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Is induced abortion with misoprostol a risk factor for late abortion or preterm delivery in subsequent pregnancies?
European Journal of Obstetrics & Gynecology and Reproductive Biology 145 (2009) 53–56
Contents lists available at ScienceDirect
European Journal of Obstetrics & Gynecology and Reproductive Biology journal homepage: www.elsevier.com/locate/ejogrb
Is induced abortion with misoprostol a risk factor for late abortion or preterm delivery in subsequent pregnancies? Norbert Winer a,*, Mathieu Resche-Rigon b, Christine Morin c, Yves Ville c, Patrick Rozenberg c a
Department of Obstetrics and Gynecology, Centre Hospitalier Universitaire, Nantes, France Department of Biostatistics, Saint-Louis Hospital, Assistance Publique-Hoˆpitaux de Paris, University Paris VII, U 717 INSERM, France c Department of Obstetrics and Gynecology, Reproductive Biology and Cytogenetics, Poissy-Saint Germain Hospital, University Versailles-St Quentin, France b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 7 October 2008 Received in revised form 21 April 2009 Accepted 23 April 2009
Objective: To examine whether a first or second trimester induced abortion with misoprostol influences the risk of late abortion or preterm delivery in subsequent pregnancies. Study design: Case–control study in a teaching hospital from January 2005 to June 2006. The cases had singleton pregnancies delivered at 16–36 weeks of gestation after spontaneous late abortions, preterm labor or preterm premature rupture of membrane, or induction of labor for preterm premature rupture of membrane before 37 weeks. The control group was composed of the two consecutive spontaneous singleton deliveries at 37 weeks of gestation after each new case (ratio 2/1). The principal outcome measure was late abortion or preterm delivery. The association between late abortion or preterm delivery and a previous induced abortion with misoprostol was first assessed with the Cochran-MantelHaenszel chi-square test. Conditional logistic regression models adapted for clustered data were then further used to quantify the effect size, measured by estimated odds ratios (ORs) with their 95% confidence intervals (95% CI). Results: The study included 245 cases and 490 controls. There was no significant difference in mean maternal age, number of pregnancies, parity, smoking, or history of first trimester miscarriage between cases and controls. However, a history of late abortion or previous preterm delivery was significantly more frequent among cases than controls. Forty (16.3%) cases and 56 (11.5%) controls had a history of cervical ripening with misoprostol before vacuum curettage or evacuation, or of medical abortion by misoprostol alone or with mifepristone (OR 1.51, 95% CI: 0.95–2.39; p = 0.08). After adjustment for maternal age and number of pregnancies with a multivariable conditional regression model, the adjusted OR was estimated at 1.33 (95% CI: 0.81–2.17; p = 0.25). Conclusion: Despite the need for prudence, these results provide some reassurance that induced abortion with misoprostol during the first or second trimester of pregnancy is safe for subsequent pregnancies. ß 2009 Elsevier Ireland Ltd. All rights reserved.
Keywords: Misoprostol Induced abortion Termination of pregnancy Preterm delivery Late abortion
1. Introduction Various techniques have been proposed for induced abortions during the first or second trimester [1]. They include vacuum curettage, dilation and evacuation, and prostaglandin E2 (PGE2) vaginal suppositories. More recently, misoprostol, a prostaglandin E1 analog, has become an alternative to the rigid dilators or laminaria tents frequently used and has also been suggested for medical abortions [2–10]. Each year in France, there are about
* Corresponding author at: Service de Gyne´cologie-Obste´trique, CHU Nantes, 38 bd Jean Monnet, 44093 Nantes, France. Tel.: +33 2 40 08 31 90; fax: +33 2 40 08 47 90. E-mail address: [email protected] (N. Winer). 0301-2115/$ – see front matter ß 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ejogrb.2009.04.028
200,000 first trimester and 5600 second trimester induced abortions [11]. Most of these procedures are now performed with misoprostol, alone or combined with mifepristone. Several large case–control studies suggest that a history of induced abortion increases the risk of preterm delivery in subsequent pregnancies [12–16], but they have not fully explored the respective role of the surgical and medical techniques used. The side effects of misoprostol include nausea, vomiting, diarrhea, shivering and fever, and related complications include hemorrhaging, endometritis and, very rarely, uterine rupture. While the studies mentioned above have examined these side effects and complications, to our knowledge, no publication has evaluated the risk of late abortion or preterm delivery after a first or second trimester induced abortion with misoprostol.
