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Special Session on Quinacrine Nonsurgical Sterilization at XV FIGO World Congress of Gynecology and Obstetrics Copenhagen August 7, 1997 (continued)
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Risk of Ectopic Pregnancy
Do Trong Hieu, MD, PhD
Director
MCH and Family Planning
Ministry of Health
Hanoi, Vietnam | |  |
We previously reported a field trial of 31,781 cases of quinacrine sterilization (QS), primarily conducted in rural areas of Vietnam from 1989 to 1992. The method was well accepted with very few serious complications and pregnancy failures similar to that of IUDs in Vietnam. A major concern was risk of ectopic pregnancy, of which there were 19 in this study, including 6 in Nam Ha Province. Although there was no case fatality in the 19 ectopics reported, a 20th, occurred after the study period, and the woman died. We decided to do an additional assessment of ectopic pregnancy risk in Nam Ha Province where data on IUDs were already available.
Among 18,000 IUD users the ectopic pregnancy rate was 0.14% compared to 0.13% among 4511 QS cases. The proportion of pregnancy failures that were ectopic among the QS cases was 3.5%. The ectopic pregnancy incidence among QS users was 0.89 per 1000 woman-years.
Since 1990, surgical female sterilization has been made more widely available in Vietnam. While surgical sterilization has been associated with its expected procedure case fatalities, and none were reported for QS, we are interested in knowing the relative ectopic pregnancy risk between QS and surgical sterilization, as these ectopics may have a 5% fatality risk. We are at present analyzing data on 830 ectopic pregnancies between 1994 and 1996 in Nam Ha Province, the results to be announced at this Congress. Ectopic pregnancy risk for laparoscopic sterilization in the United States is reported as 0.7 to 0.8 per 1000 woman-years. The percent of pregnancies that were ectopic in this report was 32.9% Recent reports of QS show a lower pregnancy failures rate than we experienced, possibly due to improvements in protocol. This should result in lower QS ectopic pregnancy risk.
Because ectopic pregnancy risks vary greatly by time and place, we shall be reporting them for both QS and surgical sterilization in Nam Ha Province for the same time period.
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Quinacrine Sterilization: Experience among High Risk Women
Ashi R. Sarin, MD
Government Medical College
Patiala, India | |
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Most clinical trial reports at this Congress, including those on quinacrine sterilization (QS), are conducted among healthy women or at least women of average health in their area. You may wonder how we came about designing a QS trial especially for high risk women. Please consider these aspects of our situation at a government medical school in a predominantly rural area of the Punjab in India. First, our government advises against surgical female sterilization for women with hemoglobin less than 7 g/dl, but 57% of women in our area are so anemic. Second, as a referral center we see women whose life would be endangered by another pregnancy but who are very poor risks for any surgery. Third, sterilization failures are frequently referred to us, but it is known that previous pelvic surgery increases the risk of a serious complication for female surgical sterilization 2.7 times. Fourth, we find many women who desire no more children who just fear any additional surgery, in spite of obvious need for sterilization. And finally, our department has a leadership tradition in promoting choice among well-informed women. One must also consider the general situation of women and their children in the Punjab; 52% are illiterate with mean number of years of schooling being 2.0 years. Our women had an average of 2.9 children compared to 3.4 for all of India, but 46% of our children under 4 years of age are underweight and 40% are stunted. Less than half of women who say they want no more children are actually protected by sterilization.
It was in this context and after reviewing published reports showing safety and reasonable efficacy of QS that we decided to make this method available in our department.
During an ongoing trial we have studied until May 31, 1997, 132 women of reproductive age who had a transcervical insertion, by a modified IUCD inserter, of seven quinacrine pellets (252 mg) and two diclofenac sodium pellets (50 mg), both supplied by the International Federation for Family Health. These were two insertions at monthly intervals, along with one 150 mg injection of depot medroxyprogesterone acetate (DMPA) with the first one as an additional contraceptive. Ninety cases were considered at high risk for surgery (mainly severe anemia, cardio-vascular disease and sepsis); 27 had voluntarily chosen a nonoperative procedure; and 15 were cases of earlier laparoligation failure. No serious side effects were encountered and these were mainly menstrual irregularities due to simultaneous DMPA administration. The mean follow-up period was 19.7 months. There have been no pregnancy failures to date. We conclude that quinacrine sterilization is a promising alternative to surgery for women at high risk of associated complications and for those desiring sterilization, but fearful of surgery.
