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Contraceptive Use and Subsequent Fertility*
FERTILITY AND STERILITY Copyright © 1977 The American Fertility Society
Vol. 28, No.6, June 1977
Printed in U.SA.
CONTRACEPTIVE USE AND SUBSEQUENT FERTILITY*
GEORGE R. HUGGINS, M.D.t Division of Human Reproduction, Department of Obstetrics and Gynecology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104
Partially because of the continuing reports in both the lay press and scientific publications, there seems to be a shifting of preference away from the oral contraceptives and the intrauterine devices to barrier methods. Usage of the IUD decreased 4% from 1974 to 1975 in the United States l (Table 1). It is still premature to document decisively that this indeed represents a major and continuing shift in attitudes and usage patterns. This past year one study by Tietze et aU has indicated that the "safest" method of contraception is the use of a barrier device (condom or diaphragm) backed up by first-trimester abortion in the event of a method failure and an ensuing unwanted pregnancy. Several assumptions are made in their article which are valid for only certain segments of the population in the United States. One assumption is that all patients who experience an unwanted or unplanned pregnancy will elect first-trimester abortion. The recent large-scale study by Vessey et al. 2 showed that, among parous women who experienced a single unplanned pregnancy as a result of method failure, more than one-half elected to carry their pregnancies to term (Table 2). The maternal mortality rate for term pregnancies is of course much higher than the mortality rate for the current conventional methods of contraception, including oral contraceptives and IUDs. A second assumption is that all patients experiencing a method failure can readily obtain firsttrimester abortion. Experience in this country, as
The issue offertility following contraceptive use is of utmost importance to any patient or couple seeking advice as to the "best" method of contraception for them. Few things are as disheartening to a couple and their physician as the discovery that the couple has an infertility problem after having postponed their childbearing functions for many years to achieve financial, social, or educational goals. The late discovery of an unsuspected infertility problem often occurs in patients who have utilized long-term steroidal contraception, an intrauterine device (IUD), or a combination thereof. Contraception usage today is heavily concentrated in the utilization of oral contraceptives or intrauterine devices. In fiscal year 1975 over 3.8 million women in the United States were using organized family planning services delivered primarily through the efforts of Federally subsidized programs and hospitals, health departments, and free-standing clinics. Planned Parenthood affiliates accounted for approximately 25% of patients served and Health Department clinics for 42% 1 Vessey and co-workers2 analyzed contraceptive usage among 17,000 women in Great Britain and found 56% using oral contraception, 25% using the diaphragm, and 19% using IUDs. Patients obtaining contraception from private physicians also elect oral contraceptives in very high percentages. In addition to the preventive contraceptive methods, approximately 1 million elective abortions are performed each year in the United States. 3
TABLE 1. Percentage Distribution of Contraceptive Methods Used by Patients-Organized Programs, Fiscal Year 1975
Received April 12, 1977. *Supported in part by Grant 103-HOOO, 217-03 from the Department of Health, Education and Welfare, United States Public Health Service (Region III). tReprint requests: G. R. Huggins, M.D., Department of Obstetrics and Gynecology, Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, Pa. 19104.
603
Contraceptive
%
Oral IUD Sterilization Other None
71
10 1 10 8
604
HUGGINS
June 1977
TABLE 2. Outcome of Singleton Unplanned Pregnancies in Parous Women According to Method ofContraception 2 Whi{:h Failed Contraceptive Group and outcome
Oral
Diaphragm
IUD
% pregnancies
Live birth Normal Malformed Stillbirth Miscarriage Ectopic gestation Subtotal Termination Total
81.9 4.5 0 13.6 0
78.3 1.8 1.8 18.1 0
33.0 0.9 1.7 55.7 8.7
100.0 (166)
100.0 (115)
(8)
(56)
(50)
(30)
(222)
(165)
100.0 (22)a
aNumbers of pregnancies are shown in parentheses.
well as in others, has demonstrated repeatedly that many patients are unable, for a multitude of reasons, to obtain first-trimester termination and are forced to utilize second-trimester termination. These, of course, carry with them a significantly increased incidence of maternal morbidity and even mortality. Both oral contraceptives and IUDs have been implicated in a number of possible complications which relate not only to immediate morbidity and mortality rates during their usage, but also to subsequent effects that usage may have on fertility. Of equal concern is the question of possible chromosomal damage and resulting fetal malformations following the use of a contraceptive modality. HORMONAL CONTRACEPTION
The issues considered with regard to hormonal contraception are (1) epidemiologic problems associated with studies on safety of oral contraceptives, (2) chromosomal abnormalities, (3) masculinization of the female fetus, and (4) subsequent fertility and amenorrhea.
Epidemiologic Problems Associated with Studies of Safety of Oral Contraceptives The causal association between any drug ingestion and a subsequent increased incidence of fetal malformations or other pathologic states is extremely difficult to "prove." Siegel and Corfman5 have outlined the problems inherent to detecting a 2-fold increase in drug-induced side effects when the annual incidence of the specific effect and the number of patients needed for follow-up in order to establish this relationship prospectively are considered. The same analogy may be used in at-
tempting to detect a causal relationship between drug usage and the subsequent incidence of fetal malformations. For any given lesion with a low rate of occurrence the sample size must be large (Table 3).
Oral Contraceptives and Chromosomal Abnormalities There have been sporadic reports and speculation of various fetal malformations occurring in the offspring of women taking oral contraceptives. These have included (1) an increased incidence of fetal chromosomal abnormalities in spontaneously aborted fetuses among women who had recently discontinued oral contraceptives6 ,7; (2) masculinization of the genitalia of female offspring of women inadvertently taking oral contraceptives during early pregnancy8; (3) a possible relationship between exposure to combined oral contraceptives and progestin derivatives during pregnancy and birth defects (vertebral, anal, cardiac, tracheal, esophageal, renal, and limb [VACTERLl anomalies)9.13; and (4) the possible occurrence of Down's syndrome. 14 Incidence of Fetal Chromosomal Abnormalities. The data ofCarr6 and Poland and Ash 15 suggesting an increased incidence oftriploidy, other chromosomal abnormalities, and growth disorganization in the abortuses of a small number of women taking oral contraceptives raised valid concerns TABLE 3. Minimal Sample Size To Detect a 2-Fold Increase in Side Effects or Malformations' Annual incidence (rate in controlsll.OOO)
No. followed for 1 year
0.22 0.56 0.75 2.0 30.0
85,000 35,000 25,000 9,000 600
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CONTRACEPTIVE USE AND SUBSEQUENT FERTILITY
over a causal relationship between previous contraception and these defects. In the initial report of the Royal College of General Practitioners16 on oral contraceptives and health, published in 1974, the incidence of chromosomal abnormalities in the offspring of2,583 pregnancies in pill users did not differ significantly from that in 7,405 pregnancies in control patients. Their latest reporP7 compares the outcome of 5,500 pregnancies in previous pill users with that of 11,000 pregnancies in controls. There were 86 congenital abnormalities, or a rate of 19.2/ 100,000, in former pill-users versus 177, or 19.40/ 100,000, in the controls. The ratio of these rates is 1.03 and is not significant. Analysis of the types of abnormalities reported revealed no significant grouping in the VACTERL types in either group. Klinger et al. 18 recently conducted chromosome studies on 3080 products of conception; these consisted of both newborn infants and medically induced abortuses. Mothers were divided into three groups: (1) those who had used oral contraceptives, (2) those who had used nonhormonal contraceptives, and (3) a group which had not used any contraceptive. Chromosomal analyses were completed on 1670 newborn infants, 1233 products of induced abortion, 98 products of spontaneous abortion, 68 products of abortion of unknown type, and material from 11 ectopic pregnancies. The types of oral contraception used by the women in the newborn and induced-abortion groups were similar. These included a wide spectrum of lowdose pills, approximately 6% sequential preparations, and approximately 5% both combined and sequential preparations. An abnormality rate of 6.8/1000 was found for conceptions in women who had used oral contraceptives. The authors concluded that this incidence could easily have been due to chance (P > 0.25). The abnormality rate for the conceptuses of women who had never used any contraceptive was 4.9/1000. An interesting finding was that the incidence of abnormalities decreased as the length of oral contraceptive use increased. The observed abnormality rates in this study agree closely with the rate of 5.6/1,000 obtained from over 43,000 liveborn babies reported by Jacobs et al. 19
Down's Syndrome. Recently, Janerich et al.14 studied the question of Down's syndrome and oral contraceptive usage. A group of 103 mothers whose infants had Down's syndrome was compared with an equal number of matched controls consisting of mothers whose infants lacked Down's syndrome. The methodology in this study was the
605
same as that used in their former report on the incidence of limb-reduction defects.9 The incidence of pill users in the control group was actually higher than that in the group whose infants had Down's syndrome, but was not considered significant. Carr6 reported an increased incidence oftriploidy in a small number of women taking oral contraceptives. Poland and Ash 15 noted an increased incidence of abortuses with chromosomal abnormalities and growth disorganization. Reports by Garcia,20 the Royal College of General Practitioners,17 Janerich et al.,14 and others12, 18, 19, 21, 22 are somewhat reassuring in pointing out that there are no conclusive data to associate previous pill usage with an increased incidence of VACTERL defects, Down's syndrome, or triploidy in live-born infants. This does not, however, settle the question of the incidence of defects in patients inadvertently taking oral contraceptives while pregnant. This is an area of valid concern, and such individuals need to be closely monitored as these pregnancies occur and are reported. Masculinization of the Female Fetus. In 1960 Wilkins8 reported 70 cases of masculinization of female infants associated with oral administration ofprogestins to mothers during the first trimester of pregnancy. Of these, 34 cases were associated with the use of 17a-ethinyltestosterone, 35 cases were associated with the administration of Norlutin (17a-ethinyl-19-nortestosterone), and 1 case was associated with the administration of norethynodrel-mestranol (Enovid). Patients had received 20 to 25 mg/day of 17a-ethinyltestosterone for varying periods of time; those patients treated with Norlutin had received doses of 10 to 40 mg/day. In addition to the progestational agents, some of the patients had received high doses of diethylstilbestrol, ethinylestradiol, or conjugated equine estrogens. The clinical findings included phallic enlargement and, in some cases, varying degrees of labioscrotal fusion. Subsequent to the report by Wilkins 8 and others, the progestational and estrogenic dosage of the oral contraceptives has been dramatically reduced. It is difficult to find any case reports or valid studies in the literature at the present time that document clinically evident masculinization offemale infants born to mothers taking combined oral contraceptive pills containing 1 mg of a progestogen during early pregnancy. Although we are unable to detect gross fetal abnormalities, it is possible that the ingestion of these compounds might produce minor abnor-
606
June 1977
HUGGINS
malities not detectable by gross physical examination. Prudence, therefore, dictates that oral contraceptives be discontinued in any patient suspected of being pregnant. Such patients must, however, be provided with an alternative method of contraception.
val between discontinuation and subsequent conception in oral contraceptive users.