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N. Winer et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 145 (2009) 53–56
The aim of this study was to examine whether an induced abortion using misoprostol during the first or second trimester influences the risk of late abortion or preterm delivery in subsequent pregnancies. 2. Material and methods This prospective study took place from January 2005 to June 2006 at the Poissy-Saint Germain Hospital, where about 1500 induced elective abortions and 250 abortions for medical indications are performed each year. This case–control study sought to determine whether late abortion or preterm delivery might be associated with a history of cervical ripening with misoprostol before vacuum curettage or evacuation, or of medical abortion with misoprostol alone or combined with mifepristone. In our institution and indeed, in the institutions in our perinatal network, the first and second trimester induced abortions use the following protocol: 200 mg of mifepristone by mouth, followed 48 h later by 400 mg of misoprostol administered vaginally and repeated every 4 h up to a maximal dose of 1200 mg/day. Our network does not use the procedure involving a laminaria tent and dilatation and extraction. We note that as a level-3 reference facility, most of the patients referred to us come from other institutions in our network. The cases included all singleton pregnancies during the study period who delivered at 16–36 weeks of gestation after a spontaneous late abortion, preterm labor, or preterm premature rupture of membranes, or who had induction of labor for preterm premature rupture of membrane before 37 weeks. The control group was composed of the two consecutive spontaneous singleton deliveries at 37 weeks of gestation or later after each case (ratio 2:1). Exclusion criteria for both cases and controls were: multiple pregnancies; induction of labor for any medical or obstetrical indication other than preterm premature rupture of membrane or chorioamnionitis; a history of vacuum curettage or dilatation and evacuation where rigid dilators or laminaria tents were used for cervical dilatation to facilitate procedures; an induced abortion during the first or second trimester of a previous pregnancy by a method other than misoprostol alone or with mifepristone; or a history of a first trimester missed or incomplete abortion managed with misoprostol, or of induction of labor at term with misoprostol. We computed the sample size necessary to detect an odds ratio of 2.0, given an expected proportion of misoprostol exposure in the control group of 0.10, with a type I error rate of 0.05 and a type II rate of 0.20. Applying the Connett formula for pair-matched case– control studies [17], we calculated that we needed a sample size of 230 cases and 230 controls. To increase power, we decided to pair two controls to each case. Finally, since about 15 late abortions or preterm deliveries were expected each month, the duration of the study was set at 18 months. Women were enrolled during the postpartum period in the hospital. Data were obtained in part from the medical records and in part from interviews with the women within 3 days of delivery. Data extracted from the medical records included maternal age, obstetrical and medical history, including the method used for any induced abortions, history of late abortions or preterm deliveries, details about the management and complications of the current pregnancy, the delivery and the baby’s health. The interviews of the mothers provided information only about social and demographic characteristics and smoking habits before and during pregnancy. Maternal smoking (yes or no) during pregnancy was assessed dichotomously, regardless of the number of cigarettes. Data were summarized as incidences and percentages for categorical variables. Quantitative variables were summarized as medians and 25th and 75th percentiles (with ranges). Cases and controls were compared with the Cochran-Mantel-Haenszel chi-
square test for categorical variables, with each cluster composed of each case and its two controls. The association between late abortion or preterm delivery and a history of either cervical ripening with misoprostol before vacuum curettage or evacuation or of medical abortion with misoprostol, alone or in combination with mifepristone, was first examined by a Cochran-MantelHaenszel chi-square test. Conditional logistic regression models adapted to clustered data were used to quantify the effect size, measured by estimated odds ratio (OR) with their 95% confidence intervals (95% CI). Crude and adjusted ORs were computed. Adjustments were made with multivariable models that introduced factors associated with the outcome at a p-value of 0.20 in the univariable analyses or known as risk factors. All tests were two-sided with a significance level of 0.05. Analyses were performed with the R statistical package (online at http:// www.R-project.org). The institutional review board (Comite´ de Protection des Personnes of Saint-Germain-en-laye) was consulted and determined that its approval was unnecessary under French law because all patients received standard management without any additional, unusual or innovative diagnostic or follow-up procedures. 