PrefS'nancy after Clom,iphene Citrate Treatment

Transcription

1 .. PrefS'nancy after Clom,iphene Citrate Treatment WILLIAM C. KAROW, M.D., and SHELDON A. PAYNE, M.D. RR YEARS the gynecological endocrinologist has been seeking an effective gonadotrophin for the treatment of ovarian dysfunction and anovulation in the human. 7 Animal preparations have been self-limiting because of allergic reactions, antihormone formation, failure to obtain a uniform response from a standard dose, and the absence of data on animal specificity. A breakthrough occurred in 1958 when Gemzell et al. reported a human pituitary gonadotropin which induced follicular growth and estrogen production in the ovaries of amenorrheic women. The human source does not permit widespread application of this material. A few years later, Pergonal (HMG ),* a human menopausal urine gonadotropin which had similar effects,16 was developed; but standardization of HMG has been difficult and the extraction process complicated and expensive. A most important contribution was made in 1959 by Tyler et al., who were able to induce ovulation in 6 patients with severe anovulatory problems, and in 1960 by Kistner and Smith, who successfully induced ovulation in 4 patients with the Stein-Leventhal syndrome, by using the estrogen antagonist MER 25.t Related compounds were further investigated and clomiphene citrate (Clomidt) proved more effectiv.e and had fewer side effects. 5, 12 The exact mechanism of action of the drug is stili in doubt. It is postulated that clomiphene acts either directly on the hypothalamic-pituitary axis, causing an increase in gonadotropin output,9, 12, 17 or sensitizes the ovary to respond more readily to endogenous gonadotropins. 6 Smith and Kistner believe that Clomid directly influences the enzyme systems involved in ovarian steroidogenesis, or merely acts as a potentiator of gonadotropins. Pildes believes that there is a change in the synthesis of From The Shelton Clinic, Los Angeles, Calif. Presented at the meeting of the Pacific Coast Fertility Society, Palm Springs, Calif., Oct , *Institute Farmacologico Serano, Rome, Italy. t'rhe W'm. S. Merrell Co., Cincinnati, Ohio. 351

2 352 KAROW & PAYNE FERTILITY & STERILITY estrogen in both the adrenals and ovaries at the pre-estradiol phase of steroid synthesis. Dickey et al. postulate a direct anti-estrogen effect in the system involved in estrogen metabolism, with subsequent stimulation of the hypothalamic-pituitary axis due to a fall in estrogen levels. Probably more than one mechanism of action is responsible for the response to the drug. We first used clomiphene in the treatment of infertile patients with impaired ovarian function in May Because of the frequent side effects such as large ovarian cysts, reported by the early investigators, its use was limited to women with major endocrine defects and in cases where all other treatments had failed. With more experience and smaller dosages, mg. daily for a short period of time, 3-5 days of each cycle, the drug was effective and most of the side effects were eliminated.14 With a program of at least monthly checkups, the drug proved safe and we have extended its use to infertile patients with only minor problems of ovarian dysfunction. All patients, prior to treatment, have a thorough infertility and endocrine evaluation. The patient who is a proper candidate for this drug should be one with a moderately intact pituitary-ovarian axis and norm~d or low total urinary gonadotropin levels, although we have had several patients with mildly elevated total gonadotropin who have responded. The patient should have a fair endogenous estrogen production. Thyroid function is usually normal or mildly subnormal. The 17-ketosteroid concentration is usually normal, although 32.5% of our patients who conceived did show levels of 13.0 mg.j24 hr. or more. Several of these decreased to normal levels after treatment with clomiphene; Pildes has reported a similar finding. Of our patients who conceived, 35.5% showed a diabetic or a prediabetic glucose tolerance curve on initial evaluation. Pituitary tumors should be ruled out. Patients with ovarian damage due to chronic infection are not likely to respond. Since clomiphene citrate is detoxified in the liver, one should be hesitant to prescribe the drug to a patient with chronic liver disease. Visualization of the ovaries by culpotomy with ovarian biopsy or culdoscopy is helpful in establishing the diagnosis, especially in patients who fail to respond. MATERIAL This clinic treated 410 infertile women with clomiphene citrate from May 1962 through September In this series, 163 patients (39.8%) conceived, which resulted in 180 pregnancies within 6 months of the last dose or with clomiphene in the cycle of conception itself. These women

