New Hormonal Contraceptive Agents during Lactation

Existing Recommendations

The CDC and WHO guidelines are mostly in agreement; however, a few differences exist. Based on the available evidence, expert opinion in the United States holds that postpartum no women should use combined (i.e., estrogen-containing) hormonal contraceptives during the first 3 weeks after delivery because of concerns about increased risk for venous thromboembolism, and nursing mothers generally should not use combined hormonal contraceptives for an additional week postpartum because, “theoretical or proven risks usually outweigh the advantages.” In this case, the risk is for interference with lactation. ¹ Postpartum breastfeeding women with other risk factors for venous thromboembolism generally should not use combined hormonal contraceptives until 6 weeks after delivery.^1,3 WHO guidelines are somewhat more restrictive, stating that combined oral contraceptives should not be used in nursing mothers before 42 days postpartum and the disadvantages of using the method generally outweigh the advantages between 6 weeks and 6 months postpartum. ²

A recent study emphasized the concerns regarding estrogen's effects on lactation. Data from the subset of women who intended to breastfeed for 3 months or longer postpartum during their third trimester of pregnancy and who were using a contraceptive at 3 months postpartum were analyzed (n = 1,349). Women were followed from the third trimester of pregnancy throughout the first year postpartum. Those who intended to breastfeed for at least 4 months and were taking an estrogen-containing combined oral contraceptive (estrogen dose not specified) were only 17% as likely to be breastfeeding (exclusive or nonexclusive) at 4 months compared to women who used a nonhormonal contraceptive. Women who said they would breastfeed for 3–4 months were 34% as likely to be breastfeeding as those using a nonhormonal contraceptive. These rates were much lower than those of women who were taking a progestin-only oral contraceptive, who breastfed at a rates similar to women using nonhormonal contraception at 4 months postpartum. ⁵

Current guidelines are based on studies with higher estrogen combination products (i.e., ethinyl estradiol 30–50 μg), but no robust studies on newer low-dose (i.e., ethinyl estradiol 10–20 μg) products' effect on lactation have been performed. ⁴ One old, nonrandomized study found that daily use of a combination contraceptive containing 10 μg of ethinyl estradiol and 350 μg of norethindrone in 6 women resulted in decreases in protein, lipids, calcium, and phosphorus compared to 11 women who received nonhormonal contraception. These differences were not statistically significant, possibly because of the small number of subjects. Milk volume was similar in the two groups. ⁶

Several interesting new contraceptive drugs and dosage forms have become available that in some cases might have advantages for nursing mothers.

A New Estrogen

Estetrol is also referred to as fetal estrogen or E4. It is produced by both male and female fetal livers in utero, but the marketed drug is a plant-based synthetic product. Unlike estradiol, which is poorly absorbed orally, the bioavailability of estetrol is about 70–90%. Estetrol has lower estrogenic activity than estradiol; thus, estetrol may potentially reduce thrombotic complications of contraceptive treatment, and especially the risk of breast cancer. One study found that the effects of the combination of estetrol and drospirenone on gonadotropins, cortisol, cortisol-binding globulin, angiotensinogen, sex hormone-binding globulin, and triglycerides were less pronounced than with ethinyl estradiol-containing products. The combination of estetrol with drospirenone (approved in 2021 as Nextellis^® in the United States) did not decrease serum prolactin in nonbreastfeeding women, so it might interfere less with lactation than other estrogen-containing contraceptives, but clinical data are currently insufficient to recommend this product over other estrogen-containing products in nursing mothers.^7,8 No studies have been performed to measure estetrol in breast milk.

Progestins

Progestins are synthetic hormones with progestogenic activity that are sometimes confused with and mistakenly called progesterone, which is the natural hormone produced in the body. Currently, the most commonly used progestins in oral contraceptives and some nonoral products is levonorgestrel, the levo-isomer of the older drug, norgestrel. Most older progestins, such as norgestrel, levonorgestrel, and norethindrone are chemical modifications of testosterone, which confers some residual androgenic activity. However, some newer agents are different in this respect.

