Ectopic Pregnancy Risk and Levonorgestrel-Releasing IUD

Researchers report that use of any levonorgestrel-releasing intrauterine system was associated with a significantly increased risk of ectopic pregnancy, compared with other hormonal contraceptives, in a study published in JAMA.

A national health database analysis headed by Amani Meaidi, MD, PhD, of the Danish Cancer Society Research Center, Cancer Surveillance and Pharmacoepidemiology, in Copenhagen, compared the 13.5-mg with the 19.5-mg and 52-mg dosages of levonorgestrel-releasing intrauterine systems (IUSs).

The hormone content in levonorgestrel-releasing IUSs must be high enough to maintain optimal contraceptive effect but sufficiently low to minimize progestin-related adverse events, Dr. Meaidi and colleagues noted; they advised using the middle dosage of 19.5 mg. All dosages are recommended for contraception, with the highest dosage also recommended for heavy menstrual bleeding.

“If 10,000 women using the hormonal IUD for 1 year were given the 19.5-mg hormonal IUD instead of the 13.5-mg hormonal IUD, around nine ectopic pregnancies would be avoided,” Dr. Meaidi said in an interview.

“Ectopic pregnancy is an acknowledged adverse event of hormonal IUD use. Although a rare event, it is a serious one, and a difference in ectopic pregnancy safety between the two low-dose hormonal IUDs would impact my recommendations to women.”

The study

Dr. Meaidi’s group followed 963,964 women for 7.8 million person-years. For users of levonorgestrel IUS dosages 52 mg, 19.5 mg, and 13.5 mg, and other hormonal contraceptives, the median ages were 24, 22, 22, and 21 years, respectively.

Eligible women were nulliparous with no previous ectopic pregnancy, abdominal or pelvic surgery, infertility treatment, endometriosis, or use of a levonorgestrel IUS. They were followed from Jan. 1, 2001, or their 15th birthday, until July 1, 2021, age 35, pregnancy, death, emigration, or the occurrence of any exclusion criterion.

During the study period, the cohort registered 2,925 ectopic pregnancies, including 35 at 52 mg, 32 at 19.5 mg, and 80 at 13.5 mg of levonorgestrel. For all other types of hormonal contraception, there were 763 ectopic pregnancies.

In terms of adjusted absolute rates of ectopic pregnancy per 10,000 person-years, compared with other hormonal contraceptives (rate = 2.4), these were 7.7 with 52 mg levonorgestrel IUS, 7.1 with 19.5 mg, and 15.7 with 13.5 mg. They translated to comparative differences of 5.3 (95% confidence interval, 1.9-8.7), 4.8 (95% CI, 1.5-8.0), and 13.4 (95% CI, 8.8-18.1), respectively.

Corresponding adjusted relative rate ratios were 3.4, 4.1, and 7.9. For each levonorgestrel IUS dosage; the ectopic pregnancy rate increased with duration of use.

The adjusted ectopic pregnancy rate difference per 10,000 person-years between the 19.5-mg and 52-mg levonorgestrel dosages was −0.6 , and between the 13.5-mg and 52-mg doses, 8.0, with a rate ratio of 2.3. The rate difference between the 13.5-mg and 19.5-mg levonorgestrel IUS was 8.6, with a rate ratio of 1.9.

An outsider’s perspective

Offering an outsider’s perspective on the study, Eran Bornstein, MD, vice-chair of obstetrics and gynecology at Lenox Hill Hospital in New York, said these data should spark further evaluation of risk of ectopic pregnancy with levonorgestrel-releasing IUDs. “The best advice for clinicians is to individualize the choice of which contraceptive to use, and when levonorgestrel IUD is selected, to individualize the appropriate dose and timing of placement,” he said in an interview.

Several additional factors may determine the best choice, Dr. Bornstein added, including medical conditions that contraindicate other contraceptives and those conditions that justify avoidance of pregnancy, as well as uterine myomas or malformation, the ability of the patient to comply with other options, and informed patient choice. “It is important to remember the potential risk for expulsion and ectopic pregnancy, maintain alertness, and use ultrasound to exclude these potential complications if suspected,” he said.

Dr. Meaidi said the mechanism of ectopic pregnancy with hormonal IUDs is unclear, but in vitro and animal studies have observed that levonorgestrel reduces the ciliary beat frequency in the fallopian tubes. “Thus, it could be hypothesized that if a woman was unfortunate enough to become pregnant using a hormonal IUD, the hormone could inhibit or slow down the movement of the zygote into the uterus for rightful intrauterine implantation and thereby increase the risk of ectopic pregnancy.”

Two coauthors of the study reported financial support from private-sector companies. Dr. Meaidi had no conflicts of interest. Dr. Bornstein disclosed no competing interests.

This article originally appeared on, part of the Medscape Professional Network.

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