Ectopic Pregnancy and Emergency Contraceptive Pills: A Systematic Review

Abstract

Objective

To evaluate the existing data to estimate the rate of ectopic pregnancy among emergency contraceptive pill treatment failures.

Data Sources

Our initial reference list was generated from a 2008 Cochrane review of emergency contraception. In August 2009, we searched Biosys Previews, the Cochrane Database of Systematic Reviews, Medline, Global Health Database, Health Source: Popline, and Wanfang Data (a Chinese database).

Methods of Study Selection

This study included data from 136 studies which followed a defined population of women treated one time with emergency contraceptive pills (either mifepristone or levonorgestrel), and in which the number and location of pregnancies were ascertained.

Results

Data from each article were abstracted independently by two reviewers. In the studies of mifepristone, 3 out of 494 (0.6%) pregnancies were ectopic; in the levonorgestrel studies, 3 out of 307 (1%) were ectopic.

Conclusion

The rate of ectopic pregnancy when treatment with emergency contraceptive pills fails does not exceed the rate observed in the general population. Since emergency contraceptive pills are effective in lowering the risk of pregnancy, their use should reduce the chance that an act of intercourse will result in ectopic pregnancy.

Introduction

At least 36% of all pregnancies worldwide are unintended (1). In the event of contraceptive mishap or non-use, or nonconsensual intercourse, emergency contraceptive pills provide women with a means of preventing unintended pregnancy after sex. Emergency contraceptive pills have been shown to be safe, effective and well-tolerated; according to the World Health Organization’s Medical Eligibility Criteria, the benefits of their use always outweigh the medical risks (2).

The safety of emergency contraceptive pills has been extensively studied and is well-established (3). However, concern persists about whether their use increases the risk of ectopic pregnancy should treatment fail. This issue was first raised in New Zealand. Based on case reports of three ectopic pregnancies following use of levonorgestrel-only emergency contraceptive pills, the New Zealand Medicines and Medical devices Safety Authority warned in 2002 that “the possibility of an ectopic pregnancy should be considered” (4) if a pregnancy test is positive following use of levonorgestrel emergency contraceptive pills. In an editorial published a year later, the authors noted that 12 ectopic pregnancies in women who used levonorgestrel emergency contraceptive pills had been reported in the United Kingdom and that a handful of additional cases had been reported in other countries (5). As the authors acknowledge, this information cannot be used to calculate the probability that a pregnancy occurring after use of the treatment will be ectopic because the total number of pregnancies needed for the denominator of the calculation is unknown. Nevertheless, based on these case reports, Britain’s Committee on Safety of Medicines also advised that if a woman who has used progestin-only emergency contraceptive pills becomes pregnant, “the possibility of an ectopic pregnancy should be considered” (6). Recent published case reports cite ectopic pregnancy as a known risk of using levonorgestrel emergency contraceptive pills (7,8). Several patient information websites, including one provided by the United States National Library of Medicine and National Institutes of Health, currently note a potential link between use of emergency contraceptive pills and ectopic pregnancy (9–12). In addition, the patient labeling information in Ireland for NorLevo (manufactured by Cardinal Health France), a dedicated levonorgestrel emergency contraceptive pill, lists previous ectopic pregnancy as a contraindication (13).

Among women who have not used emergency contraceptive pills, the chance that a pregnancy will be ectopic has been estimated at 0.8% to 2% of all reported pregnancies (14–20). This range likely reflects differences in how rates are calculated and reported (21) as well as true variation in incidence among populations. Ectopic pregnancy is a potentially life-threatening condition, and accurate assessment of its risk factors is an important step in helping clinicians, public health professionals and pharmaceutical regulatory bodies generate optimal guidelines for women’s health.

Our prior review of 5 prospective efficacy trials of levonorgestrel-only emergency contraceptive pills suggested that the risk of ectopic pregnancy when that regimen fails is unlikely to be raised (22). Here we update that report with an additional 131 studies, including trials of emergency contraceptive regimens containing mifepristone as well as trials of levonorgestrel-only emergency contraceptive pills. These drugs are the active agents in most currently marketed dedicated emergency contraceptive products worldwide.