Relationship between Oral Contraceptive Use, Progestin Administration, and Congenital Birth Defects. In 1974 J anerich et al. 9conducted a study of 108 mothers who had delivered infants with congenital limb-reduction defects and compared them with 108 controls who had delivered normal infants. The ingestion of exogenous steroids was investigated. Among the mothers with malformed children, there were 15 patients who had a history of exposure to exogenous hormones. Six had received progestins as a supportive measure during pregnancy, three had received short-term progestogens for pregnancy testing, and the other six had inadvertently taken combined oral contraceptive medication during early pregnancy. Among the 108 control mothers, a history of exposure to exogenous hormones was elicited in 4. In contradistinction to the report by Wilkins,8 these defects were confirmed solely to male offspring. This small case-control study has not been confirmed by significant numbers in larger-scale studies. However, these data, showing a relative risk of 4.7 for congenital defects with the inadvertent administration of progestins during early pregnancy, are disturbing. At the present time, with easy access to abortion in many areas ofthis country, the continued use of withdrawal type hormonal pregnancy tests may be justified. However, for patients who cannot elect therapeutic termination of pregnancy as an alternative or for those who live in a geographic area where these services are unavailable, the use of the provocative withdrawal pregnancy tests using progestational agents should be abandoned. The development of highly sensitive pregnancy tests which can detect pregnancy as early as 8 to 10 days after conception also makes withdrawal pregnancy testing unnecessary. In addition to possible chromosomal abnormalities in the offspring of oral contraceptive users, an excess of female to male births has recently been reported in mothers who had used oral contraceptives and delivered low-birthweight babies. 24 Rothman and Liess 25 and others26 . 27 have reexamined this initial observation and have concluded that there is no difference in birth or sex ratio with regard to use, duration of use, or inter-
Future Fertility. There have been conflicting reports in the world literature regarding the effect oftherapeutic abortion on future fertility. Special attention has been given to the incompetent cervical os, increased prematurity rates, and pelvic adhesions which may produce infertility. 28-32 Some reports imply either an undetectable or negligible effect on future fertility.33-37 Since legal abortion is a relatively new phenomenon in this country, there are few long-term studies available in the United States. Hayashi and Momose 35 in Japan reported few or no adverse effects of legal abortion on future fertility, and the degree of physician training and experience with this procedure is excellent. Some of the other studies from outside the United States, such as that by Trichopoulos et al.,32 reported the results of illegal abortions performed by physicians who mayor may not have been well-trained, operations performed in less than ideal settings, and possible reluctance on the part of patients to report early or mild postoperative infections. This reluctance to seek care for early infections may result, in some cases, in the progression of pelvic inflammatory disease. Those of us who practiced medicine prior to the legalization of abortion in this country are well aware of this awesome problem. Trichopoulos and co-workers32 suggested that in Greece as many as 45% of secondary infertility problems might be attributable to previous illegal abortion. The variables involved in attempting to analyze these possible effects are multiple and complex. At present these issues are so confusing and conflicting that a firm consensus cannot be drawn from the existing data. One would hope that the complications of firsttrimester abortion in this country38 would result in a minimal effect on the future fertility of patients. The patient who undergoes one firsttrimester abortion in this country in skilled hands and in a well-equipped facility is probably at minimal risk for impaired future fertility. Unfortunately, increasing numbers of women are electing repeat abortion as a primary method of birth control,39.40 The risks in these patients must of necessity be compounded with each succeeding operation. In 1974, 13% of all women who obtained a legal abortion in the United States had
ABORTION
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CONTRACEPTIVE USE AND SUBSEQUENT FERTILITY
had at least one previous abortion. 41 This incidence was over 20% in New York City.39 Asherman's Syndrome. Asherman's syndrome (the presence of intrauterine synechiae which produce clinical symptoms, i.e., menstrual abnormalities, infertility, and habitual abortion) has in the past been relatively rare and, when described, has had a high correlation with pre-existing intrauterine infection associated with vigorous dilatation and curettage. The incidence seems to have been under-reported, as was confirmed in a comprehensive report by Klein and Garcia. 42 In addition to a general review of the world literature, these authors described in detail 11 additional cases. Each of these 11 patients had had an associated pregnancy trauma such as postpartum or postabortal hemorrhage with subsequent dilatation and curettage or septic abortion and dilatation and curettage. March and Israel 428 reported 10 patients who had undergone early elective first-trimester termination of pregnancy without immediate postoperative complications; all patients had had normal menses prior to pregnancy. These patients developed postabortal amenorrhea ranging in duration from 15 to 18 months. The diagnosis of Asherman's syndrome was confirmed by hysteroscopy, and the intrauterine lesions were lysed at the time of operation. Postoperative management consisted of the insertion of an inflated Foley catheter which remained in place for 5 days or the insertion of a Lippes Loop which was retained for at least 2 months. All patients were treated with broad-spectrum antibiotics. Conjugated estrogens (2.5 mg daily) were administered for 2 months and medroxyprogesterone acetate (10 mg daily) was given on days 56 to 60. Spontaneous menses with normal flow returned in all 10 patients. Two patients subsequently became pregnant within 1 year. One pregnancy was terminated by therapeutic abortion and the other was carried to term. The results in regard to return of menses were excellent and possibly may be related to absence of accompanying endometritis. It is hoped that such patients will respond with a pregnancy rate higher than that of patients who have had an accompanying infection. The follow-up interval at this point, however, is too short to allow definitive conclusions. Return of menses correlates poorly with establishment of a pregnancy which continues successfully to the term birth of a live infant. Wood and Pena43 reported only five of nine cases in which menses returned, two having successful term pregnancies. Bergman44 reported
607
a conception rate of only 30%; 50% of these pregnancies were carried to term. Klein and Garcia,42 using a similar method of therapy (i.e., insertion of a Foley catheter and exogenous administration of estrogens), restored normal menses in six of seven patients treated. Only three of these patients conceived and carried a successful term pregnancy.
SECONDARY AMENORRHEA AFrER ORAL CONTRACEPrIVE USE
The return of spontaneous menses in patients who have discontinued oral contraceptives is usually prompt, occurring within 6 to 10 weeks in the vast majority of patients. Rice-Wray et al.4 5 reported that approximately 70% of patients ovulated during their first spontaneous cycle and 98% by the third cycle. Because of a variable delay in the time of onset of the first cycle, patients must be cautioned not to expect these three cycles within the first 3 lunar months after discontinuing oral contraceptives. This return of menses does not appear to be either dose- or time-related. Recently Vessey et al. 2reported a delayed return offertility in oral contraceptive users as compared with diaphragm users or IUD users. The delay was more marked in nulliparous women than in multiparous women. However, as the authors stated, the number of patients studied is as yet too small to permit a final evaluation of this potential risk. As early as 1966, sporadic reports described the syndrome of prolonged secondary amenorrhea in patients who had taken oral contraceptives. 46-5o The cause of what has been referred to as "postpill amenorrhea" has as yet to be firmly established. In ensuing years a number of observations have been made concerning this particular entity: (1) the "syndrome" does not appear to be related to any particular compound51 -54 ; (2) it is not timerelated, having been reported in patients who had taken oral contraceptives for as short a period as 3 months55 ; and (3) it does not appear to be dose-related, since it has been reported in patients taking various doses of both combined and sequential oral contraceptive preparations. 55 The incidence of this "syndrome" is dependent in part upon the particular time period the investigator uses before the patient is diagnosed as having "postpill amenorrhea." Larsson-Cohn51 and Pettersson et al.5 2 reported amenorrhea in 0.7 to 0.8% of their patients who had discontinued oral contraceptives for at least 6 months.
608
HUGGINS
TABLE 4. Amenorrhea of More than 3 Months' Duration in 1862 Respondents 5• Group
Total no. of women with amenorrhea Pregnancy Postsurgical Secondary amenorrhea
No.
%
258
13.8
183 13 62
0.7
9.8 3.3
Golditch53 cited a crude incidence of 2.2/1,000 among almost 20,000 oral contraceptive users. Twelve different formulations had been used. In an attempt to attrubute either a causal or casual relationship to this problem, it is necessary to consider the spontaneous incidence of secondary amenorrhea in the population at large. Pettersson et al.,52 in studying the epidemiology of secondary amenorrhea in a large group of women in Sweden, reported the incidence of amenorrhea in the general population as 13.8% (Table 4). Most of these cases were related to pregnancy. The rate decreases, as would be expected, over a I-year period (Table 5). No relationship could be found between the incidence of secondary amenorrhea and age at menarche or pregnancy history. The authors concluded that the incidence of secondary amenorrhea is very low, and they were unable to arrive at a statistical correlation between the use of oral contraceptives and the occurrence of subsequent amenorrhea. In some studies,53.56 35% to 50% of patients had experienced episodes of amenorrhea, menstrual irregularities, or late onset of menses prior to taking oral contraceptives. However, women with no previous menstrual abnormalities have also developed this particular "syndrome." Such patients should be screened for the existence of a pituitary tumor, especially if the amenorrhea is associated with galactorrhea. If a tumor can be ruled out, the major consideration influencing treatment should be the desire for pregnancy by the patient. Several therapeutic approaches may be considered. One consists of the administration of clomiphene citrate in a starting dose of 50 mg/day for 5 days. Should this dosage schedule fail to induce ovulation, the dosage may be increased cautiously to 200 mg/day for 5 days of TABLE 5. Incidence and Prevalence Rates of Secondary A menorrhea 52 Secondary amenorrhea
I-Year rate >3 rno
>6 rno
3.3
0.7
4.4
1.8
>12 rno
%
Incidence Prevalence
1.1
June 1977 each cycle. 53, 55 One should be willing to persist for at least 6 months with clomiphene therapy before abandoning it for other approaches such as gonadotropin administration. The patient must be followed closely to detect early significant side effects such as enlarging or polycystic ovaries. The majority of such patients will respond to this particular regimen with evidence of ovulation and the return of menses. The most responsive patients are those with adequate endogenous estrogen production. However, a relatively large percentage of patients who ovulate and menstruate after clomiphene therapy do not achieve a pregnancy. Shearman55 studied 103 patients with secondary amenorrhea lasting more than 12 months following pill usage, 30 of whom underwent spontaneous cure. Treatment of 61 patients consisted of clomiphene citrate in some and subsequent administration of human pituitary gonadotropin in others (Table 6). This treatment resulted in a pregnancy rate of 43.6%. Unfortunately, 14 patients who achieved a pregnancy subsequently developed persistent amenorrhea. TABLE 6. Results of Treatment in Patients with Postpill Amenorrhea of More than 12 Months'Duration 55 Treatment
No. of patients
Total Apparently ovulating Conceiving
Clomiphene citrate
Human pituitary gonadotropin
61
7 7 4
34
22
Certain patients with secondary amenorrhea will also develop galactorrhea and have high levels of serum prolactin. Women with amenorrhea-galactorrhea and high serum prolactin levels usually have normal to low levels of serum gonadotropins and estrogens. 56-58 Since patients with low estrogen levels respond poorly to the administration of clomiphene and/or human pituitary gonadotropin, other forms of therapy have been explored. 58-63 The compounds 2-bromo-a-ergocryptine and 2 -chloro-6-methy lergoline-8B-acetoni trite methanesulfonate have been used with varying degrees of success in reducing prolactin levels. 59-63 The use of these agents in women with amenorrheagalactorrhea syndrome results in resumption of menses, ovulation, and (in SOn,:le cases) pregnancy. Unfortunately, a certain percentage of these women not only will remain refractory to this therapy but will, as with clomiphene, revert to an amenorrheic state following discontinuation of the therapy.
