CHAPTER 1.1 LITERATURE REVIEW AND OBJECTIVES
1.1.4 SIDE EFFECTS
1.1.4.1 Menstrual Disturbances
Fraser, 1983; Howardet al,1985; Belseyet al,1986;Fraser, 1986b; Salemet al, 1988;
Kaunitz, 1992; Olive and Schlaff,1992; Dateyet al,1995; Be1sey and World Health
Organization Task Force, 1988; Hadisaputra and Affandi,1990; Keller, 1995;Lande 1995;
Polaneczkyetal,1996; Paul et ai,1997; Beksinskaetal,1998; Bigriggetal, 1999;
Chotnopparatpattara and Taneepanichskul, 2000; Danli etal,2000; Kaunitz, 2000;
Beksinskaet ai, 2001a).
Findings from earlier studies have been criticized, with clinical evaluations referred to by Olive and Schlaff (1992) as "crude and inadequate" because, for instance,of the lack of uniformity in definitions. From the mid-eighties methodological advances led to a more standardized approach and more sophisticated analytical procedures (Olive and Schlaff, 1992).In contrast to the prolific amount of published information worldwide,and despite the widespread use of the injectable contraceptive in South Africa, little data on side effects experienced by South African injectable users are published. One very early South African study was undertaken which compared two dosage regimens ofDMPA (150mg every three months and 450 mg every 6 months) (Rallet ai, 1977). This was a large study (n=19875) undertaken from 1970 to 1975 and few side effects were reported. However,the authors point out that a large number of participants were lost to follow-up and it was not known what proportion of these dropped out for personal reasons.
Bleeding disturbances frequently reported are amenorrhoea, irregular bleeding, spotting between periods,unpredictable bleeding patterns, heavy bleeding, prolonged menses (Kaunitz, 1992; Kaunitz, 2000; International Planned Parenthood Federation, 2002). Some side effects (e.g. amenorrhoea) predominate in the early months of use, but with increased duration of use, amenorrhoea becomes very common (Kaunitz, 1992;Kaunitz, 2002). The
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effects of the IPCs on the menstrual cycle result in what has been referred to as
"menstrual chaos" (Fraser, 1986b; Dateyet al, 1995). Tyler (1970, p.3), in referring to
bleeding problems associated with DMP A,states that"Th ese occurrences are so numerous as to be considered an inherent part of the method."
DMPA Studies
Data from menstrual diary records of 314 women using DMP A were analysed by Belsey and the World Health Organization Task Force (1988) and showed that DMPA users had unpredictable menstrual patterns. What is predictable however is that the proportion of woman experiencing excessive bleeding decreases over time (Schwallie and Azenzo,
1973). In the study by Belsey and the World Health Organization Task Force, (1988),the rate of amenorrhoea rose from 8% in the first injection interval to 45% in the fourth. By contrast, prolonged bleeding decreased from 29% in the first injectable interval to 10% in the fourth. Further,a marked inter-regional variation in bleeding patterns was noted. For instance, by the fourth dosing interval amenorrhoea was reported by 25% of respondents from Europe compared with 72% of those from North Africa (Belseyetal,1988). In a study among 108 Thai adolescents (under 19 years) amenorrhoea increased from 7% in the first injection cycle to 58% by the fourth. In the same time-frame, irregular bleeding decreased from 94% to 42% ChotnopparatIJattara and Taneepanichskul,2000).The main side effects reported in a multi-centre clinical trial ofDMPA use among 1994 Chinese women who were followed up for a total of 20294 months were spotting,bleeding, prolonged bleeding and amenorrhoea (Danli et al, 2000). Sixty Thai women between 36 and 45 years were followed for a year and most commonly reported irregular bleeding with DMPA use (Taneepanichskul, 2000).
NET-EN Studies
In a trial conducted from 1968 to 1971 amongst 171 NET-EN users in Egypt, El-Mahgoub and Karim (1972) found that a high proportion (46-71 %) of women using NET-EN had disturbed menstrual cycles. Menstrual irregularities (prolonged bleeding,spotting or amenorrhoea) were the most commonly reported side effects reported in a London-based clinical trial of NET-EN undertaken among 707 women,from 1974 to 1981 (total women months=9024) (Howard etal,1985). In an analysis of clinical trials carried out by the Indian Council of Medical Research from 1981 to 1987,Dateyet al, (1995) determined that NET-EN use (2 monthly and 3 monthly dosage regimen) resulted in disturbances in bleeding pattern in the majority of users (80% during the first year of use). The proportion of women experiencing bleeding disturbances did not improve with prolonged use. Very heavy or prolonged bleeding was uncommon with infrequent bleeding more commonly observed (Dateyet al, 1995).