3. Results During the study period, 267 women were admitted to our unit for a late abortion or preterm delivery. Missing medical reports about previous preterm delivery or induced abortion resulted in excluding 22 cases, before any controls were included for pairing with them. The study thus included 245 cases with deliveries at 16–36 weeks and 490 control women who gave birth at or after 37 weeks of gestation. The study thus included 735 patients in all. The median duration of pregnancy (first and third quartiles) was 227.8 (210, 254) days [range 110, 258] in the case group and 279.9 (274, 287) days [range 259, 295] in the control group. Table 1 summarizes the population’s general and obstetrical characteristics. Cases and controls did not differ significantly for mean maternal age, number of pregnancies, parity, smoking status, or history of first trimester miscarriage. A history of spontaneous late abortion or preterm delivery was significantly more frequent among case than control patients. In all, 40 (16.3%) case women and 56 (11.5%) control women had a history of induced abortion by misoprostol in the first or second trimester of pregnancy. The observed effect size, measured by the odds ratio, was estimated at 1.51 (95% CI: 0.95–2.39; p = 0.08). Even after adjustment for maternal age and number of pregnancies with a multivariable conditional regression model, the effect size of a history of induced abortion with misoprostol on late abortion or preterm delivery remained lower than expected: the adjusted OR was estimated at 1.33 (95% CI: 0.81–2.17; p = 0.25) (Table 2). 4. Discussion Our data suggest that a history of induced abortion with misoprostol is not a risk factor for late abortion or preterm delivery in subsequent pregnancies. MEDLINE, PubMed and the Cochrane library were searched for articles published in English from January 1980 to August 2007 with the keywords ‘‘misoprostol’’, ‘‘induced abortion’’ or ‘‘medical abortion’’ or ‘‘medical induced abortion’’ or ‘‘termination of pregnancy’’; and ‘‘preterm delivery’’ or ‘‘preterm birth’’ or ‘‘late abortion’’ or ‘‘spontaneous late abortion’’ or ‘‘low birth weight’’ or ‘‘subsequent adverse pregnancy outcome’’. These issues have not been thoroughly examined before and the literature is both scarce and conflicting. Some studies conclude that induced abortion during the first trimester does not
N. Winer et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 145 (2009) 53–56
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Table 1 General and obstetrical characteristics of the population. Values are given as n (%). Cases, n = 245 (%)
Controls, n = 490 (%)
Age (years) [17,27] [27,30] [30,34] [34,51]
80 46 62 57
(32.7) (18.8) (25.3) (23.3)
130 122 142 96
(26.5) (24.9) (29.0) (19.6)
Number of pregnancies 1 2 3 4
92 60 44 49
(37.6) (24.5) (18.0) (19.9)
195 153 66 76
(39.8) (31.2) (13.5) (15.5)
122 70 37 16
(49.8) (28.6) (15.1) (6.5)
243 152 62 33
(49.6) (31.0) (12.7) (6.7)
p-Value 0.08
0.07
Parity 1 2 3 4
0.80
Smoked during pregnancy Previous preterm delivery Previous spontaneous late abortion
38 (16.6) 43 (17.6) 11 (4.6)
61 (13.1) 29 (5.9) 3 (0.6)
0.25 <0.0001 0.0006
Surgical abortion <15 weeks’ gestation Medical abortion >15 weeks’ gestation Exposed
32 (13.1) 10 (4.1) 40 (16.3)
47 (9.6) 10 (2.0) 56 (11.4)
0.09
Gestational age, median (Q1–Q3)
32 (27,34)
38 (37,39)
increase the risk of preterm birth in subsequent pregnancies [18– 21]. Raatikainen et al. [20] analyzed a population-based database in Finland that contained 26,976 singleton pregnancies between 1989 and 2001. Although preterm birth appeared to be more frequent among women with one prior abortion, logistic regression analysis found no evidence of adverse pregnancy outcomes in this group. They concluded that induced abortion was not an independent risk factor for adverse obstetric outcome. However, several recent publications suggest an increased risk of preterm birth in subsequent pregnancies after induced abortion [12–16]. Three were large retrospective cohort studies, covering from 10,6345 to 61,753 pregnancies [12–14] and two were large case–control studies [15,16]. Henriet and Kaminski [14] and Ancel et al. [15] showed that the risk of preterm birth increased with the number of previous abortions. Martius et al. [12] concluded that preterm birth <32 weeks was associated with previous history of induced abortion, and this was confirmed by Moreau et al. [16], who also suggested that the strength of this association increased with decreasing gestational age at delivery. Second trimester surgical abortions that use dilatation and evacuation may be associated with a higher risk of subsequent premature delivery [22,23]. Uncontrolled and small series [24–27] suggest, however, that this method is not a risk factor for Table 2 Multivariable analysis of the association between late abortion or preterm delivery and a history of either cervical ripening with misoprostol prior to vacuum curettage or evacuation, or of medical abortion with misoprostol alone or with mifepristone. OR (95% CI)
p-Value
Number of pregnancies Age [17,27] [27,30] [30,34] [34,51]
0.97 (0.85; 1.10)
0.60
1.63 (1.02; 2.58) 1 1.12 (0.69; 1.81) 1.57 (0.94; 2.61)
0.02 0.65 0.08
Previous preterm delivery Previous late abortion TOP with misoprostol
2.23 (1.41; 3.51) 7.10 (1.78; 28.2) 1.53 (0.92; 2.55)
0.0006 0.006 0.10
The group in bold characters is the reference group with the lowest risk of preterm birth.
midtrimester pregnancy loss or spontaneous preterm birth. These conflicting results can be at least partly explained by differences or weaknesses in their methods, including their use of registries or databases, small series with a consequent lack of power, retrospective studies, absence of a control group, heterogeneity in abortion techniques, differences in gestational age at abortion, and possibly uncontrolled biases, despite the use of logistic regression analysis to control the potential confounders. Our study did not include surgical abortions by dilatation and evacuation, but evaluation is limited by the fact that this procedure is not employed in our hospital or our perinatal network. Instead, the protocol we used calls for administering misoprostol, 400 mg, orally or vaginally, and repeating it every 4 h until expulsion and vacuum aspiration, sometimes preceded 48 h earlier by 200 mg of oral mifepristone. Only two studies have specifically examined whether a medical abortion in the first trimester of pregnancy influences the risk of late abortion or preterm delivery in subsequent pregnancies. A cohort study by Chen et al. [28] examined the effect of mifepristone-induced first trimester abortions on the outcome of subsequent wanted pregnancies. The risk of preterm delivery did not differ significantly between women with previous mifepristone abortions, women with surgical abortions, and women with no abortions at all. In a large cohort study, Virk et al. [29] recently used the Danish national birth registries to compare the effect on subsequent pregnancies of previous medical and surgical abortions. They found no evidence that a medical abortion, with misoprostol alone or preceded by mifepristone, increased the risk of spontaneous abortion or preterm birth compared with a previous surgical abortion 9 weeks of gestation. Our results confirm that induced abortion with misoprostol in the second trimester of pregnancy does not significantly increase the risk of late abortion or preterm delivery in subsequent pregnancies. One weakness of this study is that we did not collect information on the interval between the abortion and the subsequent birth. Nonetheless, consideration of that information might have been complex, especially for patients with more than one induced abortion. Would the interval be defined according to the first misoprostol exposure or the last? The inclusion criterion was qualitative (yes/no) for exposure to misoprostol and did not consider dose. In the absence of a national abortion registry and in
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N. Winer et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 145 (2009) 53–56
view of the possibly long latency between exposure to misoprostol and late abortion or preterm delivery in subsequent pregnancies, a prospective cohort study was not feasible. Another potential limitation of our study is that some potential confounders might have been ignored or that their measurement was biased. Nevertheless, even though cases and controls were not matched, for simplicity’s sake, we looked for and found no statistically significant differences in the main baseline characteristics between cases and controls. Notably, there were no significant differences between cases and controls in mean maternal age, number of pregnancies, parity, or smoking. However, it may be objected that a randomized controlled trial would have been preferable. Finally, we note that since misoprostol is the standard of care here, this study cannot compare the role of misoprostol with other methods of cervical ripening or induction. In addition, many other factors may affect the risk of preterm birth in a subsequent pregnancy after an induced abortion in a previous pregnancy. These include baseline risk factors, psychological issues, and lifestyle. The safety of medical or surgical methods in the first and second trimester and their effects on subsequent pregnancies can probably be assessed only through large case–control or cohort studies. The size of the study and the case–control design with prospective collection of late abortions and preterm delivery information are major strengths. Our unit is a referral center for high-risk pregnancies where women with preterm labor are referred from within a perinatal network covering 20,000 deliveries per year. Nonetheless, we cannot rule out the possibility that we lacked the power to observe a difference with an OR < 2 between cases and controls. The retrospective nature and limitations of this study require prudence in drawing conclusions. Nonetheless these results provide some reassurance that administration of misoprostol in first and second trimester medical abortions does not create a risk for subsequent pregnancies. Conflict of interests The authors have no potential conflicts of interest to disclose. None of the manufacturers of misoprostol provided financial support or had any role in the design, the conduct, interpretation or reporting of this study. Acknowledgment None. Contribution to authorship: Norbert Winer and Yves Ville wrote the paper. Matthieu Resche-Rigon and Christine Morin analyzed the data. Patrick Rozenberg conceived and designed the study. Ethics approval: The institutional review board (Comite´ de Protection des Personnes of Saint-Germain-en-laye) was consulted and determined that its approval was unnecessary under French law since patients received standard management without any additional, unusual or innovative diagnostic or follow-up procedures (Files enclosed). References [1] Stubblefield PG, Carr-Ellis S, Borgatta L. Methods for induced abortion. Obstet Gynecol 2004;104:174–85.
[2] Ngai SW, Chan YM, Tang OS, Ho PC. The use of misoprostol for preoperative cervical dilatation prior to vacuum curettage: a randomized trial. Hum Reprod 1999;14:2139–42. [3] MacIsaac L, Grossman D, Baliestreri E, Darney P. A randomized controlled trial of laminaria, oral misoprostol, and vaginal misoprostol before abortion. Obstet Gynecol 1999;93:766–70. [4] Christin-Maitre S, Bouchard P, Spitz IM. Medical termination of pregnancy. N Engl J Med 2000;342:946–56. [5] Jain JK, Mishell DR. A comparison of intravaginal misoprostol with prostaglandin E2 for termination of second-trimester pregnancy. N Engl J Med 1994;331:290–3. [6] Dickinson JE, Evans SF. The optimization of intravaginal misoprostol dosing schedules in second-trimester pregnancy termination. Am J Obstet Gynecol 2002;186:470–4. [7] Tang OS, Lau WN, Chan CC, Ho PC. A prospective randomised comparison of sublingual and vaginal misoprostol in second trimester termination of pregnancy. BJOG 2004;111:1001–5. [8] Edwards RK, Sims SM. Outcomes of second-trimester pregnancy terminations with misoprostol: comparing 2 regimens. Am J Obstet Gynecol 2005;193: 544–8. [9] Hamoda H, Ashok PW, Flett GM, Templeton A. A randomized trial of mifepristone in combination with misoprostol administered sublingually or vaginally for medical abortion at 13–20 weeks gestation. Hum Reprod 2005; 20:2348–54. [10] Goh SE, Thong KJ. Induction of second trimester abortion (12–20 weeks) with mifepristone and misoprostol: a review of 386 consecutive cases. Contraception 2006;73:516–9. [11] Branger B, Winer N. Epidemiology of anti-D allo-immunization during pregnancy. J Gynecol Obstet Biol Reprod 2006;35:1S87–11S. [12] Martius