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CONTRACEPTIVE USE AND SUBSEQUENT FERTILITY
In society today, increasing numbers of couples are delaying their childbearing functions into the late second and early third decades because of financial and/or educational considerations. It is especially important that the physician apprise individuals who have abnormal menstrual patterns of the possibility of infertility following the use of any contraceptive modality, including the oral contraceptives. Many of these patients do not understand that the use of oral contraceptives which produce an artificial regularity of menses may indeed mask an underlying infertility problem.
INTRAUTERINE DEVICES
A significant percentage of infertile patients have potentially surgically correctable lesions. Usually the presence of tubo-ovarian, peritubal, and other associated pelvic adhesions can be related to a recognized episode or multiple episodes of prior pelvic inflammatory disease. This may include endometritis with associated salpingitis, prior pelvic surgery, a ruptured appendix with abscess formation, or possibly an episode of ruptured bowel diverticula. The relationship among prior pelvic infection, the formation of adhesions, and resultant infertility should not be the subject of serious academic debate. The use of the Grafenberg IUD and its modifications in the early 1900s was condemned and its use discontinued primarily because of an unacceptably high incidence of acute pelvic inflammatory disease associated with maternal mortality. Following the reintroduction of the modem intrauterine devices in the early 1960s, the question of whether the IUD causes an increased incidence of clinical or subclinical pelvic inflammatory disease persisted. The withdrawal from use of the Dalkon Shield in 1974 was in part the result of reports of serious pelvic infections with the subsequent death of some pregnant patients who continued to wear the device. 64 -67 One explanation for this outcome was the multifilament tail appended to the device, which acts as a wick, drawing fluid and viable bacteria into the intrauterine cavity. Tatum and co-workers68, 69 have demonstrated this wicklike effect and have cultured both aerobic and anaerobic bacteria from the intrauterine portion of the string. In addition, they reported that more than 35% of the devices studied showed breaks in the sheath of the tail within the intrauterine cavity. However, speculation still persists as to whether
609
the multifilament tail is indeed the sole cause for the development of pelvic inflammatory disease. Patients with other devices containing monofilament tails are included in the reports of sepsis with the Dalkon Shield. 64 , 70-72 Mishell et al. 73 have shown that, with the introduction of an intrauterine device, each patient has her intrauterine cavity contaminated by bacteria. However, over a short period of time the uterus, through multiple biologic mechanisms, is apparently able to cleanse and sterilize its environment. Recently Taylor et aJ.7° described a syndrome of unilateral tubo-ovarian abscess in 16 patients wearing IUDs. In none of these patients was Gonococcus cultured. Unilateral tubo-ovarian abscess has, as a general rule, been a rare clinical condition unless it followed the development of other unilateral pelvic disease or followed pelvic surgery. The observations by Taylor et aJ.7° were confirmed in several other institutions in which the occurrence of unilateral pelvic abscess was also associated with a high incidence of IUD usage. 70 Willson and Ledger74 have shown an increased incidence of overt pelvic inflammatory disease in a population consisting primarily of private patients wearing IUDs as compared with those using other forms of contraception or no contraception. Wright and Laemmle 75 reported that, in an indigent population at Grady Hospital in Atlanta, the over-all crude attack rate of pelvic inflammatory disease was approximately 1%. When postpartum returnees were studied and analyzed, the patients who accepted an IUD had an incidence of pelvic inflammatory disease of 66.2/1000 woman-years; those accepting oral contraception, 13.411000 woman-years; and foam acceptors, 25.2/1000 woman-years. Faulkner and Ory 76 studied a group of febrile and afebrile patients seen in an emergency room with a diagnosis of pelvic inflammatory disease. These patients were then matched with control patients seen in the same area with complaints other than abdominal pain or discomfort who had no gynecologic pathologic diagnosis. The results revealed a significantly higher proportion of IUD users among the febrile cases of pelvic inflammatory disease than among controls (38% versus 11%, respectively). Their conclusion was that an IUD user is approximately 4 times more likely to develop pelvic inflammatory disease than is a nonuser.
610
HUGGINS
June 1977
TABLE 7. Study of Women Using Different Methods of Contraception 2 Disease of reproductive system"
Salpingitis, pelvic inflammatory disease, endometritis
Type of event
Inpatient Over-all
Method of contraception in use on admission Oral
Diaphragm
IUD
0.63 1.02
0.58 0.94
1.81 2.46
Total
x'
0.84 (47)b 1.27 (71)
14.5 14.6
"Standardized first-event rates (per 1000 woman-years) in each entry group. bTotal numbers of affected women are shown in parentheses.
One problem inherent to a study such as this is the possible relative over-reporting of diagnoses of pelvic inflammatory disease in a clinic population. There still persists in some areas the concept that clinic patients are subject to pelvic inflammatory disease while private patients are predisposed to endometriosis. Jacobson and Westrom 77 in Sweden compared the results of laparoscopic diagnosis of pelvic inflammatory disease with that of clinical diagnosis and found that, of patients suspected of having pelvic inflammatory disease, visual confirmation could be made in only 65%. This experience has been shared in our own institution by physicians at all stages of training and expertise. Without documenting the exact incidence of incorrect diagnosis, it should be well accepted that our clinical acumen with regard to diagnosing pelvic inflammatory disease is not totally satisfactory. Westrom et al.72 compared the frequency ofIUD use in 515 patients who had laparoscopy-confirmed acute salpingitis with that in 741 sexually active, matched controls. The frequency of IUD usage was significantly higher (p < 0.001) in study patients than in controls. The increased risks for pelvic inflammatory disease for never-pregnant patients was 7-fold. Vessey et ai.2 found a significant increase in the frequency of diagnosis of pelvic inflammatory disease in both inpatient and outpatient IUD users versus oral contraceptive or diaphragm users (Table 7). With regard to the IUD and future fertility, concern and speculation have centered primarily on the incidence of pelvic inflammatory disease and whether or not an IUD increases the risk of this disease process. Even if certain assumptions are made, it is difficult to define exactly what constitutes pelvic inflammatory disease and to evaluate its degree of severity. The issue of the subsequent development of pelvic adhesions which may contribute to infertility is dependent on many variables. It is difficult to draw definitive conclusions regarding these questions because the incidence, the treatment patterns, the progression, and the recurrence of the disease process are m ul tifactorial.
Tietze and Lewitt78 were unable to demonstrate impaired fertility among women who discontinued the intrauterine device because of a desire for pregnancy; over 30% conceived within 1 month, approximately 60% within 3 months, and almost 90% within 1 year. Tatum79 reported a cumulative pregnancy rate of 84.6% in 1 year among 553 women who had had Copper-Ts removed in order to establish another pregnancy. The figures reported in these studies are within the same range for all women attempting to achieve a pregnancy. These authors concluded that short-term use (1 to 3 years) of an intrauterine device does not impair future fertility. SUMMARY
There is a very small correlation, if any, between the prior use of oral contraceptives and congenital malformations, including Down's syndrome. There are few, if any, recent reports on masculinization of a female fetus born to a mother who took an oral contraceptive containing 1 mg of a progestogen during early pregnancy. However, patients suspected of being pregnant and who are desirous of continuing that pregnancy should not continue to take oral contraceptives, nor should progestogen withdrawal pregnancy tests be used. Concern still exists regarding the occurrence of congenital abnormalities in babies born to such women. The return of menses and the achievement of a pregnancy may be slightly delayed after oral contraceptives are discontinued, but the fertility rate is within the normal range by 1 year. The incidence of postoperative infection following first-trimester therapeutic abortion in this country is low. However, increasing numbers of women are undergoing repeated pregnancy terminations, and their risk for subsequent pelvic infections may be multiplied with each succeeding abortion. No firm conclusion can be reached with regard to the incidence of prematurity due to cervical incompetence or surgical infertility following pregnancy terminations in the United States. Asherman's syndrome may occur following nonseptic therapeutic abortion. The success-
. Vol. 28, No.6
CONTRACEPTIVE USE AND SUBSEQUENT FERTILITY
ful pregnancy rate following treatment of this syndrome is low. The incidence of "postpill" amenorrhea of more than 6 months' duration is probably less than 1%. The occurrence of the "syndrome" does not seem to be related to length of use or type of pill. Patients with prior normal menses as well as those with menstrual abnormalities before use of oral contraceptives may develop this syndrome. Patients with normal estrogen and gonadotropin levels usually respond with return of menses and ovulation when treated with clomiphene. The rate for achievement of pregnancy is much lower than that for return of menses. If serum prolactin levels are elevated and gonadotropin and estrogen levels are low, patients respond poorly to any treatment regimen. There are no standard, accepted, criteria for defining pelvic inflammatory disease or for categorizing its severity. The incidence of pelvic inflammatory disease appears to be higher among IUD users than among patients taking oral contracepti ves or using a barrier method. The effect of infection on future development of pelvic adhesions with resultant infertility is difficult to appraise. All present methods of contraception entail some risk to the patient. The risk of impaired future fertility with the use of any method appears to be low. Careful identification of patients who may be at high risk, such as those with a history of oligomenorrhea or pelvic inflammatory disease, may allow the physician to suggest a method which imposes the least risk to future fertility. REFERENCES 1. The Allan Guttmacher Institute: Organized family planning services in the United States: FY 1975. Fam Plann Perspect 8:269, 1976 2. Vessey M, Doll R, Peto R, Johnson B, Wiggins P: A longterm follow-up study of women using diffierent methods of contraception: an interim report. J Biosoc Sci 8:373, 1976 3. Weinstock E, Tietze C, Jaffe FS: Legal abortions in the United States since the 1973 Supreme Court decisions. Fam Plann Perspect 7:23, 1975 4. Tietze C, Bongaarts J, Schearer B: Mortality associated with the control offertility. Fam Plann Perspect 8:6, 1976 5. Siegel D, Corfman P: Epidiological problems with studies of the safety of oral contraceptives. JAMA 203:950, 1968 6. Carr D: Chromosomes after oral contraceptives. Am J Obstet Gynecol 97:283, 1967 7. Carr D: Chromosome studies in selected spontaneous abortions: conception after oral contraceptives. Can Med Assoc J 103:343. 1970 8. Wilkins L: Masculinization of the female fetus due to use of orally given progestins. JAMA 172:1028, 1960 9. Janerich DT, Piper JM, Glebatis D: Oral contraceptives and congenital limb-reduction defects. N Engl J Med 291:697, 1974
611
10. Nora JJ, Nora AH: Birth defects and oral contraceptives. Lancet 1:941, 1973 11. Levy EP, Cohen A, Fraser FC: Hormone treatment during pregnancy and congenital heart defects. Lancet 1:611, 1973 12. Oakley GP Jr, Flynt WJ Jr, Falek A: Hormonal pregnancy tests and congenital malformations. Lancet 2:256, 1973 13. Kaufman RL: Birth defects and oral contraceptives. Lancet 1:1396, 1973 14. Janerich DT, Flink EM, Koegh MD: Down's syndrome and oral contraceptive usage. Br J Obstet Gynaecol 83:617, 1976 15. Poland VJ, Ash KA: The influence of recent use of an oral contraceptive on early intrauterine development. Am J Obstet Gynecol 116:1138, 1973 16. Royal College of General Practitioners: Oral Contraceptives and Health. London, Pitman Medical Publishers, 1974, p 71 17. Royal College of General Practitioners: the outcome of pregnancy in former oral contraceptive users. Br J Obstet Gynaecol 83:608, 1976 18. Klinger HP, Glasser M, Kava W: Contraceptives and the conceptu8---{:hromosome abnormalities of the fetus and neonate related to maternal contraceptive history. Obstet Gynecol 48:40, 1976 19. Jacobs PA, Melville M, Ratcliffe S: A cytogenetic survey ofll,680 newborn infants. Ann Hum Genet 37:359,1974 20. Garcia CR: The oral contraceptive-an appraisal and review. Am J Med Sci 253:718, 1967 21. Littlefield LG, Mailhes JB: Comparison of chromosome breakages in lymphocytes and fibroblasts from control women taking oral contraceptives. Fertil Steril 26:828, 1975 22. Robinson SC: Pregnancy outcome following oral contraceptives. Am J Obstet Gynecol 109:354, 1970 23. Deleted in proof 24. Crawford JS: Pre-pregnancy oral contraceptives and respiratory distress syndrome. Lancet 1:858, 1973 25. Rothman KJ, Liess J: Gender of offspring after oral contraceptive use. N Engl J Med 295:859, 1976 26. Keserii TL, Maraz A, Szabo J: Oral contraception and sex ratio at birth. Lancet 1:369, 1974 27. Oechsli FW: Oral contraception and sex ratio at birth. Lancet 1:1004, 1974 28. Dykova H, Havranek F, Pospisil J: Backflow of the blood into the oviducts as a possible cause of sterility after abortion. Zentralbl Gynaekol 82:1228, 1960 29. Midak E: Bezposrednie i Pozne nastepstwa zabiegow przerywania ci~. Pol Tyg Lek 21:1063, 1966 30. Pantelakis SN, Papadimitriou GC, Doxiadis SA: Influence of induced and spontaneous abortions on the outcome of subsequent pregnancies. Am J Obstet Gynecol 116:799, 1973 31. Louros N, Danezis J, Trichopoulos D: Population Policy in Developed Countries, Edited by B Berelson. New York, McGraw-Hill, 1974, p 171 32. Trichopoulos D, Handanos N, Danezis J, Kalandidi A, Kalapothaki V: Induced abortion and secondary infertility. Br J Obstet Gynaecol 83:645, 1976 33. Comninos AC: In Proceedings of the VIIth World Congress on Fertility and Sterility, Japan, Tokyo and Kyoto, 1972, p 393 34. Gebhard PH, Pomeroy WB, Martin CE, Christenson CV: Pregnancy, Birth and Abortion. Third Report. Institute for Sex Research of Indiana University. New York, Harper and Row, 1958 35. Hayashi M, Momose K: Harmful Effects of Induced Abortion, Edited by Y Koya. Japan, Sanshu Printing Industry, 1966, p 3 36. Glenc F: Early and late complications after therapeutic abortion. Am J Obstet Gyneco1118:34, 1974
612
HUGGINS
37. L.indahl J: Somat~c Complications following Legal Abortion. London, Hememann Medical Books 1959 38. Teitze C, Lewitt S: Highlights ofthe Joint Program for the study of Abortion (JPSA): early medical complications of legal abortion. Adv Planned Parent 8:173, 1973 39. Pakter J, Nelson F, Svigir M: Legal abortion: a half-decade o~ experience. Fam Plann Perspect 7:248,1975 40. TIetze C: The problem of repeat abortions. Fam Plann Perspect 6:148, 1974 41. C.enter for Disease Control, Department of Health, Education and Welfare: Abortion Surveillance, Annual Summary 1974, 1976, P 33 42. Klein SM, Garcia CR: Asherman's syndrome: a critique and current review. Fertil Steril 24:722, 1973 42a. March CM, Israel R: Intrauterine adhesions secondary to elective abortion. Obstet Gynecol 48:422, 1976 43. Wood J, Pena G: Treatment of traumatic uterine synechiae. Int J Fertil 9:405, 1964 44. Bergman P: Traumatic intrauterine lesions. Acta Obstet Gynecol Scand [Suppl 4] 40:1, 1961 45. R.ice-Wray E, Correu S, Gordovsky J, Esquiver J, GoldZIeher JW: Return of ovulation after discontinuance of oral contraception. Fertil Steril 18:212, 1967 46. Shearman RP: Amenorrhoea after treatment with oral contraceptives. Lancet 2:1110, 1966 47. Whitelaw MJ, Nora VF, Kalman CF: Iregular menses, amenorrhea, and infertility following synthetic pregestational agents. JAMA 195:780, 1966 48. Friedman S, Goldfein A: Amenorrhea and galactorrhea following oral contraceptive therapy. JAMA 210:1888, 1969 49. Halbert DR, Christian DC: Amenorrhea following oral contraceptives. Obstet Gynecol 34:161, 1969 50. Shearman RP: Prolonged secondary amenorrhoea after oral contraceptive therapy. Natural and unnatural history. Lancet 2:64, 1971 51. Larsson-Cohn U: The length of the first three menstrual cycles after combined oral contraceptive treatment. Acta Obstet Gynecol Scand 48:416, 1969 52. Pettersson F, Fries H, Nillius JS: Epidemiology of secondary amenorrhea. Am J Obstet Gynecol 117:80, 1973 53. Golditch 1M: Postcontraceptive amenorrhea. Obstet Gynecol 39:903, 1972 54. Furuhjelm M, Carlstrom K: Amenorrhea following use of combined oral contraceptives. Acta Obstet Gynecol Scand 52:373, 1973 55. Shearman RP: Secondary amenorrhea after oral contraceptives-treatment and follow-up. Contraception 11 :123 ~% ' 56. Archer DF, Nankin HR, Gabos PF, Maroon J, Nosetz S, Washwa SR, Josimovich JB: Serum prolactin in patients with inappropriate lactation. Am J Obstet Gynecol 119:466, 1974 57. Franks S, Murray MAF, Jequier AM, Steele SJ, Nabarro JDN, Jacobs HS: Incidence and significance of hyperprolactinaemia in women with amenorrhoea. Clin Endocrinol (OxD 4:957, 1975 58. Spark RF, Pallotta J, N aftolin F, Clemens R: Galactorrheaamenorrhea syndromes: etiology and treatment. Ann Intern Med 84:532, 1976 59. Lloyd SJ, Josimovich JB, Archer DF: Amenorrhea and galactorrhea: results of therapy with 2-bromo-alphaergocryptine (CB-154). Am J Obstet Gynecol 122:85, 1975 60. Thorner MO, McNeilly AS, Hagan C, Besser GM: Longterm treatment of galactorrhoea and hypogonadism with bromocriptine. Br Med J 25:419, 1974
June 1977 61. del Pozo E, Brun del Re R, Varga L, Friesen H: The inhibition of prolactin secretion in man by CB-154 (2-bromalpha-ergocryptine). J Clin Endocrinol Metab 35:768, 1972 62. Thorner MO, Besser GM, Jones A, Dacie J, Jones AE: Bromocriptine treatment of female infertility: report of 13 pregnancies. Br Med J 4:694, 1975 63. Lemberger L, Crabtree R, ClemensJ, Dyke RW, Woodburn RT: The inhibitory effect of an ergoline derivative (Lergotrile, Compound 83636) on prolactin secretion in man. J Clin Endocrinol Metab 39:579, 1974 64. Jennings J: Report of Safety and Efficacy of the Dalkon Shield and Other IUD's Prepared by the ad hoc Obstetrics and Gynecology Advisory Committee to the US Food and Drug Administration, No 16. Washington DC, United States Government Printing Office, 1974, p 29 65. Preston ES: Septic spontaneous abortion associated with the Dalkon Shield. In Analysis ofIntrauterine Contraception, Edited by F Hefnawi, S Segal. Amsterdam, North Holland Publishing Co, 1975, p 417 66. Kahn HS, Tyler CW: An association between the Dalkon Shield and complicated pregnancies among women hospitalized for intrauterine contraceptive device-related disorders. Am J Obstet GynecoI125:83, 1976 67. Christian CD: Maternal deaths associated with an intrauterine device. Am J Obstet Gynecol 119:441, 1974 68. Tatum HJ, Schmidt FH, Phillips D, McCarty M, O'Leary WM: The Dalkon Shield controversy: structural and bacteriological studies of IUD tails. JAMA 231:711, 1975 69. Tatum HJ, Schmidt FH, Phillips D: Morphological studies ofDalkon Shield tails removed from patients. Contraception 11:465, 1975 70. Taylor ES, McMillan JH, Greer BE, Droegemueller W, Thompson HE: The intrauterine device and tubo-ovarian abscess. Am J Obstet GynecoI123:338, 1975 71. Mead PB, Beecham JB, Maeck JVS: Incidence of infections associated with the intrauterine contraceptive device in an isolated community. Am J Obstet GynecoI125:79, 1976 72. Westrom L, Bengtsson LP, Mardh PA: The risk of pelvic inflammatory disease in women using intrauterine contraceptive devices as compared to non-users. Lancet 2:221, 1976 73. Mishell DR, Bell JH, Good RG, Moyer DL: The intrauterine device: a bacteriologic study of the endometrial cavity. Am J Obstet Gynecol 96:119, 1966 74. Willson RJ, Ledger WJ: Complications associated with the use of intrauterine contraceptive devices in women of middle and upper socioeconomic class. Am J Obstet Gynecol 100:649, 1968 75. Wright NH, Laemmle P: Acute pelvic inflammatory disease in an indigent population: an estimate of its incidence and relationship to methods of contraception. Am J Obstet Gynecol 101:979, 1968 76. Faulkner WL, Ory HW: Intrauterine devices and acute pelvic inflammatory disease. JAMA 235:1851, 1976 77. Jacobson L, Westrom L: Objectivized diagnosis of acute pelvic inflammatory disease. Am J Obstet Gynecol 105:1088, 1960 78. Tietze C, Lewitt S: Evaluation of intrauterine devices: ninth progress report of the Cooperative Statistical Program. Stud Fam Plann 55:1,1970 79. Tatum HJ: Comparative experience with newer models of the Copper T in the United States. In Analysis of Intrauterine Contraception, Edited by F Hefnawi, S Segal. Amsterdam, North Holland Publishing Co, 1975, p 155
Vol. 28, No.6, June 1977
Printed in U.SA.
