Association of endometriosis and spontaneous abortion: effect of control group selection

Transcription

1 FERTILITY AND STERILITY Copyright 1986 The American Fertility Society Vol. 45, No.1, January 1986 Printed in U.S A. Association of endometriosis and spontaneous abortion: effect of control group selection Deborah A. Metzger, Ph.D., M.D. * David L. Olive, M.D. *t Gene F. Stohs, M.D.:j: Robert R. Franklin, M.D. Duke University Medical Center, Durham, North Carolina, Lincoln General Hospital, Lincoln, Nebraska, and Baylor College of Medicine, Houston, Texas Endometriosis has been associated with an increased incidence of spontaneous abortion, compared with the abortion rate of the general population. To assess whether a separate control group would affect these conclusions, we studied 139 consecutive infertility patients with laparoscopically proven endometriosis to determine the incidence of spontaneous abortion. Ninety-five of these patients underwent conservative surgical resection of endometriosis, and 44 patients opted for expectant man. There was no significant difference between these two groups in average age, duration of infertility, or proportion of patients with primary infertility. The average spontaneous abortion rate before diagnosis for all patients was 63.1%. After surgical treatment, the abortion rate dropped to 0% (P < ) for all stages of disease. However, even in those patients who received expectant man only, the abortion rate fell to 16.7% and 21.4% for mild and moderate endometriosis, respectively (P < 0.001). These results suggest that the spontaneous abortion rate in untreated endometriosis may not be as high as previously reported and may not be significantly different from the rate in the general population. The data also emphasize the need for well-defined control groups when assessing the effects of a treatment regimen. Fertil Steril45:18, 1986 Endometriosis is often associated with infertility, affecting approximately 30% to 40% of infertile women. 1, 2 The mechanism by which ectopic endometrial implants interfere with fertility are poorly understood, but an increasing number of Received April 1, 1985; revised and accepted September 23, *Department of Obstetrics and Gynecology, Duke University Medical Center. tpresent address and reprint requests: David L. Olive, M.D., Department of Obstetrics and Gynecology, University of Arkansas for Medical Sciences, 4301 West Markham, Slot #518, Little Rock, Arkansas *Department of Obstetrics and Gynecology, Lincoln General Hospital. Department of Obstetrics and Gynecology, Baylor College of Medicine. 18 Metzger et al. Endometriosis and spontaneous abortion reports implicate multiple factors acting singly or in concert. 2 Several reports 3-10 have suggested an increased incidence of spontaneous abortion in these patients, with a return to the normal abortion rate after medical or surgical treatment. One major criticism of these studies is the lack of a control group derived from the patient population being studied. The study presented here was designed to determine how a control group derived from the study population would affect these conclusions. MATERIALS AND METHODS The 151 patients selected for this study were consecutive patients with the diagnosis of infertility and endometriosis, presenting between Fertility and Sterility

2 January and December All patients had a basic infertility evaluation, including semen analysis, postcoital test, hysterosalpingogram, endometrial biopsy, and laparoscopy performed in the luteal phase with chromopertubation and cervical dilatation. All patients were evaluated and laparoscoped by the same physician (R. R. F.). The diagnosis of endometriosis was made by direct observation at the time oflaparoscopic examination. The degree of involvement with disease was classified according to the staging system of Acosta et alp The patients who were diagnosed with endometriosis were offered conservative surgery as treatinent; those who refused were managed expectantly and served as the control population. Those patients managed expectantly, who by laparoscopic examination were found to have patent tubes with some degree of fimbrial agglutination, were treated with monthly hydrotubation in the proliferative phase of the menstrual cycle. Treatment was continued for up to 6 months and consisted of hydrotubation with 30 ml of normal saline. Those patients who underwent medical or combined medical-surgical therapy were excluded from this report. All patient charts were examined retrospectively and analyzed for the patients' age, gravidity, parity, number of prior spontaneous abortions, degree of endometriosis, treatment, and pregnancy outcome. Additional infertility factors, such as ovulatory dysfunction, uterine anomalies, male factor, and prior history of pelvic surgery, were noted. Documentation of prior spontaneous abortions was primarily by history alone, although where possible