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Medroxyprogesterone as Adjuvant to Quinacrine Sterilization
Biral Mullick, MBBS, PhD
Nitai R. Bairagi, DMS
Indian Rural Medical Association
Calcutta, India | |
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Our early trials of a single insertion protocol were unsuccessful until an initial comparison of depot medroxyprogesterone (DMPA) 150 mg IM and 3 cycles of oral contraceptives (OCs) as adjuvants to quinacrine nonsurgical female sterilization was completed. This was a before-after trial of single transcervical insertion of quinacrine 252 mg. The OC component was conducted in 1992-1993 and the DMPA component in 1993-1994. An important and statistically significant decline in pregnancy failures from 8.2 (SE 3.69) per 100 women at 18 months to 0.55 (SE 0.55) was noted in favor of DMPA. We had also noted in a separate before/after trial that insertion technique can influence efficacy. In this 900 case trial the insertion technique was changed after 495 cases from midlevel uterine placement of quinacrine pellets to fundal placement. A statistically significant decline in pregnancy failures from 4.4 (SE 0.92) to zero occurred per 100 women at 24 months. In order to separate the effects of DMPA and insertion technique a systematic allocation of OCs for three months or DMPA injection was administered for every other case among 635 women in 1995-1996 in a single insertion protocol. The pregnancy failures showed no statistically significant difference between the DMPA and OC groups, 3.6 (SE 1.5) and 2.4 (SE 0.9), respectively, at 18 months. We conclude that a single insertion of quinacrine with either DMPA or OCs as additional contraception for 3 months provides acceptable efficacy if fundal insertions of quinacrine pellets are consistently made. Randomized trials of insertion techniques are needed.
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Quinacrine Sterilization in Faisalabad, Pakistan
Ahmed Bashir, MD
Mother and Child Welfare Association
Faisalabad, Pakistan | |
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Quinacrine sterilization (QS) was introduced in Faisalabad in the fall of 1989 by the late Professor Altaf Bashir, founding President of the Mother and Child Welfare Association (MCWA) and then Professor of Obstetrics and Gynaecology of Punjab Medical College. Initially, a careful trial was undertaken in the medical college and in 1990 QS was gradually made part of a broad maternal and child health program in urban and rural areas of Faisalabad. This program had already achieved the sharpest decline in maternal mortality in all of South Asia and a contraceptive prevalence far higher than the average for Pakistan. Despite this, the prevalence of female sterilization in rural areas and neglected urban areas of Faisalabad remained a low 3%.
Several aspects of this comprehensive MCH program should be mentioned. Two major efforts were the training and retraining of traditional birth attendants (TBAs) and the investigation of all maternal deaths. As a result TBAs became the main referral source for contraceptive services. The investigation of maternal deaths included a report to the community of the deceased woman and no doubt had the effect of sensitizing providers of maternal care in Faisalabad. MCWA had an established network of MCH centers with trained nurse midwives who were already experienced in IUD insertions and sterilization counseling. Adding QS to this program seemed an attractive way to meet sterilization demand in the city.
Because of reports that the need for multiple insertions of quinacrine pellets was not well documented at that time and the overwhelming acceptance of this method by Faisalabad women, it was decided to use a single insertion protocol in this service program. The number of acceptors grew rapidly from 2100 in 1990 to a total of 10,000 cases by the end of 1996. This is the largest single insertion experience of QS. The initial service program monitoring showed pregnancy rates of 2% to 3% with no serious complications. Approximately 1/3 of pregnancy failures were continued to term, but most of the women requested pregnancy termination and surgical sterilization which were performed without charge.
A convenience sample of 1100 cases completed by 1996 at our 14 MCH centers was selected for an additional follow-up visit in 1997. The results show efficacy lower than that reported for other single insertion studies indicating the need for re-training of our clinicians, who were mainly nurse midwives.
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Risk/Benefit Assessment: The Case for Quinacrine Sterilization
Elton Kessel, MD, MPH
Secretary General
International Federation for Family Health | |
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In daily life, we are constantly required to make judgments based on a balance between the risks and benefits of our activities. This is especially true of medical decisions in both therapy and prevention. It is equally germane when we consider the use of a new drug. Dr. Tore Godal, Director of the UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Disease, insists there is no such thing as one global standard specifying some global level of low risk. Rather, in each local case, a rational analysis of risk against benefit is needed (1). He provides examples from trials of treatments of tropical diseases. The same applies to any preventive measure, including contraception. The difference is that in therapy the patient is known, whereas in prevention we are only aware of the number of patients benefited or at risk. Of course, risks and benefits change over time for various local situations. I shall provide an update for risks and benefits of quinacrine sterilization (QS) at this time for countries with diverse economies.