3 fp: S VOL. 19, No.3, 1968 POST-CLOMIPHENE CONCEPTION 353 were all private patients whose basic evaluation and treatment was supervised under a uniform program. Once conception had occurred, the course of pregnancy was managed by physicians specializing in obstetrics and gynecology. The age of those conceiving ranged from 21 to 44 years, with an average of 29.9 years. The duration of infertility had varied from 6 to 155 months, with an average of 40 months. The average duration of treatment was 8.6 months, varying from 1 to 40 months. Several factors contributed to the infertility problems, but in all cases, impaired ovarian function was a major or contributing factor, as confirmed by endometrial biopsy. In 71% of the couples, there was some degree of impairment of the husband's sperm count or quality. For those conceiving, the total dose of clomiphene varied from 100 to 10,050 mg. prior to conception, with an average of 1933 mg. The number of cycles in which patients received clomiphene prior to conception varied from 1 to 14, with an average of 3.1 cycles; these patients received a total of 557 courses of clomiphene treatment. RESULTS Ovulation Related to Last Dose of Clomid Clomiphene is now being introduced in some clinics to implement the rhythm system of contraception. It is hoped that the drug will provide a means of predicting the day of ovulation more accurately. In our experience, the date of ovulation is quite variable after the termination of therapy. Even in patients who had several conceptions there was some variation in th date of ovulation from one pregnancy to the next. We usually give clomiphene for 5 days, beginning on the third or fourth day of the cycle, the dose varying from 50 to 300 mg. per day. In 125 of our patients who took clomiphene during the cycle of conception, the date of ovulation varied between 4 and 17 days after the last day of therapy (Fig. 1). There were 3 patients who ovulated on Day 4 after the last day of clomiphene therapy; 15 on Days 5 and 6; 20 on Day 7; 18 on both Day 8 and Day 9; and 16 on Day 10. There were 6 patients whose ovulation occurred on Day 11 after the last day of treatment; 4 on Day 12; 3 on Day 13; 2 on Day 14; 3 on Day 15; and 1 each on Days 16 and 17. Although the majority (8l.6%) conceived between Days 5 and 10, IS.4% of ovulations occurred out of that range. Side Effects Thirty-one patients (19%) developed side effects; several had more than one. These reactions consisted of ovarian enlargement in 14 (8.6%); hot

4 354 KAROW & PAYNE FERTILITY & STERILITY flashes in 10 (6.1%); and visual symptoms in 5 (3.1%). Three patients ( 1.8%) became depressed while taking clomiphene; 1 (0.6%) had increased libido, which was also noted in several of our patients who did not conceive. Two patients (1.2%) developed severe abdominal pain following _14 - g 12 - ~1O ~ u 6 - END OF 4 MEDICATION 2-6 o L-"----::--'-:-~-:O--'---:-4 -"-C S DAYS AFTER TREATMENT Fig. 1. Conception date after last day of clomiphene therapy. ovulation, and 1 (0.6%) became consistently constipated each time sh~ took the medication. There were 13 patients who had prolonged luteal phases varying from 4 to 10 weeks. In these cases, pregnancy could not be proved since the patients did not have positive pregnancy tests, nor did the tissue passed show chorionic villi. Some of these represented pregnancies with blighted ovum, but they were not included in the total if pregnancy could not be confirmed. It is frequently our practice to give hormonal support to patients with a luteal phase of 25 days or more, even prior to the confirmation of pregnancy. If pregnancy cannot be confirmed over the next 4 weeks, this is discontinued. This would account for some of the luteal phases that lasted 7 or 8 weeks. We have found that it is not unusual for the vec pregnancy test to take longer than the usual days,20 after ovulation, to become positive in an infertility patient. Outcome of Pregnancies after Treatment There were 140 pregnancies of known outcomes of which 90 patients delivered at 36 weeks or more, including 4 sets of twins: all 94 infants survived (Table 1). Of the twins, there were.5 males and 3 females. Nineteen pregnancies terminated prematurely (2~36 weeks), including 6 sets of twins. Of the 25 infants, one was stillborn at 32 weeks due to an

