An important contraceptive option for women is the drug levonorgestrel (LNG), popularly known as the morning-after pill. When taken properly, it is effective at preventing pregnancy following unprotected sex. But, like many medications, it is not 100 percent effective—and when it comes to matters as important as pregnancy, any lapses in efficacy are important topics of clinical research.

Melissa Natavio, MD, MPH

Researchers have already identified obesity as a risk factor for emergency contraceptive failure: analyses show a decrease in efficacy of LNG in concert with increasing body weight and body mass index (BMI), said Melissa Natavio, MD, MPH, an Associate Professor of Clinical Obstetrics and Gynecology at the USC Keck School of Medicine for 10 years, and a resident and fellow for five years previously. She recently relocated to the University of Hawaii. Family planning, with a focus on contraception, are Natavio's primary research interests.

"Emergency contraception medications are a woman's last chance to try to prevent pregnancy after unprotected or inadequately protected intercourse," said Natavio. LNG is the most readily available option for emergency contraception, sold under the brand name Plan B One-Step and in generic forms.

"LNG has a failure rate of about 1 to 3 percent generally, but overweight or obese women may be four times more likely to get pregnant after taking the drug," said Natavio. "We need to understand why so that we can make the medications more effective in this population."

Natavio's study examined the pharmacokinetics of LNG following ingestion, hypothesizing that obese women would experience reduced levels of the drug in their blood. As expected, the study found that the obese women had lower total levels of the drug in their blood. But it wasn't that simple: the drug also tends to bind to proteins, altering its bioavailability. When the researchers measured the free LNG drug levels (traditionally thought to be the active form of LNG) they found no difference between lighter-weight and heavier women, but there were differences in the bioavailable levels, another form of the drug that may play a role in its efficacy.

"Total levels and bioavailable levels are not the same thing in all medications," said Natavio. "This tells us that we have to try to understand which is the most important level to look at for a particular drug."

The Southern California Clinical and Translational Science Institute (SC CTSI) provided support for Natavio's study by offsetting costs involved in the use of its Clinical Trials Unit (CTU), where participants remained for several hours at a stretch during the study. The CTU, a resource of the SC CTSI's Clinical Research Support core, offers a range of services and expertise to assist researchers with all operational aspects of initiation and conduct of human studies. In addition, said Natavio, the SC CTSI's Biostatistics, Epidemiology and Research Design core group assisted in the development of the study’s statistical analysis plan.

Natavio is continuing to investigate the effect of obesity and body mass on emergency contraception drugs as part of an NIH-sponsored multisite Contraceptive Clinical Trials Network study at her current position at the University of Hawaii.

But with obesity widespread in the United States among people of all ages, Natavio pointed out, the impact of body mass index on drug efficacy is a question that should be studied in the context of many medications. The question of bioavailability of a medication, as well as total and free quantities of the medications, could inform such investigations.

The study, "Pharmacokinetics of the 1.5 mg levonorgestrel emergency contraceptive in women with normal, obese and extremely obese body mass index" was published in 2019 in the journal Contraception.  Authors included Natavio, Frank Z. Stanczyk, PhD; Emilie A.G. Molins, Anita Nelson, MD, and William J. Jusko, PhD.

NIH Funding Acknowledgment: Important - All publications resulting from the utilization of SC CTSI resources are required to credit the SC CTSI grant by including the NIH funding acknowledgment and must comply with the NIH Public Access Policy.