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Special Session on Quinacrine Nonsurgical Sterilization at XV FIGO World Congress of Gynecology and Obstetrics Copenhagen August 7, 1997
The International Federation for Family Health (IFFH) conducted a Special Session on Quinacrine Nonsurgical Sterilization at the XV FIGO World Congress of Gynecology and Obstetrics in Copenhagen August 3-8 1997.
A comprehensive update on quinacrine sterilization (QS) was presented, with 30 minutes reserved for discussion. The speakers include Dr. Jaime Zipper, developer of QS, Dr. Elton Kessel, Secretary General of IFFH, and four researchers with broad QS experience: Dr. Do Trong Hieu of Vietnam, Drs. Ashi Sarin and Biral Mullick of India, and Dr. Ahmed Bashir of Pakistan. A summary of their presentations appears on these pages.
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Session Chairman
Dr. J. K. Jain
President,
International Federation for Family Health
New Delhi, India | |
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The International Federation for Family Health has been the principle organization supporting and documenting clinical trials of quinacrine sterilization (QS), conducted primarily in developing countries where the benefits of the procedure far outweigh theoretical risks of QS. The method is now well documented to be easy to deliver, economical, highly acceptable, reasonably effective and safer than surgical sterilization in terms of serious early complications or risk of ectopic pregnancy among sterilization failures.
While on one hand the enormous research data emanating from more than 100,000 cases cannot be ignored, one must take into account the validity of World Health Organization objections. WHO is not opposed to the idea of contraceptive research. It insists only that remaining toxicological investigation of intrauterine administration of quinacrine, including the rodent carcinogenicity studies required by the United States Food & Drug Administrator (FDA), be completed before the method's wider application is permitted in human beings. Unlike the Special Programme on Research in Tropical Diseases of WHO, which undertakes a risk and benefit analysis into account, the Special Programme in Research and Research Training in Human Reproduction refuses to deviate from its standard protocol. With all due respect to WHO's objections, one ought at the same time to reach for solutions to the problem. Why have the remaining toxicological studies, including those with rodents, not been undertaken? Because it costs about 8 million U.S. dollars.
This drug as well as the method are in the public domain and cannot be patented. Consequently, no pharmaceutical company would benefit from funding this research. But women would benefit. If QS holds the potential to reduce their morbidity and mortality from unwanted pregnancies and also helps population control programs, especially in developing countries including their rural areas, why, then, are public resources not mobilized for the purpose?We appeal to United Nations agencies, governments and foundations to supply this needed support.
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Session Co-Chair
Sarah G. Epstein,
Washington, DC
USA | |
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I have been aware of family planning for a long time as my father, Dr. Clarence Gamble, was an advisor to Margaret Sanger and later founder of Pathfinder International. With training as a psychiatric social worker, I have devoted many hours to counseling clients at Planned Parenthood and patients at the Washington, DC, General Hospital. Overseas, I have visited and reviewed Pathfinder projects. Today, I recognize the need for a sure, safe, inexpensive, non-surgical method of sterilization. I think quinacrine sterilizations should be offered as a choice, with proper counseling, to all women seeking an end to child-bearing.
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Development of the Method
Jaime Zipper, MD
Department of Physiology and Biophysics
Faculty of Medicine
University of Chile and Sotero del Rio Hospital
Santiago, Chile | |
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My interest in developing a method of nonsurgical female sterilization in the 1960s was to prevent the large numbers of septic abortions that filled our gynecologic wards in Chile and claimed the lives of many women. A high proportion were high parity women who obviously did not want this last pregnancy. Abortion remains illegal to this day in Chile. An additional way to prevent further unwanted pregnancies was clearly needed. I looked for an agent that was cytotoxic to tissues that might close the tubal ostia. Several were tried experimentally in rats by depositing a solution of the agent in one horn and using the other as a control. It became clear that such agents upon local application could prevent fertility. The next step was a search for a nontoxic agent. We chose quinacrine as it had been demonstrated to cause adhesions when injected in the pleural cavity and its safety for oral use as an antimalarial, helvetica had been well documented.
