Original research article| Volume 63, ISSUE 4, P187-209, April 2001

Post-marketing surveillance of Norplant® contraceptive implants: II. Non-reproductive health1


      This controlled cohort study aimed to evaluate the safety and efficacy of Norplant contraceptive implants in developing countries. Women initiating Norplant implants were index subjects and women initiating intrauterine devices (IUDs) or surgical sterilization were controls. Consenting participants at 32 clinics in eight developing countries were admitted and followed-up every 6 months for 5 years. Major and less serious health events during follow-up were recorded. Incidence rate ratios of health events adjusted for clinic were estimated for initial and current method use. This paper reports non-reproductive health events. The study involved 7,977 women initiating use of Norplant, 6,625 of IUD, and 1,419 of sterilization. Five years follow-up was completed for 94.6% of the women. The study accumulated 78,323 woman-years of observation. The initial method chosen accounted for 84.4% or more of observed woman-years in users of Norplant, IUD, or sterilization. Twenty-two of the recorded 34 deaths were due to accidents, suicide or homicide. Few deaths or major health events were due to cancer or acute cardiovascular diseases and were not associated with the contraceptive method used. The incidence rates of major health events were low and with two exceptions, there was no significant excess risk of serious morbidity for Norplant users compared with controls; among Norplant initiators gallbladder disease occurred at an incidence rate of 1.5 per 1,000 woman-years and was weakly associated with use of Norplant (rate ratio 1.52 [95% C.I. 1.02, 2.27]). For current Norplant users compared to controls, the rate ratio of a combined variable of hypertension and borderline hypertension was significantly elevated (1.81, [1.12, 2.92]). The occurrence of less serious health events was also low and several of them were significantly more often reported among Norplant users. Headache-migraine, weight gain, mood disturbances, pruritus, eczema, and acne had incidence rates among Norplant users of 11.5, 4.5, 2.8, 1.5, 1.4, and 0.9 per 1,000 woman-years, respectively, and were significantly higher than in controls. Respiratory health problems, nonspecific symptoms, and several ill-defined conditions were also significantly more often reported for Norplant users, but some of the excess incidence may be attributable to reporting and detection bias. The study confirms the safety with respect to serious disease of Norplant, IUDs, and sterilization.
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        • World Health Organization, Special Programme of Research, Development and Research Training in Human Reproduction
        Guidelines for the toxicological and clinical assessment and post-registration surveillance of steroidal contraceptive drugs. World Health Organization, Geneva1987
        • Royal College of General Practitioners
        Oral Contraceptives and Health. Pitman Medical, London1974
        • Vessey M.
        • Doll R.
        • Peto R.
        • Johnson B.
        • Wiggins P.
        A long-term follow-up study of women using different methods of contraception—an interim report.
        J Biosoc Sci. 1976; 8: 373-427
        • Ramcharan S.
        • Pellegrin F.A.
        • Ray R.M.
        • Hsu P.-J.
        The Walnut Creek Contraceptive Drug Study.
        J Reprod Med. 1980; 25: 346-372
        • Sivin I.
        International experience with NORPLANT and NORPLANT-2 contraceptives.
        Stud Fam Plann. 1988; 19: 81-94
        • Sivin I.
        Contraception with NORPLANT implants.
        Human Reprod. 1994; 9: 1818-1826
        • International Collaborative Post-Marketing Surveillance of Norplant
        Post-Marketing surveillance of Norplant contraceptive implants.
        Contraception. 2001; 63: 167-186
        • World Health Organization
        International classification of diseases, 9th revision. World Health Organization, Geneva1977
        • Craft N.
        Women’s health is a global issue.
        BMJ. 1997; 315: 1154-1157
        • Farley T.M.M.
        • Collins J.
        • Schlesselman J.J.
        Hormonal contraception and risk of cardiovascular disease.
        Contraception. 1998; 57: 211-230
        • Shen Q.
        • Lin D.
        • Jiang X.
        • Li H.
        • Zhang Z.
        Blood pressure changes and hormonal contraceptives.
        Contraception. 1994; 50: 131-141
        • Wysowski D.K.
        • Green L.
        Serious adverse events in Norplant users reported to the Food and Drug Administration’s MedWatch Spontaneous Reporting System.
        Obstet Gynecol. 1995; 85: 538-542
        • Petitti D.B.
        • Siscovick D.S.
        • Sidney S.
        • Schwartz S.M.
        • et al.
        Norplant implants and cardiovascular disease.
        Contraception. 1998; 57: 361-362
        • World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception
        Cardiovascular disease and use of oral and injectable progestogen-only contraceptives and combined injectable contraceptives.
        Contraception. 1998; 57: 315-324
        • Rizk D.E.
        Subdermal levonorgestrel implants. Three years’ experience in Cairo, Egypt.
        J Reprod Med. 1995; 40: 638-644
        • Diaz S.
        • Pavez M.
        • Robertson D.N.
        • et al.
        A three-year clinical trial with levonorgestrel silastic implants.
        Contraception. 1979; 19: 557-573
        • Konje J.C.
        • Otolorin E.O.
        • Ladipo O.A.
        Changes in carbohydrate metabolism during 30 months on Norplant.
        Contraception. 1991; 44: 163-172
        • Thijs C.
        • Knipschild P.
        Oral contraceptives and the risk of gallbladder disease.
        Am J Publ Health. 1993; 83: 1113-1120
        • Kaye C.R.
        The Royal College of General Practitioners’ Oral Contraceptive Study.
        Clin Obstet Gynaecol. 1984; 11: 759-786
        • Wagner K.
        • Berenson A.
        Norplant-associated major depression and panic disorder.
        J Clin Psych. 1994; 55: 478-480
        • Wagner K.
        Major depression and anxiety disorders associated with Norplant.
        J Clin Psych. 1996; 57: 152-157
        • Janowsky E.C.
        • Kupper L.L.
        • Hulka B.S.
        Meta-analyses of the relation between silicone breast implants and the risk of connective-tissue diseases.
        N Engl J Med. 2000; 342: 781-790
        • Haze J.M.
        • van Zeben D.
        Oral contraception and its possible protection against rheumatoid arthritis.
        Ann rheum Dis. 1991; 50: 72-74
        • Du M.K.
        • Zheng H.M.
        • Chen H.C.
        • Chow L.P.
        Study of Norplant implants in Shanghai.
        Int J Gynaecol Obstet. 1990; 33: 345-357
      1. Graves, EJ. Detailed diagnosis and procedures, National Hospital Discharge survey 1987–1988-1989–1990. National Center for Health Statistics, Vital Health statistics 13, (107) 1991; 13, (107) 1991; 13, (108) 1991; 13, (113) 1992.