CONTRACEPTIVE USE AND SUBSEQUENT FERTILITY*
GEORGE R. HUGGINS, M.D.t Division of Human Reproduction, Department of Obstetrics and Gynecology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104
Partially because of the continuing reports in both the lay press and scientific publications, there seems to be a shifting of preference away from the oral contraceptives and the intrauterine devices to barrier methods. Usage of the IUD decreased 4% from 1974 to 1975 in the United States l (Table 1). It is still premature to document decisively that this indeed represents a major and continuing shift in attitudes and usage patterns. This past year one study by Tietze et aU has indicated that the "safest" method of contraception is the use of a barrier device (condom or diaphragm) backed up by first-trimester abortion in the event of a method failure and an ensuing unwanted pregnancy. Several assumptions are made in their article which are valid for only certain segments of the population in the United States. One assumption is that all patients who experience an unwanted or unplanned pregnancy will elect first-trimester abortion. The recent large-scale study by Vessey et al. 2 showed that, among parous women who experienced a single unplanned pregnancy as a result of method failure, more than one-half elected to carry their pregnancies to term (Table 2). The maternal mortality rate for term pregnancies is of course much higher than the mortality rate for the current conventional methods of contraception, including oral contraceptives and IUDs. A second assumption is that all patients experiencing a method failure can readily obtain firsttrimester abortion. Experience in this country, as
The issue offertility following contraceptive use is of utmost importance to any patient or couple seeking advice as to the "best" method of contraception for them. Few things are as disheartening to a couple and their physician as the discovery that the couple has an infertility problem after having postponed their childbearing functions for many years to achieve financial, social, or educational goals. The late discovery of an unsuspected infertility problem often occurs in patients who have utilized long-term steroidal contraception, an intrauterine device (IUD), or a combination thereof. Contraception usage today is heavily concentrated in the utilization of oral contraceptives or intrauterine devices. In fiscal year 1975 over 3.8 million women in the United States were using organized family planning services delivered primarily through the efforts of Federally subsidized programs and hospitals, health departments, and free-standing clinics. Planned Parenthood affiliates accounted for approximately 25% of patients served and Health Department clinics for 42% 1 Vessey and co-workers2 analyzed contraceptive usage among 17,000 women in Great Britain and found 56% using oral contraception, 25% using the diaphragm, and 19% using IUDs. Patients obtaining contraception from private physicians also elect oral contraceptives in very high percentages. In addition to the preventive contraceptive methods, approximately 1 million elective abortions are performed each year in the United States. 3
TABLE 1. Percentage Distribution of Contraceptive Methods Used by Patients-Organized Programs, Fiscal Year 1975
Received April 12, 1977. *Supported in part by Grant 103-HOOO, 217-03 from the Department of Health, Education and Welfare, United States Public Health Service (Region III). tReprint requests: G. R. Huggins, M.D., Department of Obstetrics and Gynecology, Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, Pa. 19104.
603
Contraceptive
%
Oral IUD Sterilization Other None
71
10 1 10 8
604
HUGGINS
June 1977
TABLE 2. Outcome of Singleton Unplanned Pregnancies in Parous Women According to Method ofContraception 2 Whi{:h Failed Contraceptive Group and outcome
Oral
Diaphragm
IUD
% pregnancies
Live birth Normal Malformed Stillbirth Miscarriage Ectopic gestation Subtotal Termination Total
81.9 4.5 0 13.6 0
78.3 1.8 1.8 18.1 0
33.0 0.9 1.7 55.7 8.7
100.0 (166)
100.0 (115)
(8)
(56)
(50)
(30)
(222)
(165)
100.0 (22)a
aNumbers of pregnancies are shown in parentheses.
well as in others, has demonstrated repeatedly that many patients are unable, for a multitude of reasons, to obtain first-trimester termination and are forced to utilize second-trimester termination. These, of course, carry with them a significantly increased incidence of maternal morbidity and even mortality. Both oral contraceptives and IUDs have been implicated in a number of possible complications which relate not only to immediate morbidity and mortality rates during their usage, but also to subsequent effects that usage may have on fertility. Of equal concern is the question of possible chromosomal damage and resulting fetal malformations following the use of a contraceptive modality. HORMONAL CONTRACEPTION
The issues considered with regard to hormonal contraception are (1) epidemiologic problems associated with studies on safety of oral contraceptives, (2) chromosomal abnormalities, (3) masculinization of the female fetus, and (4) subsequent fertility and amenorrhea.
Epidemiologic Problems Associated with Studies of Safety of Oral Contraceptives The causal association between any drug ingestion and a subsequent increased incidence of fetal malformations or other pathologic states is extremely difficult to "prove." Siegel and Corfman5 have outlined the problems inherent to detecting a 2-fold increase in drug-induced side effects when the annual incidence of the specific effect and the number of patients needed for follow-up in order to establish this relationship prospectively are considered. The same analogy may be used in at-
tempting to detect a causal relationship between drug usage and the subsequent incidence of fetal malformations. For any given lesion with a low rate of occurrence the sample size must be large (Table 3).
Oral Contraceptives and Chromosomal Abnormalities There have been sporadic reports and speculation of various fetal malformations occurring in the offspring of women taking oral contraceptives. These have included (1) an increased incidence of fetal chromosomal abnormalities in spontaneously aborted fetuses among women who had recently discontinued oral contraceptives6 ,7; (2) masculinization of the genitalia of female offspring of women inadvertently taking oral contraceptives during early pregnancy8; (3) a possible relationship between exposure to combined oral contraceptives and progestin derivatives during pregnancy and birth defects (vertebral, anal, cardiac, tracheal, esophageal, renal, and limb [VACTERLl anomalies)9.13; and (4) the possible occurrence of Down's syndrome. 14 Incidence of Fetal Chromosomal Abnormalities. The data ofCarr6 and Poland and Ash 15 suggesting an increased incidence oftriploidy, other chromosomal abnormalities, and growth disorganization in the abortuses of a small number of women taking oral contraceptives raised valid concerns TABLE 3. Minimal Sample Size To Detect a 2-Fold Increase in Side Effects or Malformations' Annual incidence (rate in controlsll.OOO)
No. followed for 1 year
0.22 0.56 0.75 2.0 30.0
85,000 35,000 25,000 9,000 600
Vol. 28, No.6
CONTRACEPTIVE USE AND SUBSEQUENT FERTILITY
over a causal relationship between previous contraception and these defects. In the initial report of the Royal College of General Practitioners16 on oral contraceptives and health, published in 1974, the incidence of chromosomal abnormalities in the offspring of2,583 pregnancies in pill users did not differ significantly from that in 7,405 pregnancies in control patients. Their latest reporP7 compares the outcome of 5,500 pregnancies in previous pill users with that of 11,000 pregnancies in controls. There were 86 congenital abnormalities, or a rate of 19.2/ 100,000, in former pill-users versus 177, or 19.40/ 100,000, in the controls. The ratio of these rates is 1.03 and is not significant. Analysis of the types of abnormalities reported revealed no significant grouping in the VACTERL types in either group. Klinger et al. 18 recently conducted chromosome studies on 3080 products of conception; these consisted of both newborn infants and medically induced abortuses. Mothers were divided into three groups: (1) those who had used oral contraceptives, (2) those who had used nonhormonal contraceptives, and (3) a group which had not used any contraceptive. Chromosomal analyses were completed on 1670 newborn infants, 1233 products of induced abortion, 98 products of spontaneous abortion, 68 products of abortion of unknown type, and material from 11 ectopic pregnancies. The types of oral contraception used by the women in the newborn and induced-abortion groups were similar. These included a wide spectrum of lowdose pills, approximately 6% sequential preparations, and approximately 5% both combined and sequential preparations. An abnormality rate of 6.8/1000 was found for conceptions in women who had used oral contraceptives. The authors concluded that this incidence could easily have been due to chance (P > 0.25). The abnormality rate for the conceptuses of women who had never used any contraceptive was 4.9/1000. An interesting finding was that the incidence of abnormalities decreased as the length of oral contraceptive use increased. The observed abnormality rates in this study agree closely with the rate of 5.6/1,000 obtained from over 43,000 liveborn babies reported by Jacobs et al. 19
Down's Syndrome. Recently, Janerich et al.14 studied the question of Down's syndrome and oral contraceptive usage. A group of 103 mothers whose infants had Down's syndrome was compared with an equal number of matched controls consisting of mothers whose infants lacked Down's syndrome. The methodology in this study was the
605
same as that used in their former report on the incidence of limb-reduction defects.9 The incidence of pill users in the control group was actually higher than that in the group whose infants had Down's syndrome, but was not considered significant. Carr6 reported an increased incidence oftriploidy in a small number of women taking oral contraceptives. Poland and Ash 15 noted an increased incidence of abortuses with chromosomal abnormalities and growth disorganization. Reports by Garcia,20 the Royal College of General Practitioners,17 Janerich et al.,14 and others12, 18, 19, 21, 22 are somewhat reassuring in pointing out that there are no conclusive data to associate previous pill usage with an increased incidence of VACTERL defects, Down's syndrome, or triploidy in live-born infants. This does not, however, settle the question of the incidence of defects in patients inadvertently taking oral contraceptives while pregnant. This is an area of valid concern, and such individuals need to be closely monitored as these pregnancies occur and are reported. Masculinization of the Female Fetus. In 1960 Wilkins8 reported 70 cases of masculinization of female infants associated with oral administration ofprogestins to mothers during the first trimester of pregnancy. Of these, 34 cases were associated with the use of 17a-ethinyltestosterone, 35 cases were associated with the administration of Norlutin (17a-ethinyl-19-nortestosterone), and 1 case was associated with the administration of norethynodrel-mestranol (Enovid). Patients had received 20 to 25 mg/day of 17a-ethinyltestosterone for varying periods of time; those patients treated with Norlutin had received doses of 10 to 40 mg/day. In addition to the progestational agents, some of the patients had received high doses of diethylstilbestrol, ethinylestradiol, or conjugated equine estrogens. The clinical findings included phallic enlargement and, in some cases, varying degrees of labioscrotal fusion. Subsequent to the report by Wilkins 8 and others, the progestational and estrogenic dosage of the oral contraceptives has been dramatically reduced. It is difficult to find any case reports or valid studies in the literature at the present time that document clinically evident masculinization offemale infants born to mothers taking combined oral contraceptive pills containing 1 mg of a progestogen during early pregnancy. Although we are unable to detect gross fetal abnormalities, it is possible that the ingestion of these compounds might produce minor abnor-
606
June 1977
HUGGINS
malities not detectable by gross physical examination. Prudence, therefore, dictates that oral contraceptives be discontinued in any patient suspected of being pregnant. Such patients must, however, be provided with an alternative method of contraception.
val between discontinuation and subsequent conception in oral contraceptive users.