5 VOL. 19, No.3, 1968 POST-CLOMIPHENE CONCEPTION 355 TABLE 1. Known Outcome of Conceptions after Clomiphene Treatment Twin Outcome % Pregnancies Infants sets Survived Term (36 wks +) Premature (28-36 wks) Immature (20-28 wks) Abortion (less than 20 wks)* It 0 TOTAL * Included 2 ectopic pregnancieh. t Aborted because of rubella. abruption in a patient with thrombocytopenia and subsequent hypofibrinogenemia. Another patient abrupted at 31 weeks; however, the infant lived for 25 hr. before dying of hyaline membrane disease. The third delivered at 29 weeks with labor's having been precipitated by an incompetent cervix; infant death resulted from atelectasis and prematurity. Of those infants surviving, 1 was delivered at 2m~ weeks.because of a premature rupturing of the membranes, and 1 at 30 weeks because of premature labor due to an incompetent cervix. The 6 sets of twins included 5 males and 7 females, all of whom survived. One set of twins was delivered at 33 weeks, 1 at 34 weeks, and 4 at 35 weeks. Four pregnancies terminated immaturely (20-28 weeks); included among these is 1 set of twins delivered at 20 weeks as a result of premature labor. The other 3 patients had an incompetent cervix; 1 also had an associated abruption. All infants were born alive, but none survived. Of the 124 infants there were 56 males and 68 females. There were 27 abortions including 1 of a set of twins at 8 weeks, induced because of German measles, and 2 ectopics. One pregnancy was lost to follow-up and 39 are undelivered to date. Conception in the First Clomiphene Cycle It has been stated, but not confirmed, that patients conceiving in their first cycle of clomiphene treatment are more likely to abort and more prone to have twin pregnancies.s Of our 180 pregnancies, 32 (17.7%) were conceived in their first cycle of this drug; of these, 6 (18.75%) aborted. There were 15 term infants. Of the 6 premature deliveries, including 2 sets of twins, 7 infants survived. There was 1 immature twin delivery at 20 weeks. To date, 4 pregnancies are undelivered. Our incidence of twins here was 9.5%.

6 TABLE 2. Pregnancy Outcome as Related to Menstrual History Total Cycles Patients conceptions Term Premature Immature.'lb. Undel. Regular (25-33 days) (2) 9 (2) 1 (1) 17* 23 Moderately irregular (2-12 weeks) (1) 6 (2) 6 (1) 8 Primary amenorrhea Secondary amenorrhea (3-36 months) (1) Postpartum amenorrhea (8-30 months) (1) 2 3 Post-contraceptive amenorrhea (6-12 mos) Stein-Leventhal syndrome (1) 3 Figures in parentheses represent sets of twins. * Includes both ectopic pregnancies. Lost 1

7 VOL. 19, No.3, 1968 POST-CLOMIPHENE CONCEPTION 357 Pregnancy Outcome and Menstrual History The patients were classified on the basis of menstrual history (Table 2). There were 89 patients with regular menstrual cycles (25-33 days), who conceived 94 times; 44 pregnancies were delivered at term (2 twins); 9 prematurely (2 twins); and 1 immaturely (twins); 17 were abortions, including both ectopics. Twenty-three are undelivered to date. With moderate menstrual irregularities (2-12 weeks), 44 patients conceived 50 times, including 30 term deliveries (1 twin), 6 prematurely (2 twins), 6 abortions (1 twin), and 8 undelivered as yet. Of the 2 patients with primary amenorrhea, 1 patient on 2 occasions had menstruation, ovulation, and conception precipitated by clomiphene. Without the drug she is amenorrheic. Her first pregnancy terminated at 20 weeks because of an incompetent cervix; her second terminated at 39 weeks at section after a Shirodkar suture was placed at 14 weeks. The other patient delivered a viable 5-lb. male at 35 weeks. The 11 secondary amenorrheic patients (3-36 months) had 5 term deliveries (1 twin), 1 premature, and 2 immature; 2 abortions, 1 undelivered pregnancy, and 1 which was lost to follow-up. Seven patients developed postpartum amenorrhea of 8-30 months. These patients had had 3 term infants, 1 premature set of twins, and 2 abortions;.3 are undelivered. Of 3 patients with post-contraceptive amenorrhea of 6-12 months, 2 delivered at term and 1 aborted. The 7 patients who had the Stein-Leventhal syndrome, delivered 4 term infants and 1 immature set of twins; 3 are undelivered. Pregnancy Outcome with Prediabetic-Diabetic Glucose Tolerance Curve Of the 163 patients who conceived, 52 (35.6%) showed a diabetic or prediabetic glucose tolerance curve on their initial evaluation. When the tests were repeated during pregnancy, usually in the third trimester, without exception the abnormality was still present. These 52 patients conceived 58 times with 44 surviving children. Twentynine have delivered at term (1 twins), 11 prematurely (4 twins), and 2 immaturely (1 twins); 11 have aborted including 1 with an ectopic pregnancy. There are 5 still undelivered to date. Pregnancy Outcome and 17 -Ketosteroid Level of 13 Mg./24 Hr. or More There were 47 (32.. 5%) patients, conceiving 53 times (28 surviving children), who had a 17-ketosteroid level of 13 mg.j24 hi. or more. Of these, 21 delivered at term, 7 prematurely including 1 set of twins, and 2 immaturely; 11 have aborted, and 12 are undelivered to date.