QS involves transcervical placement of quinacrine pellets (252 mg) in the proliferative phase of the menstrual cycle, using a modified Copper T IUD inserter. Most protocols require a second insertion a month later and 3 months' additional contraception such as OCs. Over 100,000 monitored QS cases have been completed (2), without a case fatality and with lower rates of serious complications than surgical sterilization. In particular, the risk of ectopic pregnancy among failures is lower for QS than for surgical sterilization (3). Efficacy is also lower for QS, but the difference has been narrowing and is presently estimated as about one pregnancy per 100 women at 2 years for QS when newer protocols are followed by well trained clinicians (4), compared to 0.84 for surgical sterilization (5). While risks of a new contraceptive may be similar, although not identical, for different locales where it is to be used, the benefits vary greatly. In a developing country with low contraceptive prevalence and high maternal mortality, the benefits are considerable, as a new contraceptive method can raise contraceptive prevalence and thereby lower maternal deaths. If each additional sterilization prevents 2 pregnancies and maternal mortality is 5 per 1000 live births, then each 1000 additional QS procedures prevents approximately 10 maternal deaths. By the same argument, few maternal deaths are prevented in an industrialized society with high contraceptive prevalence and low maternal mortality.
Lacking for QS is completion of standard, modern toxicology studies for intrauterine use. The United States Food and Drug Administration requires as a next step a rodent carcinogenicity study, estimated to cost 1 million dollars. Customarily, pharmaceutical companies pay for this type of research. But, because QS is already in the public domain and cannot be patented, no company will make such an investment. There is, however, some long-term follow-up of QS cases for up to 14 years in Chile, where Dr. Jaime Zipper developed the method (6). In this study the observed to expected ratio for cancer was 1.44 with 95% confidence limits of 0.84 to 2.30. The study concluded that no evidence was found of excess cancer risk associated with quinacrine pellet sterilization.
One should also be aware of limits of toxicology studies in judging risks of QS. These studies have high sensitivity; that is, they are likely to be positive if the drug tested does cause cancer in rodents and humans. What is of more interest for quinacrine, which is mutagenic, is the level of false positive results. For this, knowledge of the specificity of the toxicology studies is required, but is actually unknown. Toxicologists warn that their studies are of less value than human experience (7). They are most useful in assessing risks of a new drug. Toxicologists also caution that duration of exposure is important in identifying risk. Carcinogenetic potency of a drug appears to be less important than duration of exposure (8). Exposure to quinacrine in QS is minimal: two insertions of a low dose in the life of the woman. I am unaware of a report of any drug given once or twice at a therapeutic dose as causing cancer in humans.
Quinacrine by oral administration has been ingested by millions of adults and children at higher doses than required for QS. Its use as an antimalarial, helvetica drug in World War II was critical to the Allied victory. If modern toxicology studies were applied to quinacrine today as a new drug for oral use it might not have reached the market, despite the present reemergence of malaria. In our day, maternal mortality and rapid population growth are emergencies comparable to those during World War II.
It is time for additional countries and NGOs to conduct this risk/benefit assessment adapted for their own local conditions.
References
1. Godal T. Fighting the parasites of poverty: public research, private industry, and tropical diseases. Science. 1994:264:1864-6.
2. Kessel E. 100,000 quinacrine sterilizations. Adv Contracept 1996; 12:69-76.
3. Kessel E. Ectopic pregnancy. Am J Obstet Gynecol 1996 (letter); 175:1675.
4. Kessel E. Quinacrine sterilization (QS) failures estimated as twice that of surgical sterilization. Quinacrine Sterilization Newsletter July 1996; 1:4-5. International Federation for Family Health, 720 Deer Meadow Road, Leasburg, NC 27291.
5. Peterson H, Zhisen X, Hughes J, et al. The risk of pregnancy after tubal sterilization: findings from the U.S. Collaborative Review of Sterilization. Am J Obstet Gynecol 1996; 174:1161-70.
6. Sokal DC, Zipper J. Guzman-Serani R, Aldrich TE. Cancer risk among women sterilized with transcervical quinacrine hydrochloride pellets, 1988-1991. Fertil Steril 1995; 64:324-34.
7. Tomatis L, Bartsch H. The contribution of experimental studies to risk assessment of carcinogenetic agents in humans. Exp Pathol 1990; 40(4):251-66.
8. Bartsch H, Malaveille C. Prevalence of genotoxic chemicals among animal and human carcinogens evaluated in the IARC Monograph series. Cell Biol Toxicol 1989; 5:115-27.
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