JA, Steck T, Oehler MK, Wulf KH. Risk factors associated with preterm (<37 + 0 weeks) and early preterm birth (<32 + 0 weeks): univariate and multivariate analysis of 106 345 singleton births from the 1994 statewide perinatal survey of Bavaria. Eur J Obstet Gynecol Reprod Biol 1998;80:183–9. [13] Zhou W, Sorensen HT, Olsen J. Induced abortion and subsequent pregnancy duration. Obstet Gynecol 1999;94:948–53. [14] Henriet L, Kaminski M. Impact of induced abortions on subsequent pregnancy outcome: the 1995 French national perinatal survey. BJOG 2001;108:1036–42. [15] Ancel PY, Lelong N, Papiernik E, Saurel-Cubizolles MJ, Kaminski M. EUROPOP. History of induced abortion as a risk factor for preterm birth in European countries: results of the EUROPOP survey. Hum Reprod 2004;19:734–40. [16] Moreau C, Kaminski M, Ancel PY, et al. EPIPAGE Group. Previous induced abortions and the risk of very preterm delivery: results of the EPIPAGE study. BJOG 2005;112:430–7. [17] Connett JE, Smith JA, McHugh RB. Sample size and power for pair-matched case–control studies. Stat Med 1987;6:53–9. [18] de Haas I, Harlow BL, Cramer DW, Frigoletto Jr FD. Spontaneous preterm birth: a case–control study. Am J Obstet Gynecol 1991;165:1290–6. [19] Frank PI, McNamee R, Hannaford PC, Kay CR, Hirsch S. The effect of induced abortion on subsequent pregnancy outcome. Br J Obstet Gynaecol 1991;98: 1015–1024. [20] Raatikainen K, Heiskanen N, Heinonen S. Induced abortion: not an independent risk factor for pregnancy outcome, but a challenge for health counseling. Ann Epidemiol 2006;16:587–92. [21] Che Y, Zhou W, Gao E, Olsen J. Induced abortion and prematurity in a subsequent pregnancy: a study from Shanghai. J Obstet Gynaecol 2001;21: 270–273. [22] Atrash HK, Hogue CJ. The effect of pregnancy termination on future reproduction. Bailliere Clin Obstet Gynaecol 1990;4:391–405. [23] Infante-Rivard C, Gauthier R. Induced abortion as a risk factor for subsequent fetal loss. Epidemiology 1996;7:540–2. [24] Kalish RB, Chasen ST, Rosenzweig LB, Rashbaum WK, Chervenak FA. Impact of midtrimester dilation and evacuation on subsequent pregnancy outcome. Am J Obstet Gynecol 2002;187:882–5. [25] Chasen ST, Kalish RB, Gupta M, Kaufman JE, Rashbaum WK, Chervenak FA. Dilation and evacuation at > or = 20 weeks: comparison of operative techniques. Am J Obstet Gynecol 2004;190:1180–3. [26] Chasen ST, Kalish RB, Gupta M, Kaufman J, Chervenak FA. Obstetric outcomes after surgical abortion at > or = 20 weeks’ gestation. Am J Obstet Gynecol 2005;193:1161–4. [27] Jackson JE, Grobman WA, Haney E, Casele H. Mid-trimester dilation and evacuation with laminaria does not increase the risk for severe subsequent pregnancy complications. Int J Gynaecol Obstet 2007;96:12–5. [28] Chen A, Yuan W, Meirik O, et al. Mifepristone-induced early abortion and outcome of subsequent wanted pregnancy. Am J Epidemiol 2004;160: 110–117. [29] Virk J, Zhang J, Olsen J. Medical abortion and the risk of subsequent adverse pregnancy outcomes. N Engl J Med 2007;357:648–53.
Contents lists available at ScienceDirect
European Journal of Obstetrics & Gynecology and Reproductive Biology journal homepage: www.elsevier.com/locate/ejogrb
Is induced abortion with misoprostol a risk factor for late abortion or preterm delivery in subsequent pregnancies? Norbert Winer a,*, Mathieu Resche-Rigon b, Christine Morin c, Yves Ville c, Patrick Rozenberg c a
Department of Obstetrics and Gynecology, Centre Hospitalier Universitaire, Nantes, France Department of Biostatistics, Saint-Louis Hospital, Assistance Publique-Hoˆpitaux de Paris, University Paris VII, U 717 INSERM, France c Department of Obstetrics and Gynecology, Reproductive Biology and Cytogenetics, Poissy-Saint Germain Hospital, University Versailles-St Quentin, France b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 7 October 2008 Received in revised form 21 April 2009 Accepted 23 April 2009
Objective: To examine whether a first or second trimester induced abortion with misoprostol influences the risk of late abortion or preterm delivery in subsequent pregnancies. Study design: Case–control study in a teaching hospital from January 2005 to June 2006. The cases had singleton pregnancies delivered at 16–36 weeks of gestation after spontaneous late abortions, preterm labor or preterm premature rupture of membrane, or induction of labor for preterm premature rupture of membrane before 37 weeks. The control group was composed of the two consecutive spontaneous singleton deliveries at 37 weeks of gestation after each new case (ratio 2/1). The principal outcome measure was late abortion or preterm delivery. The association between late abortion or preterm delivery and a previous induced abortion with misoprostol was first assessed with the Cochran-MantelHaenszel chi-square test. Conditional logistic regression models adapted for clustered data were then further used to quantify the effect size, measured by estimated odds ratios (ORs) with their 95% confidence intervals (95% CI). Results: The study included 245 cases and 490 controls. There was no significant difference in mean maternal age, number of pregnancies, parity, smoking, or history of first trimester miscarriage between cases and controls. However, a history of late abortion or previous preterm delivery was significantly more frequent among cases than controls. Forty (16.3%) cases and 56 (11.5%) controls had a history of cervical ripening with misoprostol before vacuum curettage or evacuation, or of medical abortion by misoprostol alone or with mifepristone (OR 1.51, 95% CI: 0.95–2.39; p = 0.08). After adjustment for maternal age and number of pregnancies with a multivariable conditional regression model, the adjusted OR was estimated at 1.33 (95% CI: 0.81–2.17; p = 0.25). Conclusion: Despite the need for prudence, these results provide some reassurance that induced abortion with misoprostol during the first or second trimester of pregnancy is safe for subsequent pregnancies. ß 2009 Elsevier Ireland Ltd. All rights reserved.
