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While a post-marketing study of the Norplant contraceptive adds to the body of positive evidence on its use, American providers continue to wait for results of product stability tests for suspect lots of the implant.
The just-released post-marketing surveillance marks the first of three publications from the large-scale international investigation.1 Researchers used controlled cohort methodology to compare the experiences of women using Norplant against those who chose two other forms of long-term birth control: the intrauterine device (IUD) and surgical sterilization. The study confirms the safety with respect to serious disease and the high contraceptive efficacy of Norplant, copper IUD, and sterilization.
While the post-marketing surveillance gives providers further understanding of the use of the contraceptive implant in international settings, American family planners look to product stability tests from Wyeth-Ayerst Pharmaceuticals of Phila-delphia on certain suspect lots of the product.
The company issued an advisory in August 2000 which alerted providers that routine shelf-life stability laboratory tests indicated product from certain specified lots might not release enough levonorgestrel to deliver effective, ongoing contraception. (See Contraceptive Technology Update October 2000, p. 117, and November 2000, p. 129, for complete information on the suspect lots.) Some 22,000 kits were contained in the suspect lots, according to company estimates.
Wyeth continues to conduct additional testing and analysis of the lots in question and has submitted results of these analyses to the Food and Drug Administration (FDA), reports Audrey Ashby, company spokeswoman.
"We are working with the FDA to evaluate this information and are making every effort to provide additional information about the contraceptive efficacy of Norplant from the specified lots," says Ashby. "Women who began using Norplant before Oct. 20, 1999, are not affected, and the Norplant System remains an effective long-term contraceptive."
Look at the study
The post-marketing surveillance is unique since there have been no other large-scale studies of Norplant with a parallel, comparable control group of women using nonhormonal methods, explains Tim Farley, PhD, co-author of the study and a scientist in epidemiology and evaluation in the Geneva-based World Health Organization’s Special Programme of Research, Development, and Research Training in Human Reproduction, Department of Reproductive Health and Research.
"This allows us to compare the effectiveness and safety of the method and to assess the incidence of minor side effects with the incidence among women using nonhormonal methods of contraception," he notes.
Altogether, 7,977 women initiated Norplant, with 6,625 choosing the IUD, and 1,419 selecting sterilization. A total of 32 family planning clinics in eight developing countries participated in the research. Participants were interviewed and examined at semiannual visits and followed for five years, regardless of change of contraceptive methods. Incidence rate ratios of health events were estimated for initial and current method use.
The overall follow-up rate was 94.6%, with 78,323 woman-years of observation accumulated. Pregnancy rates for Norplant, copper IUD, and sterilization each averaged less than one per 100 woman-years, further evidence of the long-term effectiveness of the three methods.
With two exceptions, no significant excess risk of serious morbidity was detected for Norplant users compared with controls, the study reveals. The incidence of gallbladder disease was higher
in women who initiated Norplant use than in controls, as was the incidence of hypertension and borderline hypertension in current implant users.
It is difficult to know what to add about the reported higher incidence of hypertension/borderline hypertension in the Norplant users compared with the control women, Farley says. Such a finding has not been reported previously for Norplant users; however, assessment of blood pressure was more frequent among the Norplant users compared with the women in the control group, he states.
"If the observed increased incidence is true and of the actual magnitude observed, it would theoretically result in one more case of hypertension per annum in 3,000 Norplant users than in a similar number of IUD users," says Farley.
Further examination of the comparative data between the Norplant and IUD groups might yield more information, says Irving Sivin, study co-author and senior scientist with The Population Council in New York City. Implants were removed at the end of five years, but many women retained their IUD, and that practice might have resulted in the elevated blood pressure readings, he hypothesizes.
Look for more information to come from the post-marketing surveillance, says Farley. The current paper serves as a summary of key findings; two papers that provide extensive details on contraceptive efficacy and reproductive health, and another on nonreproductive health, are in press with the journal Contraception, he reports.
1. Meirik O, Farley TM, Sivin I. Safety and efficacy of levonorgestrel implant, intrauterine device, and sterilization. Obstet Gynecol 2001; 97:539-547. n
For more information on the Norplant post-marketing surveillance research, contact:
• Irving Sivin, Center for Biomedical Research, The Population Council, 1230 York Ave., New York, NY 10021.