Sources

Our initial reference list was generated from a 2008 Cochrane review of emergency contraception (23). To ensure completeness and timeliness, we identified relevant studies by conducting computerized literature searches using the following databases and search terms:

BIOSYS PREVIEWS: (CC=(Pharmacology - Reproductive system OR Reproductive system - Physiology "and" biochemistry OR Reproductive system - General "and" methods) AND MC=(Reproduction OR Gynecology OR Oncology) AND PY=(2004 OR 2005 OR 2006 OR 2007 OR 2008 OR 2009) AND TS=(postcoit* or post-coit* or emergenc* same contracept* or morning same after or ru-486 or mifepristone or levonorgestrel or ulipristal or cbd-2914 or cdb2914) AND TA=(Hominidae)

COCHRANE DATABASE: (Topic: Fertility Regulation, Emergency Contraception); Medline ((MH "Contraceptives, Postcoital") not PT case report not PT comment not PT editorial not PT review; date of Publication from: 200401–201012; English Language; Human)

GLOBAL HEALTH: (emergency contracept* OR postcoit* contracept*)

EALTH SOURCE: (emergency contracept* OR postcoit* contracept*)

POPLINE: (emergency contracept*) & (ru-486 / mifepristone / levonorgestrel / ulipristal / cbd-2914 / cdb2914)

WANFANG DATA (Chinese): (emergency contraception, mifepristone, levonorgestrel)

Study Selection

Our review included any study published by August 2009 in English or Chinese with a defined population of women whom investigators treated one time with either levonorgestrel or mifepristone alone for emergency contraception, and in which the number and location of pregnancies were ascertained. We also included one large study with a levonorgestrel arm which we knew to have been completed by August 2009, but which was not published until February 2010. We did not include advance provision studies (in which emergency contraceptive pills are dispensed to study subjects in anticipation of future need) or repeat use studies. We did not include the newly-approved emergency contraceptive pill ulipristal acetate, which has been marketed in Europe since October 2009, as only three studies of this regimen had been published at the time of writing. We excluded studies of emergency contraceptive regimens containing both estrogen and progestin, as this regimen is now increasingly being replaced by the levonorgestrel-only regimen, and we also excluded studies of other combinations of drugs.

After appropriate studies were identified, data from each article were abstracted independently by two reviewers. If the study report did not explicitly state whether each pregnancy was intrauterine or ectopic, we contacted the authors to obtain this information. Each author whom we contacted responded to our queries, so we did not find it necessary to exclude any studies from the analysis based on missing information. We excluded from our analyses all subjects who were believed by the authors to have been pregnant before treatment. Discrepancies were identified and reconciled after reviewers re-assessed the original data.

Results

Our search identified 137 studies that fit our criteria. We excluded one study from our analyses because it was designed to measure bleeding effects of emergency contraceptive pills and explicitly excluded women who became pregnant after treatment (24). Among the remaining 136 studies, 114 were published in Chinese (25–138) and 22 were published in English (139–160). Mifepristone in doses from 10 mg to 600 mg was the most commonly-studied regimen in our review (Table 1). One-third of the studies included a levonorgestrel-only regimen.

Table 1.

Number of studies included in review, by regimen

Regimen	Dose	Studies*
Mifepristone	10 mg – 600 mg	124
Levonorgestrel	0.75 mg × 2 or 1.5 mg	46

^*Because many studies included more than one regimen, the number of studies in this table exceeds the total number of studies in our review.

Of the included studies, 130 (95.6%) ascertained pregnancy by urine or serum hCG assay 7 to 10 days from the expected onset of menses (sensitivity level of tests was generally not specified), followed by ultrasound in the event of a positive test. One additional study specified that all pregnancies were confirmed to be intrauterine histologically after termination. These studies using high-certainty ascertainment methods (ultrasound or histology) contribute 716 (89.1%) of the pregnancies in this review, including all six ectopic pregnancies. For 85 (10.6%) pregnancies, the author did not specify how pregnancy location was determined, but stated (either in the paper or in follow-up communication with us) that the location was known to be intrauterine. In three cases (0.4% of all pregnancies), pregnancy location was classified as “unknown”, because the study authors were unable to designate whether the pregnancy was intrauterine or ectopic.