Keywords: Misoprostol Induced abortion Termination of pregnancy Preterm delivery Late abortion
1. Introduction Various techniques have been proposed for induced abortions during the first or second trimester [1]. They include vacuum curettage, dilation and evacuation, and prostaglandin E2 (PGE2) vaginal suppositories. More recently, misoprostol, a prostaglandin E1 analog, has become an alternative to the rigid dilators or laminaria tents frequently used and has also been suggested for medical abortions [2–10]. Each year in France, there are about
* Corresponding author at: Service de Gyne´cologie-Obste´trique, CHU Nantes, 38 bd Jean Monnet, 44093 Nantes, France. Tel.: +33 2 40 08 31 90; fax: +33 2 40 08 47 90. E-mail address: [email protected] (N. Winer). 0301-2115/$ – see front matter ß 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ejogrb.2009.04.028
200,000 first trimester and 5600 second trimester induced abortions [11]. Most of these procedures are now performed with misoprostol, alone or combined with mifepristone. Several large case–control studies suggest that a history of induced abortion increases the risk of preterm delivery in subsequent pregnancies [12–16], but they have not fully explored the respective role of the surgical and medical techniques used. The side effects of misoprostol include nausea, vomiting, diarrhea, shivering and fever, and related complications include hemorrhaging, endometritis and, very rarely, uterine rupture. While the studies mentioned above have examined these side effects and complications, to our knowledge, no publication has evaluated the risk of late abortion or preterm delivery after a first or second trimester induced abortion with misoprostol.
54
N. Winer et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 145 (2009) 53–56
The aim of this study was to examine whether an induced abortion using misoprostol during the first or second trimester influences the risk of late abortion or preterm delivery in subsequent pregnancies. 2. Material and methods This prospective study took place from January 2005 to June 2006 at the Poissy-Saint Germain Hospital, where about 1500 induced elective abortions and 250 abortions for medical indications are performed each year. This case–control study sought to determine whether late abortion or preterm delivery might be associated with a history of cervical ripening with misoprostol before vacuum curettage or evacuation, or of medical abortion with misoprostol alone or combined with mifepristone. In our institution and indeed, in the institutions in our perinatal network, the first and second trimester induced abortions use the following protocol: 200 mg of mifepristone by mouth, followed 48 h later by 400 mg of misoprostol administered vaginally and repeated every 4 h up to a maximal dose of 1200 mg/day. Our network does not use the procedure involving a laminaria tent and dilatation and extraction. We note that as a level-3 reference facility, most of the patients referred to us come from other institutions in our network. The cases included all singleton pregnancies during the study period who delivered at 16–36 weeks of gestation after a spontaneous late abortion, preterm labor, or preterm premature rupture of membranes, or who had induction of labor for preterm premature rupture of membrane before 37 weeks. The control group was composed of the two consecutive spontaneous singleton deliveries at 37 weeks of gestation or later after each case (ratio 2:1). Exclusion criteria for both cases and controls were: multiple pregnancies; induction of labor for any medical or obstetrical indication other than preterm premature rupture of membrane or chorioamnionitis; a history of vacuum curettage or dilatation and evacuation where rigid dilators or laminaria tents were used for cervical dilatation to facilitate procedures; an induced abortion during the first or second trimester of a previous pregnancy by a method other than misoprostol alone or with mifepristone; or a history of a first trimester missed or incomplete abortion managed with misoprostol, or of induction of labor at term with misoprostol. We computed the sample size necessary to detect an odds ratio of 2.0, given an expected proportion of misoprostol exposure in the control group of 0.10, with a type I error rate of 0.05 and a type II rate of 0.20. Applying the Connett formula for pair-matched case– control studies [17], we calculated that we needed a sample size of 230 cases and 230 controls. To increase power, we decided to pair two controls to each case. Finally, since about 15 late abortions or preterm deliveries were expected each month, the duration of the study was set at 18 months. Women were enrolled during the postpartum period in the hospital. Data were obtained in part from the medical records and in part from interviews with the women within 3 days of delivery. Data extracted from the medical records included maternal age, obstetrical and medical history, including the method used for any induced abortions, history of late abortions or preterm deliveries, details about the management and complications of the current pregnancy, the delivery and the baby’s health. The interviews of the mothers provided information only about social and demographic characteristics and smoking habits before and during pregnancy. Maternal smoking (yes or no) during pregnancy was assessed dichotomously, regardless of the number of cigarettes. Data were summarized as incidences and percentages for categorical variables. Quantitative variables were summarized as medians and 25th and 75th percentiles (with ranges). Cases and controls were compared with the Cochran-Mantel-Haenszel chi-