Relationship between Oral Contraceptive Use, Progestin Administration, and Congenital Birth Defects. In 1974 J anerich et al. 9conducted a study of 108 mothers who had delivered infants with congenital limb-reduction defects and compared them with 108 controls who had delivered normal infants. The ingestion of exogenous steroids was investigated. Among the mothers with malformed children, there were 15 patients who had a history of exposure to exogenous hormones. Six had received progestins as a supportive measure during pregnancy, three had received short-term progestogens for pregnancy testing, and the other six had inadvertently taken combined oral contraceptive medication during early pregnancy. Among the 108 control mothers, a history of exposure to exogenous hormones was elicited in 4. In contradistinction to the report by Wilkins,8 these defects were confirmed solely to male offspring. This small case-control study has not been confirmed by significant numbers in larger-scale studies. However, these data, showing a relative risk of 4.7 for congenital defects with the inadvertent administration of progestins during early pregnancy, are disturbing. At the present time, with easy access to abortion in many areas ofthis country, the continued use of withdrawal type hormonal pregnancy tests may be justified. However, for patients who cannot elect therapeutic termination of pregnancy as an alternative or for those who live in a geographic area where these services are unavailable, the use of the provocative withdrawal pregnancy tests using progestational agents should be abandoned. The development of highly sensitive pregnancy tests which can detect pregnancy as early as 8 to 10 days after conception also makes withdrawal pregnancy testing unnecessary. In addition to possible chromosomal abnormalities in the offspring of oral contraceptive users, an excess of female to male births has recently been reported in mothers who had used oral contraceptives and delivered low-birthweight babies. 24 Rothman and Liess 25 and others26 . 27 have reexamined this initial observation and have concluded that there is no difference in birth or sex ratio with regard to use, duration of use, or inter-
Future Fertility. There have been conflicting reports in the world literature regarding the effect oftherapeutic abortion on future fertility. Special attention has been given to the incompetent cervical os, increased prematurity rates, and pelvic adhesions which may produce infertility. 28-32 Some reports imply either an undetectable or negligible effect on future fertility.33-37 Since legal abortion is a relatively new phenomenon in this country, there are few long-term studies available in the United States. Hayashi and Momose 35 in Japan reported few or no adverse effects of legal abortion on future fertility, and the degree of physician training and experience with this procedure is excellent. Some of the other studies from outside the United States, such as that by Trichopoulos et al.,32 reported the results of illegal abortions performed by physicians who mayor may not have been well-trained, operations performed in less than ideal settings, and possible reluctance on the part of patients to report early or mild postoperative infections. This reluctance to seek care for early infections may result, in some cases, in the progression of pelvic inflammatory disease. Those of us who practiced medicine prior to the legalization of abortion in this country are well aware of this awesome problem. Trichopoulos and co-workers32 suggested that in Greece as many as 45% of secondary infertility problems might be attributable to previous illegal abortion. The variables involved in attempting to analyze these possible effects are multiple and complex. At present these issues are so confusing and conflicting that a firm consensus cannot be drawn from the existing data. One would hope that the complications of firsttrimester abortion in this country38 would result in a minimal effect on the future fertility of patients. The patient who undergoes one firsttrimester abortion in this country in skilled hands and in a well-equipped facility is probably at minimal risk for impaired future fertility. Unfortunately, increasing numbers of women are electing repeat abortion as a primary method of birth control,39.40 The risks in these patients must of necessity be compounded with each succeeding operation. In 1974, 13% of all women who obtained a legal abortion in the United States had
ABORTION
Vol. 28, No.6
CONTRACEPTIVE USE AND SUBSEQUENT FERTILITY
had at least one previous abortion. 41 This incidence was over 20% in New York City.39 Asherman's Syndrome. Asherman's syndrome (the presence of intrauterine synechiae which produce clinical symptoms, i.e., menstrual abnormalities, infertility, and habitual abortion) has in the past been relatively rare and, when described, has had a high correlation with pre-existing intrauterine infection associated with vigorous dilatation and curettage. The incidence seems to have been under-reported, as was confirmed in a comprehensive report by Klein and Garcia. 42 In addition to a general review of the world literature, these authors described in detail 11 additional cases. Each of these 11 patients had had an associated pregnancy trauma such as postpartum or postabortal hemorrhage with subsequent dilatation and curettage or septic abortion and dilatation and curettage. March and Israel 428 reported 10 patients who had undergone early elective first-trimester termination of pregnancy without immediate postoperative complications; all patients had had normal menses prior to pregnancy. These patients developed postabortal amenorrhea ranging in duration from 15 to 18 months. The diagnosis of Asherman's syndrome was confirmed by hysteroscopy, and the intrauterine lesions were lysed at the time of operation. Postoperative management consisted of the insertion of an inflated Foley catheter which remained in place for 5 days or the insertion of a Lippes Loop which was retained for at least 2 months. All patients were treated with broad-spectrum antibiotics. Conjugated estrogens (2.5 mg daily) were administered for 2 months and medroxyprogesterone acetate (10 mg daily) was given on days 56 to 60. Spontaneous menses with normal flow returned in all 10 patients. Two patients subsequently became pregnant within 1 year. One pregnancy was terminated by therapeutic abortion and the other was carried to term. The results in regard to return of menses were excellent and possibly may be related to absence of accompanying endometritis. It is hoped that such patients will respond with a pregnancy rate higher than that of patients who have had an accompanying infection. The follow-up interval at this point, however, is too short to allow definitive conclusions. Return of menses correlates poorly with establishment of a pregnancy which continues successfully to the term birth of a live infant. Wood and Pena43 reported only five of nine cases in which menses returned, two having successful term pregnancies. Bergman44 reported
607
a conception rate of only 30%; 50% of these pregnancies were carried to term. Klein and Garcia,42 using a similar method of therapy (i.e., insertion of a Foley catheter and exogenous administration of estrogens), restored normal menses in six of seven patients treated. Only three of these patients conceived and carried a successful term pregnancy.
SECONDARY AMENORRHEA AFrER ORAL CONTRACEPrIVE USE
The return of spontaneous menses in patients who have discontinued oral contraceptives is usually prompt, occurring within 6 to 10 weeks in the vast majority of patients. Rice-Wray et al.4 5 reported that approximately 70% of patients ovulated during their first spontaneous cycle and 98% by the third cycle. Because of a variable delay in the time of onset of the first cycle, patients must be cautioned not to expect these three cycles within the first 3 lunar months after discontinuing oral contraceptives. This return of menses does not appear to be either dose- or time-related. Recently Vessey et al. 2reported a delayed return offertility in oral contraceptive users as compared with diaphragm users or IUD users. The delay was more marked in nulliparous women than in multiparous women. However, as the authors stated, the number of patients studied is as yet too small to permit a final evaluation of this potential risk. As early as 1966, sporadic reports described the syndrome of prolonged secondary amenorrhea in patients who had taken oral contraceptives. 46-5o The cause of what has been referred to as "postpill amenorrhea" has as yet to be firmly established. In ensuing years a number of observations have been made concerning this particular entity: (1) the "syndrome" does not appear to be related to any particular compound51 -54 ; (2) it is not timerelated, having been reported in patients who had taken oral contraceptives for as short a period as 3 months55 ; and (3) it does not appear to be dose-related, since it has been reported in patients taking various doses of both combined and sequential oral contraceptive preparations. 55 The incidence of this "syndrome" is dependent in part upon the particular time period the investigator uses before the patient is diagnosed as having "postpill amenorrhea." Larsson-Cohn51 and Pettersson et al.5 2 reported amenorrhea in 0.7 to 0.8% of their patients who had discontinued oral contraceptives for at least 6 months.
608
HUGGINS
TABLE 4. Amenorrhea of More than 3 Months' Duration in 1862 Respondents 5• Group
Total no. of women with amenorrhea Pregnancy Postsurgical Secondary amenorrhea
No.
%
258
13.8
183 13 62
0.7
9.8 3.3
Golditch53 cited a crude incidence of 2.2/1,000 among almost 20,000 oral contraceptive users. Twelve different formulations had been used. In an attempt to attrubute either a causal or casual relationship to this problem, it is necessary to consider the spontaneous incidence of secondary amenorrhea in the population at large. Pettersson et al.,52 in studying the epidemiology of secondary amenorrhea in a large group of women in Sweden, reported the incidence of amenorrhea in the general population as 13.8% (Table 4). Most of these cases were related to pregnancy. The rate decreases, as would be expected, over a I-year period (Table 5). No relationship could be found between the incidence of secondary amenorrhea and age at menarche or pregnancy history. The authors concluded that the incidence of secondary amenorrhea is very low, and they were unable to arrive at a statistical correlation between the use of oral contraceptives and the occurrence of subsequent amenorrhea. In some studies,53.56 35% to 50% of patients had experienced episodes of amenorrhea, menstrual irregularities, or late onset of menses prior to taking oral contraceptives. However, women with no previous menstrual abnormalities have also developed this particular "syndrome." Such patients should be screened for the existence of a pituitary tumor, especially if the amenorrhea is associated with galactorrhea. If a tumor can be ruled out, the major consideration influencing treatment should be the desire for pregnancy by the patient. Several therapeutic approaches may be considered. One consists of the administration of clomiphene citrate in a starting dose of 50 mg/day for 5 days. Should this dosage schedule fail to induce ovulation, the dosage may be increased cautiously to 200 mg/day for 5 days of TABLE 5. Incidence and Prevalence Rates of Secondary A menorrhea 52 Secondary amenorrhea
I-Year rate >3 rno
>6 rno
3.3
0.7
4.4
1.8
>12 rno
%
Incidence Prevalence
1.1
June 1977 each cycle. 53, 55 One should be willing to persist for at least 6 months with clomiphene therapy before abandoning it for other approaches such as gonadotropin administration. The patient must be followed closely to detect early significant side effects such as enlarging or polycystic ovaries. The majority of such patients will respond to this particular regimen with evidence of ovulation and the return of menses. The most responsive patients are those with adequate endogenous estrogen production. However, a relatively large percentage of patients who ovulate and menstruate after clomiphene therapy do not achieve a pregnancy. Shearman55 studied 103 patients with secondary amenorrhea lasting more than 12 months following pill usage, 30 of whom underwent spontaneous cure. Treatment of 61 patients consisted of clomiphene citrate in some and subsequent administration of human pituitary gonadotropin in others (Table 6). This treatment resulted in a pregnancy rate of 43.6%. Unfortunately, 14 patients who achieved a pregnancy subsequently developed persistent amenorrhea. TABLE 6. Results of Treatment in Patients with Postpill Amenorrhea of More than 12 Months'Duration 55 Treatment
No. of patients
Total Apparently ovulating Conceiving
Clomiphene citrate
Human pituitary gonadotropin
61
7 7 4
34
22
Certain patients with secondary amenorrhea will also develop galactorrhea and have high levels of serum prolactin. Women with amenorrhea-galactorrhea and high serum prolactin levels usually have normal to low levels of serum gonadotropins and estrogens. 56-58 Since patients with low estrogen levels respond poorly to the administration of clomiphene and/or human pituitary gonadotropin, other forms of therapy have been explored. 58-63 The compounds 2-bromo-a-ergocryptine and 2 -chloro-6-methy lergoline-8B-acetoni trite methanesulfonate have been used with varying degrees of success in reducing prolactin levels. 59-63 The use of these agents in women with amenorrheagalactorrhea syndrome results in resumption of menses, ovulation, and (in SOn,:le cases) pregnancy. Unfortunately, a certain percentage of these women not only will remain refractory to this therapy but will, as with clomiphene, revert to an amenorrheic state following discontinuation of the therapy.
