CHAPTER 1.1 LITERATURE REVIEW AND OBJECTIVES
1.1.3 RETURN TO FERTILITY DMPA Studies
1.1.3 RETURN TO FERTILITY
for 285 women who became pregnant after discontinuing the method. However the
authors warn that the number of months to conception may be biased upward as it was not known ifthe subjects, on discontinuing the method, actually tried to conceive
immediately. Schwallie and Azenzo (1973) also found no difference in time to return to fertility between short and long term users ofDMPA.Pardethaisonget al (1980), in referring to Schwallie and Azenzo's (1973) findings and McDaniel and Pardethaisong's (1973) findings, noted that these earlier studies used different study designs, had smaller sample sizes with women of differing ages and that observations were made for shorter time periods. Nevertheless, the findings from these three studies were fairly consistent. In an updated analysis of the data from the 796 Thai women (Pardethaisongetal, 1980), Pardethaisong (1984) concluded that the return of fertility with DMPA is only about a month longer (after the date of the last scheduled injection) than after removal ofthe IUD.
NET-EN Studies
In 81 Egyptian women who had received at least ten doses of NET-EN injections at a dosing interval of84 days, El-Mahgoub and Karim (1972) found that a normal menstrual pattern had been established within 2-4 months. Only seven women in the follow-up study wished to conceive, and four of these became pregnant within 5 to 14 months.
Fotherbyet al (1984) found that 14 of 40 women who stopped using NET-EN were pregnant within 12 weeks of discontinuing the method and 21 women within 6 months and suggested that NET-EN does not impair fertility. The Indian Council of Medical Research (ICMR) (Banerjeeet al, 1986) reported a median time for conception of7.8 months for 69 NET-EN users who had discontinued use because they planned to get pregnant. The dosage regimen of NET-ENused by the women participating in this study is not mentioned. The ICMR also found that the return to fertility was slower in 51
subjects who had discontinued NET-EN because of amenorrhoea. Only 51% of these women conceived within 12 months, compared with 73% of those who discontinued injectable use as they were planning a pregnancy. A difference in the median time for conception of 4 months longer in NET-EN users who had discontinued the method, compared with former copper IUD users, was reported. The authors of this study concluded that NET -EN does not adversely affect the return of fertility (Banerjeeet al, 1986).
Comparative Studies
Few studies have been undertaken which directly compare DMPA and NET-EN in terms of return to fertility. However, in a comparative pilot study carried out by the WHO to determine the pharmacokinetic and pharmacodynamic properties ofDMPA and NET-EN it was found that ovarian function returns more quickly after discontinuation ofNE'P-EN than after DMPA discontinuation (Fotherbyet al, 1980b). Garza-Flores et al (1985) in a comparative study of24 women who discontinued DMPA and NET-EN, found that the mean time to return to ovulation occurred significantly earlier with NET-EN than with DMPA - 2.6 months and 5.5 months respectively " ... overall data was interpreted as demonstrating a clear-cut difference between the two long-acting progestogens in terms of ovulation suppression" p.31. These authors also conclude that neither DMPA nor NET- EN permanently or irreversibly affect ovarian function (Garza-Floreset al, 1985).
Reviews
Several reviews of the reversibility of progestogen-only injectables have been undertaken.
Fraser (l986a, p. 40) stated that "the conception rate curve following DMPA use parallels the normal conception rate curve but is shifted 3-5 months to the right". The reviews
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show no evidence that the injectables cause permanent infertility (Fraser, 1982;Fraser and Weisberg, 1982; Fraser and Hoick, 1983; World Health Organization, 1982; Kaunitz, 1992; Kaunitz, 1994; Fraser, 1986a; Lande, 1995). Nor is it felt that any of the injectables should not be given to adolescent and nulliparous women (Fraser, 1982; Fraser and Hoick, 1983; Kaunitz, 1992;Lande, 1995) and no difference in time to return to fertility has been found when comparing long-term and short-term users (Fraser, 1982; Fraser and HoIck, 1983; Kaunitz, 1992; Lande, 1995).
In a more recent review, Bigrigget
at
(1999), in examining early data, suggest that there is no delay in return to fertility with DMP A use if one considers the methodological bias of early studies, which did not take in to account the date of the last DMPA injection.They state further that "if there is a delay it is not statistically significant and is less than 30 days. According to Hatcheret
at
(1997) return to fertility is delayed by DMPA for about 4 months longer on average compared with the combined OC method, IUD, and condoms.Itis reported that the pregnancy rates for users ofDMPA, the IUD and OCs are the same two years after discontinuation of the method (Lande, 1995).
A South African textbook (Theron and Grobler, 1991; revised edition, 1998),
recommended in the early 1990s by the National Department of Health for training of pharmacists and pharmacy students, gives the average time to pregnancy following administration of the last injection ofDMPA as 9 months and of NET-EN as 7-8 months The average time to pregnancy reported by these authors for no method is 5 months. The South African Medicines Formulary (Gibbon, 2000,p.215) gives a delay of'usually 9 months' for DMPA and 'generally' 6 months for NET-EN and the draft National Contraception Service Delivery Guidelines (Department of Health,2001) records an
average delay of 6-9 months without referring to a particular product. According to the World Health Organization medical eligibility criteria for contraceptive use, the median delay in return to fertility is ten months from the date of the last injection for DMPA and six months for NET-EN (World Health Organization, 2000).
The approved package insert for the NET-EN product (Nur-Isteratef'jregistered for use in South Africa states that "Following discontinuation, normal ability to conceive usually returns 7-8 months after the last injection" (Schering,1992). The Depo-Proveraf'package insert states that"Restoration of normal menstrual cycling may take from 5 to 28 months after the last injection..." (Pharmacia and Upjohn, 1993). There is no reference to reversibility or return to fertility in the Petogen®package insert (Intramed, 1993).
Conclusion
The delay in return to fertility with progestogen-only injectables appears to be only a few months longer than with oral contraceptives, IUDs and condoms, regardless oflength of use. The methodological bias of early studies which did not take into account the date of the last DMPA injection should be noted. Further, earlier studies also tended to have smaller sample sizes with women of differing ages, and in some cases observations were made for short time periods. The search of the literature on return to fertility revealed no publication of primary data after 1986. The existing evidence thus seems to be based entirely on these early studies.Published studies also used different study designs.While there is little direct comparative data on the delay in return to fertility between DMPA and NET-EN users,it seems that NET-EN is likely to result in a slightly shorter delay, but there appears to be little long term difference.
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