In the early 1970s a first clinical trial was conducted of a quinacrine slurry consisting of 1.5 g quinacrine in 5 ml of xylocaine instilled transcervically at the fundus by syringe and 4 mm cannula. Repeat instillations were made one and six months after the first instillation. In spite of these repeat applications there was a pregnancy rate of 7.1 per 100 women at 24 months and a 2% incidence of cortical excitation immediately after first insertions. We hypothesized that in some cases the slurry was entering the circulation through an open sinus in the endometrium.
This led to a change to pellet form of quinacrine to eliminate pressure on insertion. A Copper T IUD inserter was used for transcervical insertion of these pellets, generally seven pellets of 36 mg or 252 mg per insertion. This resulted in elimination of cortical excitation and reduction of pregnancy failures to 3.1 per 100 women at 12 months. Other investigators in 19 other countries have by now conducted trials of the quinacrine pellet method, demonstrating its safety in terms of early complications and further improvement of efficacy.
My own recent work has turned to investigation of risk of cancer for quinacrine sterilization (QS). This has included long-term follow-up of 1,514 QS cases for up to 14 years resulting in an observed to expected ratio for cancer of 1.44 with 95% confidence limits of 0.84 to 2.30, which does not indicate an increased cancer risk at this time. However, additional follow-up is needed to detect any divergence in cancer risk between QS cases and controls.
An analysis of cytological records of 1,061 QS cases and other women at Sotero del Rio Hospital in Santiago shows the incidence of high grade intraepithelial squamous lesions, precursors of cervical carcinoma, in QS cases as 2.74% compared to controls of 3.88%, suggesting no increased risk of cancer of the cervix for QS.
A recent review in this hospital of records for endometrial cancer from 1991 to 1995 among QS cases (N = 880) and surgical sterilization cases (N = 501) shows six of endometrial cancer for surgical cases and none for QS.
We also studied the effect of oral quinacrine on transplantable TAS tumors in mice. Quinacrine was found to inhibit the growth of such experimental tumors, whereas chloroquine accelerated their growth.
The International Agency for Research on Cancer (IARC) investigated the carcinogenic risk of acridine orange, a compound with the same basic acridine structure of quinacrine but not the alkyl side chain. It was concluded that there was no evidence of acridine orange carcinogenicity in the long-term carcinogenic assays in rodents. The United States Food and Drug Administration (FDA) had conducted a long-term assay in rats of oral quinacrine with no evidence of carcinogenicity.
These studies convince me that there is either no risk of cancer attributable to QS or such risk must be very low. Whatever the estimated cancer risk is, it needs to be compared to benefits of QS in the specific locale in which it is used.
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Overview of first 100,000 Quinacrine Sterilization Procedures
Elton Kessel, MD, MPH
Secretary General
International Federation for Family Health
Leasburg, North Carolina | |
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Quinacrine pellet sterilizations were first reported by Dr. Jaime Zipper in 1980. Since then over 100,000 procedures have been performed in 20 countries without a case fatality and with lower serious complications then for surgical sterilization. Gradually a standard protocol has evolved which is now described in a training video and manual. This report reviews research leading to this standard protocol and some remaining tasks for full acceptance of QS.
The presently accepted QS protocol calls for two monthly transcervical insertions of 252 mg quinacrine as seven 36 mg pellets deposited at the fundus in the proliferative phase of the menstrual cycle. This is followed by 3 months' supplementary contraception from the first insertion.
There is evidence from both prospective clinical trials and prehysterectomy studies that efficacy is directly related to dose of quinacrine; up to 324 mg is well tolerated. However, prehysterectomy studies show tubal damage extends beyond the intramural segment of the tube in a high proportion of cases using this higher dose. The question remains as to whether acceptable efficacy can be achieved within the standard 252 mg and the higher amount be reserved for the special circumstances of some women.