Among the mifepristone study subjects overall, 494 pregnancies of known location occurred after treatment, 3 of which were ectopic, resulting in an ectopic pregnancy rate of 0.6% (Table 2). Among the 307 pregnancies of known location occurring after treatment with levonorgestrel, 3 (1%) were ectopic. Results did not differ significantly between studies published in English and those published in Chinese for either regimen (for mifepristone studies, p-value for Fisher’s Exact test = 0.30; for levonorgestrel studies, p=1.00). A full table detailing results of each study is available from the authors upon request.

Table 2.

Results by regimen (pregnancies of known location only)

Regimen	Population*	Pregnancies	Ectopic	% of pregnancies that were ectopic (95% CI)
Mifepristone (all)	35,867	494	3	0.6% (0.1% – 1.8%)
English studies	14,669	179	2	1.1% (0.1% – 4.0%)
Chinese studies	21,197	315	1	0.3% (0.0% – 1.8%)
Levonorgestrel (all)	15,696	307	3	1.0% (0.2% – 2.8%)
English studies	11,405	201	2	1.0% (1.2% – 3.5%)
Chinese studies	4,291	106	1	0.9% (0.0% – 5.1%)

^†Excludes women who received treatment but either were known to have been pregnant before treatment or were lost to follow-up after treatment.

We performed a sensitivity analysis assuming that pregnancies of unknown location (two pregnancies following treatment with levonorgestrel and one following treatment with mifepristone) were ectopic. The proportion of pregnancies that were ectopic among levonorgestrel recipients was then 5/309, or 1.6% (95% CI = 0.6%–3.7%), and the proportion among those treated with mifepristone was then 4/495, or 0.8% (95% CI = 0.2%–2.1%).

Conclusion

Our results indicate that use of emergency contraceptive pills, in the two forms widely available today, does not increase the risk that a pregnancy after treatment will be ectopic. Available ectopic pregnancy rates range from 0.8% to 2% of all reported pregnancies; our study detected a range of 0.6% to 1.1%, depending on the medication used. Even when we analyzed the data under the most conservative possible scenario (assuming pregnancies of unknown location to be ectopic), we still found that the rate of ectopic pregnancy following use of levonorgestrel (1.6%) and mifepristone (0.8%) does not exceed the top of the range of rates of ectopic pregnancies among the general population. Indeed, the rate for mifepristone emergency contraceptive pills is at the bottom of that range.

In order to create as much consistency as possible across studies, we carefully considered our inclusion criteria in light of the data that were available to us from each study. We excluded pregnancies that were determined to have begun before emergency contraceptive pill treatment, but did not exclude those that may have begun after treatment had occurred as this information was not always reported. Some studies reported that subjects took additional doses of emergency contraceptive pills after the study treatment. However, because we did not have this information for every study, we did not exclude these subjects from our review.

Our review has several additional limitations. We could not include all women who were treated because some were lost to follow up, and unfortunately, we cannot assess the magnitude of this problem because not all studies reported the number of subjects who were lost. In addition, the exact methods used to ascertain the existence and location of pregnancy are not entirely consistent from study to study. While most studies stated that ultrasound or histological examination was used, this is not explicitly specified in every study. For 10.6% of pregnancies, we relied upon the authors’ assertion that the pregnancies were intrauterine. It is possible that ascertainment procedures vary from study to study, and that ectopic pregnancy is therefore under-diagnosed and underreported. Finally, we cannot be certain what the expected ectopic pregnancy rate would have been in the particular populations studied if subjects had not been treated with emergency contraceptive pills. We found it notable that two of the three ectopic pregnancies among the mifepristone recipients occurred in one study arm in which only six pregnancies were reported (151), but these pregnancies did not occur at the same study site and therefore do not in themselves raise particular concerns about differential ascertainment of pregnancy location.

Despite these limitations, this review provides the most comprehensive assessment to date of the risk of ectopic pregnancy when emergency contraceptive pill treatment fails. Based on our results, we conclude that no situations exist in which clinicians should counsel women against use of emergency contraceptive pills based solely on concerns about ectopic pregnancy. Likewise practitioners and women should have no heightened concern that if treatment fails, the pregnancy is more likely to be ectopic than a pregnancy occurring in the absence of emergency contraceptive pills. Previous studies show that emergency contraceptive pills reduce the likelihood that an act of intercourse will result in a pregnancy (3,23,161,162). Therefore, emergency contraceptive pills reduce the chance that an act of sexual intercourse will result in ectopic pregnancy.