Vol. 28, No.6
CONTRACEPTIVE USE AND SUBSEQUENT FERTILITY
In society today, increasing numbers of couples are delaying their childbearing functions into the late second and early third decades because of financial and/or educational considerations. It is especially important that the physician apprise individuals who have abnormal menstrual patterns of the possibility of infertility following the use of any contraceptive modality, including the oral contraceptives. Many of these patients do not understand that the use of oral contraceptives which produce an artificial regularity of menses may indeed mask an underlying infertility problem.
INTRAUTERINE DEVICES
A significant percentage of infertile patients have potentially surgically correctable lesions. Usually the presence of tubo-ovarian, peritubal, and other associated pelvic adhesions can be related to a recognized episode or multiple episodes of prior pelvic inflammatory disease. This may include endometritis with associated salpingitis, prior pelvic surgery, a ruptured appendix with abscess formation, or possibly an episode of ruptured bowel diverticula. The relationship among prior pelvic infection, the formation of adhesions, and resultant infertility should not be the subject of serious academic debate. The use of the Grafenberg IUD and its modifications in the early 1900s was condemned and its use discontinued primarily because of an unacceptably high incidence of acute pelvic inflammatory disease associated with maternal mortality. Following the reintroduction of the modem intrauterine devices in the early 1960s, the question of whether the IUD causes an increased incidence of clinical or subclinical pelvic inflammatory disease persisted. The withdrawal from use of the Dalkon Shield in 1974 was in part the result of reports of serious pelvic infections with the subsequent death of some pregnant patients who continued to wear the device. 64 -67 One explanation for this outcome was the multifilament tail appended to the device, which acts as a wick, drawing fluid and viable bacteria into the intrauterine cavity. Tatum and co-workers68, 69 have demonstrated this wicklike effect and have cultured both aerobic and anaerobic bacteria from the intrauterine portion of the string. In addition, they reported that more than 35% of the devices studied showed breaks in the sheath of the tail within the intrauterine cavity. However, speculation still persists as to whether
609
the multifilament tail is indeed the sole cause for the development of pelvic inflammatory disease. Patients with other devices containing monofilament tails are included in the reports of sepsis with the Dalkon Shield. 64 , 70-72 Mishell et al. 73 have shown that, with the introduction of an intrauterine device, each patient has her intrauterine cavity contaminated by bacteria. However, over a short period of time the uterus, through multiple biologic mechanisms, is apparently able to cleanse and sterilize its environment. Recently Taylor et aJ.7° described a syndrome of unilateral tubo-ovarian abscess in 16 patients wearing IUDs. In none of these patients was Gonococcus cultured. Unilateral tubo-ovarian abscess has, as a general rule, been a rare clinical condition unless it followed the development of other unilateral pelvic disease or followed pelvic surgery. The observations by Taylor et aJ.7° were confirmed in several other institutions in which the occurrence of unilateral pelvic abscess was also associated with a high incidence of IUD usage. 70 Willson and Ledger74 have shown an increased incidence of overt pelvic inflammatory disease in a population consisting primarily of private patients wearing IUDs as compared with those using other forms of contraception or no contraception. Wright and Laemmle 75 reported that, in an indigent population at Grady Hospital in Atlanta, the over-all crude attack rate of pelvic inflammatory disease was approximately 1%. When postpartum returnees were studied and analyzed, the patients who accepted an IUD had an incidence of pelvic inflammatory disease of 66.2/1000 woman-years; those accepting oral contraception, 13.411000 woman-years; and foam acceptors, 25.2/1000 woman-years. Faulkner and Ory 76 studied a group of febrile and afebrile patients seen in an emergency room with a diagnosis of pelvic inflammatory disease. These patients were then matched with control patients seen in the same area with complaints other than abdominal pain or discomfort who had no gynecologic pathologic diagnosis. The results revealed a significantly higher proportion of IUD users among the febrile cases of pelvic inflammatory disease than among controls (38% versus 11%, respectively). Their conclusion was that an IUD user is approximately 4 times more likely to develop pelvic inflammatory disease than is a nonuser.
610
HUGGINS
June 1977
TABLE 7. Study of Women Using Different Methods of Contraception 2 Disease of reproductive system"
Salpingitis, pelvic inflammatory disease, endometritis
Type of event
Inpatient Over-all
Method of contraception in use on admission Oral
Diaphragm
IUD
0.63 1.02
0.58 0.94
1.81 2.46
Total
x'
0.84 (47)b 1.27 (71)
14.5 14.6
"Standardized first-event rates (per 1000 woman-years) in each entry group. bTotal numbers of affected women are shown in parentheses.
One problem inherent to a study such as this is the possible relative over-reporting of diagnoses of pelvic inflammatory disease in a clinic population. There still persists in some areas the concept that clinic patients are subject to pelvic inflammatory disease while private patients are predisposed to endometriosis. Jacobson and Westrom 77 in Sweden compared the results of laparoscopic diagnosis of pelvic inflammatory disease with that of clinical diagnosis and found that, of patients suspected of having pelvic inflammatory disease, visual confirmation could be made in only 65%. This experience has been shared in our own institution by physicians at all stages of training and expertise. Without documenting the exact incidence of incorrect diagnosis, it should be well accepted that our clinical acumen with regard to diagnosing pelvic inflammatory disease is not totally satisfactory. Westrom et al.72 compared the frequency ofIUD use in 515 patients who had laparoscopy-confirmed acute salpingitis with that in 741 sexually active, matched controls. The frequency of IUD usage was significantly higher (p < 0.001) in study patients than in controls. The increased risks for pelvic inflammatory disease for never-pregnant patients was 7-fold. Vessey et ai.2 found a significant increase in the frequency of diagnosis of pelvic inflammatory disease in both inpatient and outpatient IUD users versus oral contraceptive or diaphragm users (Table 7). With regard to the IUD and future fertility, concern and speculation have centered primarily on the incidence of pelvic inflammatory disease and whether or not an IUD increases the risk of this disease process. Even if certain assumptions are made, it is difficult to define exactly what constitutes pelvic inflammatory disease and to evaluate its degree of severity. The issue of the subsequent development of pelvic adhesions which may contribute to infertility is dependent on many variables. It is difficult to draw definitive conclusions regarding these questions because the incidence, the treatment patterns, the progression, and the recurrence of the disease process are m ul tifactorial.
Tietze and Lewitt78 were unable to demonstrate impaired fertility among women who discontinued the intrauterine device because of a desire for pregnancy; over 30% conceived within 1 month, approximately 60% within 3 months, and almost 90% within 1 year. Tatum79 reported a cumulative pregnancy rate of 84.6% in 1 year among 553 women who had had Copper-Ts removed in order to establish another pregnancy. The figures reported in these studies are within the same range for all women attempting to achieve a pregnancy. These authors concluded that short-term use (1 to 3 years) of an intrauterine device does not impair future fertility. SUMMARY
There is a very small correlation, if any, between the prior use of oral contraceptives and congenital malformations, including Down's syndrome. There are few, if any, recent reports on masculinization of a female fetus born to a mother who took an oral contraceptive containing 1 mg of a progestogen during early pregnancy. However, patients suspected of being pregnant and who are desirous of continuing that pregnancy should not continue to take oral contraceptives, nor should progestogen withdrawal pregnancy tests be used. Concern still exists regarding the occurrence of congenital abnormalities in babies born to such women. The return of menses and the achievement of a pregnancy may be slightly delayed after oral contraceptives are discontinued, but the fertility rate is within the normal range by 1 year. The incidence of postoperative infection following first-trimester therapeutic abortion in this country is low. However, increasing numbers of women are undergoing repeated pregnancy terminations, and their risk for subsequent pelvic infections may be multiplied with each succeeding abortion. No firm conclusion can be reached with regard to the incidence of prematurity due to cervical incompetence or surgical infertility following pregnancy terminations in the United States. Asherman's syndrome may occur following nonseptic therapeutic abortion. The success-
. Vol. 28, No.6
CONTRACEPTIVE USE AND SUBSEQUENT FERTILITY
ful pregnancy rate following treatment of this syndrome is low. The incidence of "postpill" amenorrhea of more than 6 months' duration is probably less than 1%. The occurrence of the "syndrome" does not seem to be related to length of use or type of pill. Patients with prior normal menses as well as those with menstrual abnormalities before use of oral contraceptives may develop this syndrome. Patients with normal estrogen and gonadotropin levels usually respond with return of menses and ovulation when treated with clomiphene. The rate for achievement of pregnancy is much lower than that for return of menses. If serum prolactin levels are elevated and gonadotropin and estrogen levels are low, patients respond poorly to any treatment regimen. There are no standard, accepted, criteria for defining pelvic inflammatory disease or for categorizing its severity. The incidence of pelvic inflammatory disease appears to be higher among IUD users than among patients taking oral contracepti ves or using a barrier method. The effect of infection on future development of pelvic adhesions with resultant infertility is difficult to appraise. All present methods of contraception entail some risk to the patient. The risk of impaired future fertility with the use of any method appears to be low. Careful identification of patients who may be at high risk, such as those with a history of oligomenorrhea or pelvic inflammatory disease, may allow the physician to suggest a method which imposes the least risk to future fertility. REFERENCES 1. The Allan Guttmacher Institute: Organized family planning services in the United States: FY 1975. Fam Plann Perspect 8:269, 1976 2. Vessey M, Doll R, Peto R, Johnson B, Wiggins P: A longterm follow-up study of women using diffierent methods of contraception: an interim report. J Biosoc Sci 8:373, 1976 3. Weinstock E, Tietze C, Jaffe FS: Legal abortions in the United States since the 1973 Supreme Court decisions. Fam Plann Perspect 7:23, 1975 4. Tietze C, Bongaarts J, Schearer B: Mortality associated with the control offertility. Fam Plann Perspect 8:6, 1976 5. Siegel D, Corfman P: Epidiological problems with studies of the safety of oral contraceptives. JAMA 203:950, 1968 6. Carr D: Chromosomes after oral contraceptives. Am J Obstet Gynecol 97:283, 1967 7. Carr D: Chromosome studies in selected spontaneous abortions: conception after oral contraceptives. Can Med Assoc J 103:343. 1970 8. Wilkins L: Masculinization of the female fetus due to use of orally given progestins. JAMA 172:1028, 1960 9. Janerich DT, Piper JM, Glebatis D: Oral contraceptives and congenital limb-reduction defects. N Engl J Med 291:697, 1974