8 358 KAROW & PAYNE FERTILITY & STERILITY A number of the same patients are included in both this group and the abnormal glucose tolerance group, since the abnormal glucose tolerance curve and elevated 17 -ketosteroid levels seem to go hand in hand. There were 4 infants with fetal anomalies. One had pyloric stenosis, 1 had a congenital hip, 1 had club feet, and 1 had Down's syndrome. All of the mothers had received clomiphene in the cycle of conception, the dose varying from 150 to 500 mg. in that cycle. Pregnancies and Poor Speno Quality... One of the most interesting aspects of this drug, as shown in our patients, is the significant number of conceptions that have occurred from sperm of impaired quality (Table 3). Perhaps with clomiphene we were able to stimulate some conceptions which ordinarily would not have resulted, since the pregnancy rate with poor-quality sperm is not in proportion to that expected or previously found by us and other observers. IS When clomiphene therapy is administered there is frequently scanty and unfavorable mucus during treatment, and after withdrawal of the drug superior cervical mucus develops at the time of ovulation; this cervical mucus is more receptive to sperm. Perhaps this increased receptivity accounts for some of the 96 pregnancies that occurred when the husband's sperm was moderately impaired, along with the 29 pregnancies which developed with extremely poor semen. The poor sperm carried an expected increased incidence of abortion loss. Our sperm evaluation is based on a semen evaluation at the time of conception; when this information was unavailable, the over-all average of the husband's sperm counts was evaluated. We classify normal sperm quality as 60 million with 60% AB activity or better; moderately impaired sperm as million with greater than 40% Be activity and less than TABLE 3. Pregnancies Related to Speno Quality Sperm quality Outcome Normal Impaired Poor Term Premature Immature Abortions Lost to follow-up 1 Not delivered TOTAL 55 (30.6%) 96 (53.3%) 29 (16.1%)

9 VOL. 19, No.. 3, 1968 POST-CLOMIPHENE CONCEPTION % AB activity; and poor quality sperm as less than 20 million or less than 40% Be activity. Complications of Clomiphene Pregnancies Fifty pregnancies were complicated, with several patients having more than 1 complication (Table 4). There were 16 cesarean sections of which 5 followed the placing of Shirodkar sutures for an incompetent cervix; 1 of those patients had 3 separate dermoids at the time of section. Three were repeated sections, 3 were for abruptio placenta, 2 for inertia, 1 for placental insufficiency in an elderly primigravida, and 1 for myoma, at which time a multiple myomectomy was done. One patient had a section because of diabetes insipidus. There were 4 breech deliveries and 12 twin pregnancies. Two patients developed toxemia, 1 with associated chronic kidney disease who delivered a 2-lb. 12-oz. male at 35 weeks, and the other with an associated abruption; 1 patient had chronic hypertension. Twelve patients had an incompetent cervix, 9 of whom had had Shirodkar sutures. Nine of the 12 (75%) had an abnormal uterine contour on salpingogram; 1 had an associated abruption and 1 had placenta accreta. TABLE 4. Complications of Clomiphene Pregnancies Complication Total Survivals Cesarean section After Shirodkar sutures for incompetent cervix 5 5 Abruption (1 with hypofibrinogenemia) 3 1 Repeated section 3 3 Inertia 2 2 Placen tal insufficiency 1 1 Multiple myoma (with associated myomectomy) 1 1 Diabetes insipidus 1 1 Breech 4 Twins 12 Toxemia Chronic kidney disease 1 Abruption 1 1 Chronic hypertension 1 Incompetent cervix Shirodkar sutures 9 7 Accretion 1 1 Abruption 1 0 Placental insufficiency 6 6 Abruptions 5 2 Premature rupture of membranes 1 1 Premature labor 1 0