documentation by pathologic report or tissue report was obtained. Tests of statistical significance were calculated with chisquare analysis (with Yate's correction factor when necessary) and Fisher's exact test. RESULTS Of the 151 patients who qualified for inclusion in this study, many had multiple infertility factors, such as anovulation, male factor, and uterine anomalies. The latter group, which included 12 women with large myomas or uterine cavity defects was excluded from this study because the presence of these conditions have been associated with an increased spontaneous abortion rate. 12 The remaining 139 patients were included as subjects in this study. They ranged in age from 22 Yol. 45, No.1, January 1986 Table 1. Comparison of Treated and Control Subjects Expectantly Conservative managed" (n = 44) resection (n = 95) No. % No. % Age 27.4 ± ± 2.7 Duration of in- 3.0 ± ± 2.2 fertility % with primary infertili tyb 70 Cumulative spontaneous abortions (pretreatment) "There is no significant difference between those patients treated with monthly hydrotubations and those who received no therapy. bprimary infertility is defined as no prior pregnancies. to 36 years, with a mean of 27.8 years. Pregnancy rates did not differ significantly between patients grouped by age (20 to 24 years and 25 to 29 years); evaluation ranged from 1 to 12 years. Sixty-five pregnancies occurred in 45 patients (32% of the study population) before the diagnosis of endometriosis. Two of the pregnancies were terminated, 41 resulted in spontaneous abortion (less than 20 weeks' gestation), and 22 resulted in live-born infants, yielding an overall prediagnosis spontaneous abortion rate of 63.1 %. After diagnostic laparoscopic evaluation and chromopertubation, patients were offered conservative surgical resection of all visible endometriosis lesions. Forty-four patients with mild and moderate endometriosis refused medical and surgical therapy or achieved pregnancy before the institution of such therapy and thus served as the control population. A subgroup of 15 patients received monthly hydrotubations. Total length of follow-up ranged from 0.1 to 6.0 years (median, 1.1 years; mean, 1.5 years). The average time between diagnosis and surgery was 6 months (range, 0 to 1.6 years). The average length of follow-up with expectant man was 1.0 years (range, 0.1 to 6.0 years) and after surgical therapy was 1.3 years (range, 0.1 to 6.0 years). A comparison of surgically treated and control patients is presented in Table 1. No significant differences are apparent in age, duration of infertility, proportion with primary infertility, or percent with prior miscarriages. Moreover, when those patients receiving hydrotubations are compared with patients receiving no therapy, there Metzger et ai. Endometriosis and spontaneous abortion 19

3 Table 2. Pregnancy Outcome After Diagnosis and Surgical Treatment of Endometriosis No. of No. of pregnancies SABs a SAB rate Mild Prediagnosis Expectant man Surgical excision Moderate Prediagnosis Expectant man Surgical excision Severe Prediagnosis Expectant man Surgical excision O'lerall Prediagnosis Expectant man Surgical excision asab, spontaneous abortion. are no significant differences in any of these parameters. Pregnancy outcomes are presented in Table 2. For all stages of endometriosis, surgical excision of endometriotic implants is associated with a dramatic reduction in fetal wastage, compared with the pretreatment miscarriage rate. Of note is the significant, but less dramatic, reduction in the spontaneous abortion rate among women undergoing no treatment or hydrotubation therapy alone. Of particular interest is the finding that there is no significant difference in the spontaneous abortion rate between surgically and expectantly managed patients with mild and moderate disease. The spontaneous abortion rates are significantly different between the two treatment groups only when all stages of endometriosis are pooled (Table 3). Moreover, the difference in the spontaneous abortion rate between the prediagnosis group and those patients expectantly managed is highly significant (P < ). % The effect of pregnancy before diagnosis on pregnancy outcome after diagnosis and treatment was also examined. Of those patients with prior pregnancies and subsequent infertility, 60% achieved a pregnancy (27% of whom were expectantly managed and 33% of whom had conservative surgery). Forty-four percent of women with primary infertility achieved pregnancy (17% of whom were expectantly managed and 27% of whom had conservative surgery). Of those women with a history of spontaneous abortion before diagnosis of endometriosis, 7% had another spontaneous abortion (one woman subsequently had a full-term pregnancy), 55% had a full-term pregnancy, and 38% remained infertile. The effect of repetitive spontaneous abortions on subsequent pregnancy outcome is shown in Table 4. The only abortions observed occurred