        • Murray C.J.L.
        • Chen L.C.
        Understanding morbidity change.
        Pop Develop Rev. 1992; 18: 481-503
        • Fraser I.S.
        • Tiitinen A.
        • Affandi B.
        • Brache V.
        • et al.
        Norplant consensus statement and background review.
        Contraception. 1998; 57: 1-9
        • Sivin I.
        • Mishell D.R.
        • Darney P.
        • Wan L.
        • Christ M.
        Levonorgestrel capsule implants in the United States.
        Obstet Gynecol. 1998; 92: 337-344
      2. Hatcher RA, Trussel J, Stewart F, et al. Contraceptive technology, 16th ed. New York: Irvington Publishers, Inc, 1994.

        • Vessey M.P.
        • Hannaford P.
        • Mant J.
        • Painter R.
        • Frith P.
        • Chappel D.
        Oral contraception and eye disease.
        Br J Ophthalmol. 1998; 82: 538-542
        • Olsson S.E.
        • Odlind V.
        • Johansson E.
        Androgen levels in women using Norplant implants.
        Contraception. 1986; 34: 157-167
        • Sivin I.
        • Alvarez Sanchez F.
        • Diaz S.
        • et al.
        Three-year experience with NorplantTM subdermal contraception.
        Fertil Steril. 1983; 39: 799-808
      3. Luder CG, Schulz-Key H, Banla M, Pritzes S. Immunoregulation in onchocerciasis: predominance of Th1-type responsiveness to low molecular weight antigens of Onchocerca volvulus in exposed individuals without microfilaridermia and clinical disease. Clin Exp Immunol 1096;105:245–53.

        • Elliot A.M.
        • Nakiyingi J.
        • Quigley M.A.
        • French N.
        • Gilks C.F.
        • Whitworth J.A.G.
        Inverse association between BCG immunization and intestinal nematode infestation among HIV-1-positive individuals in Uganda.
        Lancet. 1999; 354: 1000-1001