611
10. Nora JJ, Nora AH: Birth defects and oral contraceptives. Lancet 1:941, 1973 11. Levy EP, Cohen A, Fraser FC: Hormone treatment during pregnancy and congenital heart defects. Lancet 1:611, 1973 12. Oakley GP Jr, Flynt WJ Jr, Falek A: Hormonal pregnancy tests and congenital malformations. Lancet 2:256, 1973 13. Kaufman RL: Birth defects and oral contraceptives. Lancet 1:1396, 1973 14. Janerich DT, Flink EM, Koegh MD: Down's syndrome and oral contraceptive usage. Br J Obstet Gynaecol 83:617, 1976 15. Poland VJ, Ash KA: The influence of recent use of an oral contraceptive on early intrauterine development. Am J Obstet Gynecol 116:1138, 1973 16. Royal College of General Practitioners: Oral Contraceptives and Health. London, Pitman Medical Publishers, 1974, p 71 17. Royal College of General Practitioners: the outcome of pregnancy in former oral contraceptive users. Br J Obstet Gynaecol 83:608, 1976 18. Klinger HP, Glasser M, Kava W: Contraceptives and the conceptu8---{:hromosome abnormalities of the fetus and neonate related to maternal contraceptive history. Obstet Gynecol 48:40, 1976 19. Jacobs PA, Melville M, Ratcliffe S: A cytogenetic survey ofll,680 newborn infants. Ann Hum Genet 37:359,1974 20. Garcia CR: The oral contraceptive-an appraisal and review. Am J Med Sci 253:718, 1967 21. Littlefield LG, Mailhes JB: Comparison of chromosome breakages in lymphocytes and fibroblasts from control women taking oral contraceptives. Fertil Steril 26:828, 1975 22. Robinson SC: Pregnancy outcome following oral contraceptives. Am J Obstet Gynecol 109:354, 1970 23. Deleted in proof 24. Crawford JS: Pre-pregnancy oral contraceptives and respiratory distress syndrome. Lancet 1:858, 1973 25. Rothman KJ, Liess J: Gender of offspring after oral contraceptive use. N Engl J Med 295:859, 1976 26. Keserii TL, Maraz A, Szabo J: Oral contraception and sex ratio at birth. Lancet 1:369, 1974 27. Oechsli FW: Oral contraception and sex ratio at birth. Lancet 1:1004, 1974 28. Dykova H, Havranek F, Pospisil J: Backflow of the blood into the oviducts as a possible cause of sterility after abortion. Zentralbl Gynaekol 82:1228, 1960 29. Midak E: Bezposrednie i Pozne nastepstwa zabiegow przerywania ci~. Pol Tyg Lek 21:1063, 1966 30. Pantelakis SN, Papadimitriou GC, Doxiadis SA: Influence of induced and spontaneous abortions on the outcome of subsequent pregnancies. Am J Obstet Gynecol 116:799, 1973 31. Louros N, Danezis J, Trichopoulos D: Population Policy in Developed Countries, Edited by B Berelson. New York, McGraw-Hill, 1974, p 171 32. Trichopoulos D, Handanos N, Danezis J, Kalandidi A, Kalapothaki V: Induced abortion and secondary infertility. Br J Obstet Gynaecol 83:645, 1976 33. Comninos AC: In Proceedings of the VIIth World Congress on Fertility and Sterility, Japan, Tokyo and Kyoto, 1972, p 393 34. Gebhard PH, Pomeroy WB, Martin CE, Christenson CV: Pregnancy, Birth and Abortion. Third Report. Institute for Sex Research of Indiana University. New York, Harper and Row, 1958 35. Hayashi M, Momose K: Harmful Effects of Induced Abortion, Edited by Y Koya. Japan, Sanshu Printing Industry, 1966, p 3 36. Glenc F: Early and late complications after therapeutic abortion. Am J Obstet Gyneco1118:34, 1974
612
HUGGINS
37. L.indahl J: Somat~c Complications following Legal Abortion. London, Hememann Medical Books 1959 38. Teitze C, Lewitt S: Highlights ofthe Joint Program for the study of Abortion (JPSA): early medical complications of legal abortion. Adv Planned Parent 8:173, 1973 39. Pakter J, Nelson F, Svigir M: Legal abortion: a half-decade o~ experience. Fam Plann Perspect 7:248,1975 40. TIetze C: The problem of repeat abortions. Fam Plann Perspect 6:148, 1974 41. C.enter for Disease Control, Department of Health, Education and Welfare: Abortion Surveillance, Annual Summary 1974, 1976, P 33 42. Klein SM, Garcia CR: Asherman's syndrome: a critique and current review. Fertil Steril 24:722, 1973 42a. March CM, Israel R: Intrauterine adhesions secondary to elective abortion. Obstet Gynecol 48:422, 1976 43. Wood J, Pena G: Treatment of traumatic uterine synechiae. Int J Fertil 9:405, 1964 44. Bergman P: Traumatic intrauterine lesions. Acta Obstet Gynecol Scand [Suppl 4] 40:1, 1961 45. R.ice-Wray E, Correu S, Gordovsky J, Esquiver J, GoldZIeher JW: Return of ovulation after discontinuance of oral contraception. Fertil Steril 18:212, 1967 46. Shearman RP: Amenorrhoea after treatment with oral contraceptives. Lancet 2:1110, 1966 47. Whitelaw MJ, Nora VF, Kalman CF: Iregular menses, amenorrhea, and infertility following synthetic pregestational agents. JAMA 195:780, 1966 48. Friedman S, Goldfein A: Amenorrhea and galactorrhea following oral contraceptive therapy. JAMA 210:1888, 1969 49. Halbert DR, Christian DC: Amenorrhea following oral contraceptives. Obstet Gynecol 34:161, 1969 50. Shearman RP: Prolonged secondary amenorrhoea after oral contraceptive therapy. Natural and unnatural history. Lancet 2:64, 1971 51. Larsson-Cohn U: The length of the first three menstrual cycles after combined oral contraceptive treatment. Acta Obstet Gynecol Scand 48:416, 1969 52. Pettersson F, Fries H, Nillius JS: Epidemiology of secondary amenorrhea. Am J Obstet Gynecol 117:80, 1973 53. Golditch 1M: Postcontraceptive amenorrhea. Obstet Gynecol 39:903, 1972 54. Furuhjelm M, Carlstrom K: Amenorrhea following use of combined oral contraceptives. Acta Obstet Gynecol Scand 52:373, 1973 55. Shearman RP: Secondary amenorrhea after oral contraceptives-treatment and follow-up. Contraception 11 :123 ~% ' 56. Archer DF, Nankin HR, Gabos PF, Maroon J, Nosetz S, Washwa SR, Josimovich JB: Serum prolactin in patients with inappropriate lactation. Am J Obstet Gynecol 119:466, 1974 57. Franks S, Murray MAF, Jequier AM, Steele SJ, Nabarro JDN, Jacobs HS: Incidence and significance of hyperprolactinaemia in women with amenorrhoea. Clin Endocrinol (OxD 4:957, 1975 58. Spark RF, Pallotta J, N aftolin F, Clemens R: Galactorrheaamenorrhea syndromes: etiology and treatment. Ann Intern Med 84:532, 1976 59. Lloyd SJ, Josimovich JB, Archer DF: Amenorrhea and galactorrhea: results of therapy with 2-bromo-alphaergocryptine (CB-154). Am J Obstet Gynecol 122:85, 1975 60. Thorner MO, McNeilly AS, Hagan C, Besser GM: Longterm treatment of galactorrhoea and hypogonadism with bromocriptine. Br Med J 25:419, 1974
June 1977 61. del Pozo E, Brun del Re R, Varga L, Friesen H: The inhibition of prolactin secretion in man by CB-154 (2-bromalpha-ergocryptine). J Clin Endocrinol Metab 35:768, 1972 62. Thorner MO, Besser GM, Jones A, Dacie J, Jones AE: Bromocriptine treatment of female infertility: report of 13 pregnancies. Br Med J 4:694, 1975 63. Lemberger L, Crabtree R, ClemensJ, Dyke RW, Woodburn RT: The inhibitory effect of an ergoline derivative (Lergotrile, Compound 83636) on prolactin secretion in man. J Clin Endocrinol Metab 39:579, 1974 64. Jennings J: Report of Safety and Efficacy of the Dalkon Shield and Other IUD's Prepared by the ad hoc Obstetrics and Gynecology Advisory Committee to the US Food and Drug Administration, No 16. Washington DC, United States Government Printing Office, 1974, p 29 65. Preston ES: Septic spontaneous abortion associated with the Dalkon Shield. In Analysis ofIntrauterine Contraception, Edited by F Hefnawi, S Segal. Amsterdam, North Holland Publishing Co, 1975, p 417 66. Kahn HS, Tyler CW: An association between the Dalkon Shield and complicated pregnancies among women hospitalized for intrauterine contraceptive device-related disorders. Am J Obstet GynecoI125:83, 1976 67. Christian CD: Maternal deaths associated with an intrauterine device. Am J Obstet Gynecol 119:441, 1974 68. Tatum HJ, Schmidt FH, Phillips D, McCarty M, O'Leary WM: The Dalkon Shield controversy: structural and bacteriological studies of IUD tails. JAMA 231:711, 1975 69. Tatum HJ, Schmidt FH, Phillips D: Morphological studies ofDalkon Shield tails removed from patients. Contraception 11:465, 1975 70. Taylor ES, McMillan JH, Greer BE, Droegemueller W, Thompson HE: The intrauterine device and tubo-ovarian abscess. Am J Obstet GynecoI123:338, 1975 71. Mead PB, Beecham JB, Maeck JVS: Incidence of infections associated with the intrauterine contraceptive device in an isolated community. Am J Obstet GynecoI125:79, 1976 72. Westrom L, Bengtsson LP, Mardh PA: The risk of pelvic inflammatory disease in women using intrauterine contraceptive devices as compared to non-users. Lancet 2:221, 1976 73. Mishell DR, Bell JH, Good RG, Moyer DL: The intrauterine device: a bacteriologic study of the endometrial cavity. Am J Obstet Gynecol 96:119, 1966 74. Willson RJ, Ledger WJ: Complications associated with the use of intrauterine contraceptive devices in women of middle and upper socioeconomic class. Am J Obstet Gynecol 100:649, 1968 75. Wright NH, Laemmle P: Acute pelvic inflammatory disease in an indigent population: an estimate of its incidence and relationship to methods of contraception. Am J Obstet Gynecol 101:979, 1968 76. Faulkner WL, Ory HW: Intrauterine devices and acute pelvic inflammatory disease. JAMA 235:1851, 1976 77. Jacobson L, Westrom L: Objectivized diagnosis of acute pelvic inflammatory disease. Am J Obstet Gynecol 105:1088, 1960 78. Tietze C, Lewitt S: Evaluation of intrauterine devices: ninth progress report of the Cooperative Statistical Program. Stud Fam Plann 55:1,1970 79. Tatum HJ: Comparative experience with newer models of the Copper T in the United States. In Analysis of Intrauterine Contraception, Edited by F Hefnawi, S Segal. Amsterdam, North Holland Publishing Co, 1975, p 155