Several clinical trials show a halving of failures for each additional insertion up to three. A number of well controlled 2-insertion trials show efficacy of about one pregnancy failure at two years of use, which is similar to that reported for laparoscopic sterilization of 0.84. Single insertion trials have produced a wide range of failures, the most common being 5 per 100 women at 12 months. The only randomized trial of single vs two insertions was conducted in Indonesia showing a life table failure rate of 4.69 (SE 1.26) for single insertion at 12 months compared to 1.12 (SE 0.79) for two insertions. However, 11 of the 31 pregnancy failures for single insertion and all 3 pregnancy failures for two insertions occurred in one of the six cooperating centers.
In a large field trial in Vietnam wide variation in efficacy by inserting clinicians was first noted. Two main techniques were used in this trial, one following the practice for placement of Copper T IUDs resulting in a column of quinacrine pellets from the fundus to the lower uterine segment of the uterus. The other involved introducing the loaded inserter to the fundus, withdrawing it 1/2 cm and then, holding the inserter straw steady, slowly advancing the plunger. In this way, all pellets are deposited at the fundus. We are still lacking a randomized trial of these two insertion techniques, but clinical trials using one or the other of them suggest that depositing all pellets at the fundus provides greater efficacy.
In reviewing several large clinical trials it was noted that pregnancy failures were higher in the first 3 months of use than in subsequent 3 month periods. In addition, a prehysterectomy study showed a higher rate of tubal closures by hystopathology the longer the insertion to hysterectomy interval. It was estimated from this study that it took at least 6 weeks for a high proportion of tubal closures to occur. This led to the recommendation for 3 months' supplementary contraception from first insertion as part of the standard protocol. A randomized trial with and without such supplementary contraception has not yet been reported.
There is great variation in incidence of reported specific side effects. All are transient and easily treated. They include uterine cramping similar to IUD insertions, backache, vaginal bleeding, fever, headache and vertigo. Pruritis is sometimes reported in the vulvar area, apparently of allergic origin from vaginal discharge of dissolved quinacrine. Amenorrhea or oligomenorrhea has been reported, generally lasting not more than five months.
Using life-threatening complication definitions of the Centers for Disease Control and Prevention, QS in Vietnam compares favorably with laparoscopic sterilization in the United States, being 0.03% vs 1.7%, respectively. It is estimated that hematometra occurs in one in 5000 cases and a generalized allergic reaction after the second insertion in one in 30,000 cases. Accidental perforation of the uterus and deposit of quinacrine in the peritoneal cavity has not been life-threatening but associated with tinnitus and severe lower abdominal pain for up to 24 hours. Repeated insertions led to synechiae which are, however, generally asymptomatic. Transient endometrial lesions have been detected by hystoscopic examination.
The risk of ectopic pregnancy for QS is far lower than such risk in a noncontracepting population. In the Vietnam QS field trial the ectopic pregnancy risk in Nam Ha Province was 0.89 per 1000 woman-years compared to an annual incidence of 0.7 or 0.8 per 1000 woman-years for laparoscopic sterilization in the United States. Since the Vietnam trial the QS failure rate is much lower, suggesting that present ectopic pregnancy risk is lower for QS than for laparoscopic sterilization.
Wherever QS has been introduced as an additional option for women it has been well accepted. In Nam Ha Province, Vietnam, QS was chosen 11 to 1 over surgical sterilization.
Only Chile has approved use of QS in its government hospitals. Other QS procedures are done under official phase 2 trials, as in Indonesia, or as medical school research, or by nongovernmental organizations that have conducted their own risk/benefit assessment and decided QS is appropriate technology for their circumstances. These decisions follow guidelines of the United States Food and Drug Administration (FDA) which permits "off label" use of drugs, i.e. for purposes other than that officially approved, at the discretion of the physician. In most countries quinacrine is approved for treatment and prophylaxis of malaria.
For approval as a sterilization method, the FDA requires as a next step a rodent carcinogenicity study, which will cost one million dollars and take three years to complete.
Benefits of QS outweigh its estimated risks, such as carcinogenicity. Use of QS continues to spread in developing countries where it has the highest benefit/risk ratio.
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