in women with a single prior abortion, and one of these women subsequently delivered a full-term infant. Thus there appears to be little evidence of repetitive pregnancy losses in women with endometriosis. DISCUSSION The study of the association of spontaneous abortion and endometriosis is an area long neglected, not by lack of studies but by the lack of a control group selected from the study group itself. Previous studies 3-10 have focused on the high rate of spontaneous abortion pretreatment (10% to 49%), which after treatment approaches the general population spontaneous abortion rate (8% to 20%) To our knowledge, this is the first study of spontaneous abortion and endometriosis that emphasizes the use of a control group selected from the study population. In agreement with other studies (Table 5),3-10 we found a dramatic reduction in the spontaneous abortion rate after conservative surgical resection of endometriosis lesions. However, we found an equally impressive and statistically significant postdiagnostic reduction in the spontaneous abortion rate among those patients who un- Table 3. Statistical Analysis of Pregnancy Outcome Prediagnosis vs. expectant man Prediagnosis vs. surgical man Expectant vs. surgical man ans, not significant. Overall Mild Moderate P < < P < 0.1 P < Severe P < < P < 0.1 P < O.()OOOOI P < P < NS 20 Metzger et al. Endometriosis and spontaneous abortion Fertility and Sterility

4 Table 4. Pregnancy Outcome After Diagnosis and Treatment of Endometriosis Before diagnosis After diagnosis Viable SABa No con pregnancy ception SAB number Ob SAB and viable pregnancy Viable pregnancies only Elective abortions asab,> spontaneous abortion. bno prior pregnancies. derwent expectant man. Thus inclusion of a control population alters the conclusions of the impact of the association of endometriosis and spontaneous abortion. There are many possible explanations for the apparent discrepancy observed in comparing prediagnosis and postdiagnosis spontaneous abortion rates. First, prediagnosis spontaneous abortions for the most part were unconfirmed, whereas those patients undergoing postdiagnostic miscarriages had tissue confirmation. Thus, in a population of women who wish to become pregnant, the prediagnosis miscarriage rate may be artificially high. Second, and more important, these women represent a preselected population distinct from the general population. They wish to become pregnant and have been unsuccessful at achieving term pregnancyl6; thus a higher spontaneous abortion rate would be expected. Third, subclinical abortions and sporadic delayed menses can alter the spontaneous abortion rate and affect in a noncomplementary fashion the prediagnosis and postdiagnosis rates.16 Fourth, Tupper and Weil17 demonstrated a significant decrease in the incidence of spontaneous abortions in women who underwent psychotherapy, compared with control subjects. It seems that the frequent visits and attention given to women in this study in the course of an infertility evaluation might serve a similar purpose. Finally, several reports suggest the therapeutic benefits of laparoscopy and chromopertubation on fertility enhancement Whether either procedure has an effect on spontaneous abortion is yet to be determined. Of particular relevance to the study presented here is the high rate of spontaneous "cure" ob- Vol. 45, No.1, January 1986 served in women with a history of early pregnancy losses.12 Even after three spontaneous abortions, there is a 68% chance of carrying a fetus to viability.12 Thus, in studies without a control group, the "cure" may be attributed to the treatment, whereas inclusion of a control group reveals the same degree of spontaneous cure. The use of a control group compatible with the study population is particularly important in dealing with infertility factors. Infertile patients are highly desirous of pregnancy but have failed to conceive or to achieve a full-term pregnancy. It is important to differentiate whether the experimental group has an increased rate of pregnancy loss as a result of their underlying disorder or whether these women as a group by chance have more spontaneous abortions unrelated to other factors. The general population spontaneous abortion rate is as high as 20%12-15 and rises to 32% after three abortions.12 The evidence that the infertile population may have an increased spontaneous abortion rate independent of endometriosis as a causative factor is supported by the findings of Olive et al. 21 In a study of women with endometriosis, the spontaneous abortion rate in fertile women was 17.1%, whereas in infertile women it was 44.3%. The choice of a suitable control group can be difficult for many reasons, foremost of which is the withholding of treatment from patients by choice or design. Patients who are self-selected for a given treatment may introduce considerable bias. Diagnostic procedures, such as dilatation and curettage, chromopertubation, or hydrotubation, could possibly even be therapeutic. Moreover, patients who become pregnant while Table 5. Literature Review of Endometriosis and Spontaneous Abortion Spontaneous abortion rate Reference Before Mter conser- Mter expecdiagnosis vative sur- tant mangery % % % Norwood, Devereux, Petersohn, Spangler et ai., Jones and Jones, Rock et ai., Naples et ai., Wheeler et ai., o Metzger et al. Endometriosis and spontaneous abortion 21