square test for categorical variables, with each cluster composed of each case and its two controls. The association between late abortion or preterm delivery and a history of either cervical ripening with misoprostol before vacuum curettage or evacuation or of medical abortion with misoprostol, alone or in combination with mifepristone, was first examined by a Cochran-MantelHaenszel chi-square test. Conditional logistic regression models adapted to clustered data were used to quantify the effect size, measured by estimated odds ratio (OR) with their 95% confidence intervals (95% CI). Crude and adjusted ORs were computed. Adjustments were made with multivariable models that introduced factors associated with the outcome at a p-value of 0.20 in the univariable analyses or known as risk factors. All tests were two-sided with a significance level of 0.05. Analyses were performed with the R statistical package (online at http:// www.R-project.org). The institutional review board (Comite´ de Protection des Personnes of Saint-Germain-en-laye) was consulted and determined that its approval was unnecessary under French law because all patients received standard management without any additional, unusual or innovative diagnostic or follow-up procedures. 3. Results During the study period, 267 women were admitted to our unit for a late abortion or preterm delivery. Missing medical reports about previous preterm delivery or induced abortion resulted in excluding 22 cases, before any controls were included for pairing with them. The study thus included 245 cases with deliveries at 16–36 weeks and 490 control women who gave birth at or after 37 weeks of gestation. The study thus included 735 patients in all. The median duration of pregnancy (first and third quartiles) was 227.8 (210, 254) days [range 110, 258] in the case group and 279.9 (274, 287) days [range 259, 295] in the control group. Table 1 summarizes the population’s general and obstetrical characteristics. Cases and controls did not differ significantly for mean maternal age, number of pregnancies, parity, smoking status, or history of first trimester miscarriage. A history of spontaneous late abortion or preterm delivery was significantly more frequent among case than control patients. In all, 40 (16.3%) case women and 56 (11.5%) control women had a history of induced abortion by misoprostol in the first or second trimester of pregnancy. The observed effect size, measured by the odds ratio, was estimated at 1.51 (95% CI: 0.95–2.39; p = 0.08). Even after adjustment for maternal age and number of pregnancies with a multivariable conditional regression model, the effect size of a history of induced abortion with misoprostol on late abortion or preterm delivery remained lower than expected: the adjusted OR was estimated at 1.33 (95% CI: 0.81–2.17; p = 0.25) (Table 2). 4. Discussion Our data suggest that a history of induced abortion with misoprostol is not a risk factor for late abortion or preterm delivery in subsequent pregnancies. MEDLINE, PubMed and the Cochrane library were searched for articles published in English from January 1980 to August 2007 with the keywords ‘‘misoprostol’’, ‘‘induced abortion’’ or ‘‘medical abortion’’ or ‘‘medical induced abortion’’ or ‘‘termination of pregnancy’’; and ‘‘preterm delivery’’ or ‘‘preterm birth’’ or ‘‘late abortion’’ or ‘‘spontaneous late abortion’’ or ‘‘low birth weight’’ or ‘‘subsequent adverse pregnancy outcome’’. These issues have not been thoroughly examined before and the literature is both scarce and conflicting. Some studies conclude that induced abortion during the first trimester does not
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Table 1 General and obstetrical characteristics of the population. Values are given as n (%). Cases, n = 245 (%)
Controls, n = 490 (%)
Age (years) [17,27] [27,30] [30,34] [34,51]
80 46 62 57
(32.7) (18.8) (25.3) (23.3)
130 122 142 96
(26.5) (24.9) (29.0) (19.6)
Number of pregnancies 1 2 3 4
92 60 44 49
(37.6) (24.5) (18.0) (19.9)
195 153 66 76
(39.8) (31.2) (13.5) (15.5)
122 70 37 16
(49.8) (28.6) (15.1) (6.5)
243 152 62 33
(49.6) (31.0) (12.7) (6.7)
p-Value 0.08
0.07
Parity 1 2 3 4
0.80
Smoked during pregnancy Previous preterm delivery Previous spontaneous late abortion
38 (16.6) 43 (17.6) 11 (4.6)
61 (13.1) 29 (5.9) 3 (0.6)
0.25 <0.0001 0.0006
Surgical abortion <15 weeks’ gestation Medical abortion >15 weeks’ gestation Exposed
32 (13.1) 10 (4.1) 40 (16.3)
47 (9.6) 10 (2.0) 56 (11.4)
0.09
Gestational age, median (Q1–Q3)
32 (27,34)
38 (37,39)
increase the risk of preterm birth in subsequent pregnancies [18– 21]. Raatikainen et al. [20] analyzed a population-based database in Finland that contained 26,976 singleton pregnancies between 1989 and 2001. Although preterm birth appeared to be more frequent among women with one prior abortion, logistic regression analysis found no evidence of adverse pregnancy outcomes in this group. They concluded that induced abortion was not an independent risk factor for adverse obstetric outcome. However, several recent publications suggest an increased risk of preterm birth in subsequent pregnancies after induced abortion [12–16]. Three were large retrospective cohort studies, covering from 10,6345 to 61,753 pregnancies [12–14] and two were large case–control studies [15,16]. Henriet and Kaminski [14] and Ancel et al. [15] showed that the risk of preterm birth increased with the number of previous abortions. Martius et al. [12] concluded that preterm birth <32 weeks was associated with previous history of induced abortion, and this was confirmed by Moreau et al. [16], who also suggested that the strength of this association increased with decreasing gestational age at delivery. Second trimester surgical abortions that use dilatation and evacuation may be associated with a higher risk of subsequent premature delivery [22,23]. Uncontrolled and small series [24–27] suggest, however, that this method is not a risk factor for Table 2 Multivariable analysis of the association between late abortion or preterm delivery and a history of either cervical ripening with misoprostol prior to vacuum curettage or evacuation, or of medical abortion with misoprostol alone or with mifepristone. OR (95% CI)
p-Value
Number of pregnancies Age [17,27] [27,30] [30,34] [34,51]
0.97 (0.85; 1.10)
0.60
1.63 (1.02; 2.58) 1 1.12 (0.69; 1.81) 1.57 (0.94; 2.61)
0.02 0.65 0.08
Previous preterm delivery Previous late abortion TOP with misoprostol
2.23 (1.41; 3.51) 7.10 (1.78; 28.2) 1.53 (0.92; 2.55)
0.0006 0.006 0.10
The group in bold characters is the reference group with the lowest risk of preterm birth.