10 360 KAROW & PAYNE FERTILITY & STERILITY Six patients had placental insufficiency, and 5 abrupted. One patient developed premature labor, the etiology of which was not determined, and 1 patient had premature rupture of the membranes. CONCLUSION Clomiphene citrate therapy is a most useful advance in the treatment of infertile women with minor deviations of ovarian function and irregular ovulation; relatively intact pituitary and endogenous estrogens are a necessary prerequisite to ovulation. The use of human pituitary extract and Pergonal should be limited to those patients with severe pituitary damage and those failing to respond to clomiphene. Although clomiphene will probably become the treatment of choice in many infertility problems, there is still a place for cortisone, PMS, HCG, and occasional wedge resection. The ovaries of women with the Stein-Leventhal syndrome are very sensitive to Clomid and respond to small doses. Cohen believes clomiphene should be tried first, and if it is unsuccessful, then a wedge resection should be done. The usual suggested dose of 50 mg. for 5 days is adequate in most cases, but there are many patients who need doses of mg. for 5-10 days to respond. Although this drug for the most part is now used in treatment of infertility, it will become an ideal method of treatment in dysfunctional uterine bleeding of adolescents and premenopausal women. The incidence of abortion, anomalies, and complicated pregnancies is no greater than that seen in infertility patients prior to the advent of the drug.lo In any infertility patient, especially one with an abnormal uterine contour, we should be continually aware of the possibility of an incompetent cervix. A Shirodkar suture and subsequent cesarean section is little enough price to pay for a healthy term infant. The side effects of ovarian enlargement should be looked for and yet seldom require surgery. These cystic ovarian enlargements usually recede with the onset of the next menstrual period. A few patients may be transiently annoyed by hot flashes while they take the drug, and the addition of estrogens is usually not helpful. A few have complained of blurring vision and scintillating, brightly colored lights in the peripheral vision in a dim light. This occurs during treatment and occasionally lingers for 7-10 days after discontinuing the drug. Although this has been attributed to the mydriatic effect of the drug,2 we have discontinued the drug when this is reported, since the phenomenon is not entirely understood. Some patients have more of an anti-estrogen effect than others and fail

11 VOL. 19, No.3, 1968 POST-CLOMIPHENE CONCEPTION 361 to develop a good-quality cervical mucus at the time of ovulation, even with very low doses of the drug. Estrogen in low doses sometimes helps. For this reason, we have tended to give the drug early in the cycle, beginning on the third or fourth day. In some of these patients, several months of clomiphene treatment will improve the quality of ovulation, and when the drug is discontinued, subsequent ovulations are of good quality and good cervical mucus returns. We do not, to date, feel that there is any reason to prevent conception in the first clomiphene cycle, as the abortion rate and twin rate in our first-cycle conceptions is not significantly different from our over-all average. It is probably wise to supplement pregnancies early with progesterone, since we have found, as did Greenblatt and Mahesh, a marked decrease in the abortion rate by administering substitute progestational agents soon after conception was confirmed. We doubt that clomiphene will ever provide a good method of implementing the rhythm system of contraception, and would expect that when it is tried, we will see not only an increase in conception rates but also an even higher incidence of multiple births in these already fertile women than that now being reported with the drug in infertile patients. The relation of sperm quality to clomiphene conceptions is difficult to explain, but anything that improves cervical mucus with associated sperm transfer and survival should improve over-all fertility. SUMMARY 1. Of 410 infertile women treated with clomiphene citrate between May 1962 and September 1966, 163 conceived 180 times, either during therapy or within 6 months of the last dose. 2. Of the 180 pregnancies, there were 140 of known outcome: 90 term deliveries, 19 prematures, 4 immatures, and 27 abortions. Thirty-nine patients are undelivered to date, and 1 was lost to follow-up. There were 12 twin pregnancies and 116 surviving infants. 3. The complication rate was similar to that in other pregnancies of infertile patients. The abortion rate and twin incidence, when conception occurred in the first clomiphene treatment cycle, was not significantly different enough from rates in other cycles to warrant preventing pregnancy in the first cycle. The number of conceptions that occurred from sperm with impaired quality is out of proportion to that expected or previously reported. 4. When infertile women with impaired ovarian function are carefully