Drospirenone

Drospirenone is an analogue of spironolactone rather than testosterone, which gives it some anti-androgenic and anti-mineralocorticoid properties. Drospirenone is available in combination with estetrol. Having both low estrogenic and antiandrogenic activity seems to confer some unique metabolic properties to the combination of estetrol and drospirenone, as noted previously, but comparative studies with other combination contraceptives have not been performed. Drospirenone is also available as 3 mg tablets combined with ethinyl estradiol 20 or 30 μg and as 4 mg tablets as a progestin-only oral contraceptive (Slynd^®).

Two studies have measured the excretion of drospirenone in milk. In one study, 6 women had milk samples taken after an oral combination product of drospirenone 3 mg plus ethinyl estradiol 30 μg. The authors estimated that a fully breastfed infant would receive a drospirenone dose of about 3 μg/day, which translates to a relative infant dosage of 1.1% of the weight-adjusted maternal dosage of drospirenone. In the second study, 12 women were given a dose of 4 mg/day of drospirenone orally. Extensive sampling of milk found that the average concentration was 5.6 μg/L, providing an exclusively breastfed infant with an average of 0.84 μg/kg of drospirenone daily, which represents a weight-adjusted relative infant dose of 1.25% of the maternal dose. The two studies are therefore in fairly close agreement that the amounts of drospirenone in milk are not of concern for the breastfed infant.

Segesterone Acetate

Another progestin that is newly available in the United States is segesterone acetate, which is a progesterone derivative. It has also been called nestorone acetate and elcometrine and is available overseas as a progestin-only subcutaneous contraceptive implant. In the United States, it was approved in 2018 combined with ethinyl estradiol as a silicone elastomer vaginal insert (Annovera^®) that remains in place for 3 weeks and is then removed for 1 week. The same insert is reinserted after the 7-day drug-free interval and used for 13 cycles over a 1-year period.

Segesterone has been measured in breast milk in three studies, but only after the use of the subdermal implant. Comparing the maternal serum concentrations reported in these published studies to those reported in the Annovera package insert reveals that similar average maternal serum segesterone acetate levels are attained. The studies on implants found milk segesterone levels ranging from 20 to 138 ng/L, so milk segesterone acetate levels after Annovera should be similarly low. More directly, infant blood samples from 25 infants found an average of 7 ng/L (range <5 to 20 ng/L) of segesterone acetate. In addition, studies on the use of segesterone acetate implants have found no adverse effects on infant growth or development.

The maternal serum ethinyl estradiol levels during Annovera use are similar to or greater than those attained with other estrogen-containing oral or vaginal contraceptive products. Therefore, Annovera has no advantages with respect to breastfeeding and its use should not be instituted any sooner than other combined oral contraceptives.

Over-the-Counter Norgestrel

The newest major development in oral contraception in the United States is the switch of 75 μg norgestrel tablets (Opill^®) from prescription to over the counter by the Food and Drug Administration (FDA) in July 2023. The manufacturer states that it will be available from retailers nationwide, online, and via subscription in early 2024. It will probably be available in grocery and convenience stores, and there will be no age restriction on its purchase or use, at least at the federal level. The principle warnings against its use are a history of breast cancer or allergy to the drug or to tartrazine (FD&C Yellow No. 5), which is a colorant in the tablet. The FDA determined that studies demonstrated that consumer understanding of information on the Opill Drug Facts label was good overall. A high proportion of consumers understood the label instructions, supporting their ability to properly use the drug as an over-the-counter product.

The Opill package labeling contains the following consumer information regarding breastfeeding:

“Is it okay to use Opill^® if I'm breastfeeding?

Yes. Opill^® is safe and effective in breastfeeding women. Small amounts of progestin may pass into the breast milk; however, no adverse effects have been found on either breastfeeding performance or infant health.”

Summary

Guidelines for the use of contraception during breastfeeding have not markedly changed for 7–8 years, but some interesting new steroidal hormones have become available in contraceptive products that might have advantages over previous products in nursing mothers. Currently, insufficient information is available to recommend any switch to these newer products in nursing mothers. Meanwhile, the over-the-counter availability of norgestrel could prove to be an important advance in contraception in the United States. Consumer labeling of this product clearly supports breastfeeding.