midtrimester pregnancy loss or spontaneous preterm birth. These conflicting results can be at least partly explained by differences or weaknesses in their methods, including their use of registries or databases, small series with a consequent lack of power, retrospective studies, absence of a control group, heterogeneity in abortion techniques, differences in gestational age at abortion, and possibly uncontrolled biases, despite the use of logistic regression analysis to control the potential confounders. Our study did not include surgical abortions by dilatation and evacuation, but evaluation is limited by the fact that this procedure is not employed in our hospital or our perinatal network. Instead, the protocol we used calls for administering misoprostol, 400 mg, orally or vaginally, and repeating it every 4 h until expulsion and vacuum aspiration, sometimes preceded 48 h earlier by 200 mg of oral mifepristone. Only two studies have specifically examined whether a medical abortion in the first trimester of pregnancy influences the risk of late abortion or preterm delivery in subsequent pregnancies. A cohort study by Chen et al. [28] examined the effect of mifepristone-induced first trimester abortions on the outcome of subsequent wanted pregnancies. The risk of preterm delivery did not differ significantly between women with previous mifepristone abortions, women with surgical abortions, and women with no abortions at all. In a large cohort study, Virk et al. [29] recently used the Danish national birth registries to compare the effect on subsequent pregnancies of previous medical and surgical abortions. They found no evidence that a medical abortion, with misoprostol alone or preceded by mifepristone, increased the risk of spontaneous abortion or preterm birth compared with a previous surgical abortion 9 weeks of gestation. Our results confirm that induced abortion with misoprostol in the second trimester of pregnancy does not significantly increase the risk of late abortion or preterm delivery in subsequent pregnancies. One weakness of this study is that we did not collect information on the interval between the abortion and the subsequent birth. Nonetheless, consideration of that information might have been complex, especially for patients with more than one induced abortion. Would the interval be defined according to the first misoprostol exposure or the last? The inclusion criterion was qualitative (yes/no) for exposure to misoprostol and did not consider dose. In the absence of a national abortion registry and in
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view of the possibly long latency between exposure to misoprostol and late abortion or preterm delivery in subsequent pregnancies, a prospective cohort study was not feasible. Another potential limitation of our study is that some potential confounders might have been ignored or that their measurement was biased. Nevertheless, even though cases and controls were not matched, for simplicity’s sake, we looked for and found no statistically significant differences in the main baseline characteristics between cases and controls. Notably, there were no significant differences between cases and controls in mean maternal age, number of pregnancies, parity, or smoking. However, it may be objected that a randomized controlled trial would have been preferable. Finally, we note that since misoprostol is the standard of care here, this study cannot compare the role of misoprostol with other methods of cervical ripening or induction. In addition, many other factors may affect the risk of preterm birth in a subsequent pregnancy after an induced abortion in a previous pregnancy. These include baseline risk factors, psychological issues, and lifestyle. The safety of medical or surgical methods in the first and second trimester and their effects on subsequent pregnancies can probably be assessed only through large case–control or cohort studies. The size of the study and the case–control design with prospective collection of late abortions and preterm delivery information are major strengths. Our unit is a referral center for high-risk pregnancies where women with preterm labor are referred from within a perinatal network covering 20,000 deliveries per year. Nonetheless, we cannot rule out the possibility that we lacked the power to observe a difference with an OR < 2 between cases and controls. The retrospective nature and limitations of this study require prudence in drawing conclusions. Nonetheless these results provide some reassurance that administration of misoprostol in first and second trimester medical abortions does not create a risk for subsequent pregnancies. Conflict of interests The authors have no potential conflicts of interest to disclose. None of the manufacturers of misoprostol provided financial support or had any role in the design, the conduct, interpretation or reporting of this study. Acknowledgment None. Contribution to authorship: Norbert Winer and Yves Ville wrote the paper. Matthieu Resche-Rigon and Christine Morin analyzed the data. Patrick Rozenberg conceived and designed the study. Ethics approval: The institutional review board (Comite´ de Protection des Personnes of Saint-Germain-en-laye) was consulted and determined that its approval was unnecessary under French law since patients received standard management without any additional, unusual or innovative diagnostic or follow-up procedures (Files enclosed). References [1] Stubblefield PG, Carr-Ellis S, Borgatta L. Methods for induced abortion. Obstet Gynecol 2004;104:174–85.
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