Comparative Studies
Menstrual irregularities are reported to occur more often with DMPA than with NET-EN use (World Health Organization,1978; Fotherbyet al, 1980b; Howard et al, 1985; Salem etaI1988). A World Health Organization (1978) multi-national comparative clinical evaluation ofthe two injectables found that 71% ofDMPA users and 47% of NET-EN users did not experience even one normal cycle over four injection intervals.Itis important to note that in these studies both NET-EN and DMPA injections were administered every twelve weeks. During the first six months of use, NET-EN was reported to result in more defined cyclic patterns and fewer prolonged bleeding and spotting episodes than DMPA (World Health Organization, 1983). These results were obtained for both NET-EN dosage
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regimens in the WHO multi-national comparative study in which NET-EN was given every 60 days to one group of women and every 60 days for 6 months and then every 84 days to another group of women. On the other hand, Swenson et al (1980) reported that NET-EN, given 10 weeks after the first injection and then every twelve weeks, resulted in more irregular bleeding than DMPA (given every 12 weeks). They found that less than
15% of both DMPA and NET-EN users reported having regular cycles by the fourth injection.
The Multi-national WHO comparative clinical trial (World Health Organization, 1978) found that amenorrhoea occurred significantly more often with DMP A than with NET-EN, with 35% ofDMPA users and 9% of NET-EN users experiencing total amenorrhoea at the end of one year. They found further that the number of women who experienced total amenorrhoea increased significantly over time for both drugs, and that the differenceinthe proportion of women experiencing amenorrhoea with use of the two drugs increased over time (World Health Organization, 1978).Itis important to note that NET-EN was
administered every 12 weeks in this study. This same trial also found that heavier women, who used DMP A, were more likely to experience total amenorrhoea than lighter women, with amenorrhoea occurring in 17% of women under 47kg, in 19% of women 48 to 61kg and in 25% of women over 62kg (World Health Organization, 1978). The relationship between weight and amenorrhoea was not found among women using NET-EN on a 12 week dosing schedule. That efficacy was found to decrease with body weight of NET-EN users (World Health Organization, 1977) has already been mentioned in sub-section 1.1.2.2 above. A later clinical trial undertaken by the World Health Organization (1983) comparing DMPA given at 90-day intervals with NET-EN given every 60 days to one group of women and with NET-EN given every 60 days for 6 months and then every 84 days to
another group of women,reported significantly less amenorrhoea with both groups of NET-EN users than with the DMPA users. Findings from a study undertaken by Swenson et al (1980) in Bangladesh, concurred with the finding of greater experience of
amenorrhoea amongst DMPA users than NET-EN users.
The World Health Organization (1978) reported that DMP A caused significantly more spotting than NET-EN (given every 12 weeks). The later World Health Organization (1983) findings are consistent and significantly longer episodes of bleeding and spotting were found to occur with DMP A than with either ofthe NET-EN regimens used. The experience of spotting is reported to diminish over time (World Health Organization, 1978), especially for DMPA and the NET-EN 60 day regimen (World Health Organization, 1983).
Chinnatamby (1971) reported that leucorrhoea is experienced more by NET-EN users than DMP A users,bearing in mind though that the number reporting this side effect at all was small.
Reviews
Comprehensive reviews highlight the extensive menstrual disturbance that occurs with injectable use (Rosenfie1d,1974; Gray, 1979; Fraser and Weisberg, 1981; Benagiano and Primiero, 1983b;Lande 1995;Bigrigget al, 1999). Kaunitz (2002) encapsulates the evidence well,noting that injectables alter menstrual bleeding patterns, particularly during the first three to six months of use when spotting and prolonged bleeding are common.
Spotting and prolonged bleeding diminish over time,but the incidence of amenorrhoea increases. Bya year after discontinuation of DMPA, regular menstrual cycles are said to be resumed in three quarters of users (Kaunitz,2002).Heavy bleeding is not a common side
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effect ofIPCs,with reported incidences of 1-2% (Fraser, 1983). Menstrual irregularities are reported to occur more often with DMP A than with NET -EN use (Fraser, 1982; Fraser, 1986b).
Amenorrhoea has been found to be more frequent in obese women than in underweight women (Fraser and Weisberg,1981; Benagiano and Primerio, 1983b). Lande (1995) suggests that bleeding patterns with IPC use may differ with ethnicity. For instance he reports that Southeast Asian women using DMP A reported more days of spotting and bleeding than those in the Caribbean, Europe,South East Asia,or North America,and amenorrhoea was reported more often by North African women than by European women.
Conclusion
Bleeding disturbances with IPC use are the norm. Amenorrhoea is the most prevalent menstrual irregularity, especially with DMPA, and incidence increases with duration of use (Table 1.1.3). The weight of evidence suggests that menstrual irregularities are reported to occur more often with DMP A than with NET-EN use. Some studies raise the possibility that factors such as body weight and ethnicity may influence the frequency of bleeding disturbances.