P = 0.58) and time to follow-up (2 = 1.86, P = 0.17) were not predictive of change in cortisol when tested separately. Changes in EPDS were not correlated with changes in cortisol levels (Pearson's correlation coefficient r = 0.10, P = 0.28).
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Discussion |
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We found that 35–36% of women who underwent abortion had increased risk for depression at their pre-abortion evaluation, independent of the type of abortion they had chosen. At follow-up, the proportion at risk for depression dropped significantly to 17–21% in both procedure groups (McNemar's
2 = 5.26, df = 1, exact P = 0.03). As we expected, women with past psychiatric disorder (Fisher's exact P = 0.05) or anxiety disorders (Fisher's exact P = 0.005) had an elevated risk for post-abortion depression. Although the change in salivary cortisol levels between pre- and post-abortion was significantly different in the women who underwent medical compared with surgical abortion (2 = 4.72, P = 0.03), this difference was not correlated with a significant reduction in mood symptoms on the EPDS (r = 0.10, P = 0.28). Our outcome findings were based on the follow-up mood data from 85% and cortisol samples from 62% of the participants. These retention rates were consistent with rates achieved by our clinic at Women's Behavioral HealthCARE, Department of Psychiatry, University of Pittsburgh, and other investigators (Hemmerling et al., 2005).
Our mood outcome data replicated the findings of (Westhoff et al., 2003) who reported that women in both surgical and medical groups experienced the same degree of mood improvement after abortion. In contrast, Urquhart and Templeton (1991) investigated 37 surgical and 54 medical abortion patients and detected a pre-abortion depression risk (EPDS > 12) in >60% of all patients. This was more than twice the pre-abortion risk for depression that we detected, indicating that the characteristics or risks of the patients enrolled in the studies likely were different. One month later, the depression risk for their patients fell to 
9% in both procedure groups, a much lower risk than what our findings implied.
When this study began, few investigators had explored the psychiatric sequelae after medical and surgical abortions. Ashok et al. (2005) used the Hospital Anxiety and Depression Scale (HADS) (Zigmond and Snaith, 1983) to assess surgical and medical abortion patients pre-procedure and 3 weeks later. Clinically significant symptoms of depression (HADS depression subscale >10) or anxiety (HADS anxiety subscale >10) were identified in 209/440 (47.5%) prior to termination and 50/274 (18.4%) at 3 weeks post-procedure. Because of the high attrition rate, as only 274/440 (62%) subjects completed follow-up assessments, it is conceivable that their data overestimated the percentage of women with clinically significant post-abortion symptoms. Of 147 mifepristone and 72 surgical patients, the rates of significant depressive symptoms (HADS >10) at pre-abortion were 21 and 22%, respectively, and 2 and 5%, 1 month post-abortion (Hemmerling et al., 2005). Therefore, the data from our study and earlier investigations suggested that the abortion method was unrelated to post-abortion depression risk. Instead, the general improvement in mood could stem from the resolution of a stressful life event or the positive solution to an internal conflict (Hemmerling et al., 2005).
Our data also indicated that women with any past psychiatric illness or anxiety were at greater risk for post-abortion depression. These findings confirmed earlier reports that pre-existing mood or anxiety symptoms and past psychiatric illness were major predictors of post-abortion psychiatric morbidity (Zolese and Blacker, 1992; Henshaw et al., 1994).
In this study, we planned to measure follow-up mood and cortisol levels 1 month post-abortion to capture the earliest onset of major depression after the procedure and after the usual time frame for adjustment to a stressful life event. This follow-up time point allowed for comparison of mood outcomes from other research (Urquhart and Templeton, 1991; Westhoff et al., 2003), but the detection of cortisol response to mifepristone may have been sacrificed. Serum mifepristone (t1/2 = 12–72 h) drops to undetectable levels by 11–15 days after a single dose and GC bioactivity typically is restored within 2 weeks after a single dose of mifepristone. This may explain our finding of no interactional effect between depression and cortisol levels in both procedure groups.