12 362 KAROW & PAYNE FERTILITY & STERILITY selected and closely followed, clomiphene is an effective and safe drug of choice for producing ovulation Wilshire Blvd. Los Angeles, Calif REFERENCES 1. BECK, P., GRAYZEL, E. F., YOUNG, I. S., and KUPPERMAN, H. S. Induction of ovulation with clomiphene. Obstet Gynec 27:54, COHEN, M. Resection of the ovary versus clomiphene for the Stein-Leventhal syndrome. Presented at American Fertility Society, Chicago, Ill., Apr. 29-May 1, DICKEY, R. P., VOVYS, N., STEVENS, V. c., BESCH, P. K., HAMWI, G. I., and ULLERY, J. C. Observations on the mechanism of action of clomiphene (MRL-41). Fertil Steril16:485, GEMZELL, C. A., DICZFALUSY, E., and TIL LINGER, K. G. Clinical effect of human pituitary follicle-stimulating hormone. I Clin Endocrinol 18: 13.33, GREENBLATT, R. B., BARFIELD, W. E., JUNGCK, E. C., and RAY, A. W. Induction of ovulation with MRL-41. lama 178: 101, GREENBLATT, R. B., and MAHESH, V. F. "Induction of Ovulation with Clomiphene Citrate." In Year Book of Endocrinology, Yr. Bk. Pubs., Chicago, 1965, p HAMBLEN, E. C., CUYLER, W. K., WILSON, M. A., and PULLEN, R. L. Endocrine therapy of functional menometrorrhagia and ovarian sterility. I Clin Endocrinol 1:742, '. 8. JOHNSON, J. E. Outcome of pregnancy following clomiphene citrate therapy. Presented at Fifth World Congress on Fertility and Sterility, Stockholm, Sweden, June , JONES, G. S., and DEMoRAES-RUEHSEN, M. Induction of ovulation with human gonadotropins and with clomiphene. Fertil Steril 16:461, KAROW, W. G., and PAYNE, S. A. Pregnancy complications in an infertility practice. Presented at Pacific Coast Fertility Society, Scottsdale, Ariz., Oct. 4-7, KISTNER, R. W., and SMITH, D. 'V. Observations on the use of a nonsteroidal estrogen antagonist: MER-25. Surg Forum 10:725, KISTNER, R. W. Further observations on the effects of clomiphene citrate in anovulatory females. Amer I Obstet Gynec 92:380, PAYNE, S. A., and SKEELS, R. F. Fertility as evaluated by artificial insemination. Fertil Steril 5:32, PAYNE, S. A., and KAROW, W. G. The use of clomiphene in the treatment of infertility due to ovarian dysfunction. West I Surg 71:86.3, PILDES, R. B. Induction of ovulation with clomiphene. Amer I Obstet Gynec 91: 466, ROSENBERG, E. Clinical evaluation of human urinary gonadotropin (Pergonal). Presented at Pacific Coast Fertility Society, Scottsdale, Ariz., Oct. 4-7, Roy, S., GREENBLATT, R. B., MAHESH, V. F., and JUNGCK, E. C. Clomiphene citrate: Further observations on its use in induction of ovulation in the human and its mode of action. Fertil Steril14:575, SMITH, G. B., and KISTNER, R. W. Action of MER-25 and clomiphene on the human ovary. lama 184:878, June 15, TYLER, E. T., OLSON, H. J., and COTLIB, M. H. The induction of ovulation with an anti-estrogen. Int I Fertil.5:429, WmTELAw, M. J., and NOLA, V. F. Accuracy of the immunologic pregnancy test in early pregnancy and abortion. Obstet Gynec 27:69, 1963.