5 awaiting surgery may not be considered a control population in the strictest sense ofthe word. Even with these limitations, however, control groups such as the one used in this study provide an essential mode of comparison. There are two studies 9, 10 on the spontaneous abortion rate in women who refused treatment. Naples et al. 9 noted a 26% rate before diagnosis and 25.5% after diagnosis, whereas Wheeler et al. lo reported 31% and 0% rates, respectively. These latter two values were not significantly different. None of these rates is different from that of the general population, and this further supports the concept that endometriosis is unrelated to a high rate of spontaneous abortions. Grant22 showed that endometriosis patients have as many diverse sterility factors as women who are not affected by endometriosis. Thus, endometriosis occurs in women already affected by sterility factors such as luteal phase deficiency,23 luteinized un ruptured follicle syndrome,24 and uterine anomalies,2 factors thought to be associated with increased rates of spontaneous abortion. The data presented here underscore the importance of including a control population derived from the study group. Studies not including an adequate control group should be viewed with caution. These data also suggest but do not prove that endometriosis may not be the causative factor in the apparent high rate of prediagnosis spontaneous abortions. REFERENCES 1. Kistner RW: Man of endometriosis in the infertile patient. Fertil Steril 26:1151, Muse KN, Wilson EA: How does mild endometriosis cause infertility? Fertil Steril 38:145, Norwood GE: Sterility and fertility in women with pelvic endometriosis. Clin Obstet Gynecol 3:456, Devereux WP: Endometriosis: long-term observation with particular reference to incidence of pregnancy. Obstet Gynecol 22:444, Petersohn L: Fertility in patients with ovarian endometriosis before and after treatment. Acta Obstet Gynecol Scand 49:331, Spangler DB, Jones GS, Jones HW Jr: Infertility due to endometriosis. Am J Obstet Gynecol 109:850, Jones GS, Jones HW Jr: Editorial. Obstet Gynecol Surv 26:539, Rock JA, Guzick DS, Sengos C, Schweditsch M, Sapp KC, Jones HW Jr: The conservative surgical treatment of endometriosis: evaluation of pregnancy success with respect to the extent of disease as categorized using contemporary classification systems. Fertil Steril 35:131, Naples JD, Batt RE, Sadigh H: Spontaneous abortion rate in patients with endometriosis. Obstet Gynecol 57:509, Wheeler JM, Johnston BM, Malinak LR: The relationship of endometriosis to spontaneous abortion. Fertil Steril 39:656, Acosta AA, Buttram VC Jr, Besch PK, Malinak LR, Franklin RR, Vanderheyden CT: A proposed classification of pelvic endometriosis. Obstet Gynecol 42:19, Glass RH, Golbus MS: Habitual abortion. Fertil Steril 29:257, Pritchard JA, MacDonald PC (Eds): Williams Obstetrics, Sixteenth edition, Chap 24. New York, Appleton-Century-Crofts, 1980, p Hellman LM, Kobayashi M, Fillisti L, Laverhan M: Growth and development of the human fetus prior to the twentieth week of gestation. Am J Obstet Gynecol 103:789, Javert CT: Spontaneous and Habitual Abortion. New York, McGraw-Hill, 1957, p Jansen RPS: Spontaneous abortion incidence in the treatment of infertility. Am J Obstet Gynecol 143:451, Tupper C, Weil RJ: The problem of spontaneous abortion for the treatment of habitual abortions by psychotherapy. Am J Obstet Gynecol 85:38, Portuondo JA, Echanojauregui AD, HeITan C, Alijarte I: Early conception in patients with untreated mild endometriosis. Fertil Steril 39:22, Seibel MM, Berger MJ, Weinstein FG, Taymor ML: The effectiveness of danazol on subsequent fertility in minimal endometriosis. Fertil Steril 38:534, Trimbos-Kemper GeM, Trimbos JB, van Hall EV: Pregnancy rates after laparoscopy for infertility. Eur J Obstet Gynecol Reprod BioI 18:127, Olive DL, Franklin RR, Gratkins LV: Association between endometriosis and spontaneous abortions: a retrospective clinical study. J Reprod Med 27:333, Grant A: Additional sterility factors in endometriosis. Fertil Steril 17:514, Hargrove JT, Abraham GE: Abnormal luteal function in endometriosis. Fertil Steril 34:302, Brosens la, Koninckx PR, Corvelyn P A: A study of plasma progesterone, oestradiol-17[3, prolactin and LH levels and of the luteal phase appearance of the ovaries in patients with endometriosis and infertility. Br J Obstet Gynaecol 85:246, Metzger et ai. Endometriosis and spontaneous abortion Fertility and Sterility