Other possible reasons could explain this finding: an inadequate dose of mifepristone to induce glucocorticoid antagonism, hypersuppression of the HPA axis similar to the DST responses in post-traumatic stress disorder (Heim et al., 2001; Yehuda et al., 2004) or inadequate sample size. It remains questionable whether the neurobiological activity of mifepristone is sustained after it is no longer being administered. The efficacy of mifepristone as an antidepressant has not been established. Since we had estimated 64 samples were necessary to detect any difference in cortisol levels between procedure groups, our failure to detect any between-group difference in post-abortion cortisol levels could have stemmed from an insufficient sample size. Findings from two double blind placebo-controlled trials (DeBattista and Belanoff, 2006) failed to demonstrate correlation between depression severity on the HAM-D and cortisol level in psychotic depression. Only one post hoc analysis (DeBattista et al., 2003) indicated a higher likelihood to achieve full response with mifepristone compared with placebo, in depressive symptoms. The lack of correlation between mood and cortisol from our data is consistent with these recent reports.
We approached women to enroll in our study only after they had confirmed their preference for the method of abortion. Our clinical rater remained blinded to the subjects' choice of procedure at both assessments to restrict biased outcomes. Although the reasons underlying the procedure choice could be linked with post-abortion depression risk, it was not feasible to rid this bias by randomly assigning an abortion method to subjects. In a separate study of 219 patients, 147 women chose medical abortion to avoid surgery and anaesthesia (84%), and due to perceptions, the method was more natural (73%) than surgery (Hemmerling et al., 2005). Of the 72 women who opted for surgical abortion, 34% preferred to avoid the pain and severe bleeding reported with medical abortion and 46% felt this method was more convenient. Often, the medical patients (78%) made the decision alone when compared with surgical patients (44%). Since we detected no significant difference in pre-and post-abortion depression risk between groups, it is less likely that factors which influenced procedure preference strongly affected depression risk.
In summary, 35–36% of women who underwent medical or surgical abortion had mood symptoms suggestive of elevated depression risk at pre-abortion. Post-abortion, this risk for depression dropped to 17–21% in both groups. There were no differences in depression risk at pre-and post-abortion in both procedure groups. Mifepristone did not confer additional protection from depression post-abortion. Women with past psychiatric history or anxiety disorders were at risk for post-abortion depression. The change in cortisol was not correlated with the change in mood symptoms.
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For their contribution to the research and preparation of the manuscript, many thanks to: Jessica Grogan, BS, Stacy Stull, MS, Eydie Moses-Kolko, MD, Andrea Confer, BS, the staff of the Planned Parenthood League of Massachusetts (PPLM), Planned Parenthood of Western Pennsylvania and the Family Planning Research Unit at Magee Womens Hospital. Also, thanks to Heather Sankey, MD, Immediate Past Medical Director of the PPLM for her help to establish the initial research collaboration with Planned Parenthood. D.S. received funding from the National Alliance for Research on Schizophrenia and Depression (NARSAD) 2002 Young Investigator Award to undertake this study. She has current pilot funds from the University of Pittsburgh, School of Medicine, General Clinical Research Center Clinical Research Feasibility Funds Award and the Office of Research Health Sciences Competitive Medical Research Funds New Investigator Award at the 45th Annual NCDEV Meeting. A.J.R. receives research support from Astra-Zeneca, Cephalon, Cyberonics, Wyeth-Ayerst, the National Institute of Mental Health (NIMH); he received past support from Corcept (1999–2001). He is a consultant for GlaxoSmithKline, Eli Lilly and Company, Pfizer Inc., Forest Pharmaceuticals and Merck & Co., Inc. He is on the speaker's bureau for Pfizer Inc., Bristol-Myers Squibb, Forest Pharmaceuticals and Eli Lilly and Company. M.D.C. receives compensation from Danco Laboratories, LLC, the US distributor of mifepristone, for providing third-party telephone consults to clinicians who call for expert advice on mifepristone. K.L.W. has grant funds from NIMH and the US Department of Health and Human Services—Health Resource and Services Administration. She has research funds from Pfizer, Inc. for a study of the pharmacokinetics of ziprasidone during pregnancy. She is on the speaker's bureau for GlaxoSmithKline.
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This research was presented in June 2005 at the 45th Annual New Clinical Drug Evaluation Unit (NCDEU) Meeting in Boca Raton, Florida, sponsored by the US National Institutes of Health and the National Institute of Mental Health. Preliminary data from this study were presented in paper sessions at the 3rd International Conference on Reproductive Disruptions, Institute for Research on Women and Gender, University of Michigan, Ann Arbor, MI in 2005, and at the Marce Society International Scientific Meeting on Perinatal Health, Oxford, UK in 2004.
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Submitted on August 11, 2006; resubmitted on October 5, 2006; accepted on October 25, 2006.
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