Preclinical abortions and endometriosis

Vol. 49, No. 2, February 1988 Printed in U.S.A.

FERTILITY AND STERILITY Copyright c 1988 The American Fertility Society

Preclinical abortions and endometriosis

Donald E. Pittaway, M.D., Ph.D.* Charles P. Ellington, M.D. Mitchell Klimek, B.A. Section on Reproductive Endocrinology, Department of Obstetrics and Gynecology, Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, North Carolina

A single human chorionic gonadotropin determination was performed. i~ 786 infe~il~ women during the late luteal pha!ile to determine the fre~uenc1es of p~ec~miCal.abortiOns and whether the frequency was increased in wom~n w1~h endometn.os1s. Th1rty-~eyen pregnancies (4.7% of cycles) were identified, of whiCh s1x were clas~1~ed as pr~chmcal abortions (0.8%). In women with endometriosis, the f~eque~cy ofprechmcal B;bort10ns was 0.9% and was not statistically different from other mfertlle subgroups. Th1s study s?ggests that preclinical abortions are not cause of infertili~y i~ eithe~ an in~ertile population as a whole or in the subgroup of women with endometnofi!IS. Fertll Sterll 49:221, 1988

The association of endometriosis and a high rate of clinically apparent spontaneous abortions has been reported. In women who present with secondary infertility and are found to have endometriosis, the prediagnosis abortion rates have ranged between 10 and 49%. 1 Although some investigators , • 2 5 have suggested a causal relationship, - more recent reports with control groups for comparison6-8 and studies examining spontaneous abortions in untreated endometriosis2 •4 •9 indicate that endometriosis is probably not a major cause of spontaneous abortions. However, previouE? studies have not examined the possibility of preclinical abortions having a role in the infertility of women with endometriosis, although some studies suggest mechanisms by which endometriosis may affect implantation.1 In order to examine a possible relationship between endometriosis and preclinical abortions, we measured serum 13-human chorionic gonadotropin (P,CG) concentrations during the late luteal phase of women being evaluated for infertility. Received August 7, 1987; revised and accepted September 29, 1987. * Reprint requests: Donald E. Pittaway, M.D., Ph.D., Department of Obstetrics and Gynecology, Bowman Gray School of Medicine, 300 South Hawthorne Road, Winston-Salem, North Carolina 27103. Vol. 49, No.2, February 1988

MATERIALS AND METHODS

Between November 1984 and April 1987, 786 women being evaluated for infertility had a single {3-hCG determination performed between 1 an~ 5 days prior to the anticipated menses. The maJor infertility factor was assigned to each patient after folcompleting the evaluation, which i~cluded lowing: semen analyses, postc01tal testmg, a timed-endometrial biopsy, hysterosalpingogram, laparoscopy, and hormonal studies, ~hen ap~>ro­ priate. Women with chronic anovulatiOn r~cetved clomiphene citrate with qocumented ovulatwn before entering tl1e study. Patients who did not complete their evaluation were assigned to an undetermined category. When severe oligospermia or azoospermia was present, the women were artificially inseminated with fresh dpnor semen. If all tests did not reveal a cause for the infertility, the couple was designated as having unexplained infertility. Serum samples had been drawn for the hormonal evaluation of the luteal phase, for preoperative laboratory studies or other hormonal assays, and then were assayed for 13-hCG by radioimmunoassay according to the manufacturer's instructions (Clinetics, Tustin, CA). The assay uses the Second International Standard, and 13-hCG concentrations ~5 miU /ml were considered as indicating im~lan-

t?e

Pittaway et al. Preclinical abortions and endometriosis

221

~

I

(/)

c 0

--•

I

1

c

I

4

3

2

c c

~

.

"E Q) Cl

cal spontaneous abortion, 1 woman with an ectopic pregnancy, and 6 women with preclinical abortions. The mean hCG concentrations for the 24 normal pregnancies were: 7.5, 12, 16, 20, and 60 miU /ml for days 5 through 1 prior to the anticipated menses. No clinical pregnancies were undetected during the late luteal phase in the study. The major infertility factors of the 786 women are listed in Table 1 with the corresponding pregnancy outcomes. Overall, pregnancies were detected in 4.7% of the cycles (37 of 786), of which 6 were preclinical abortions (0.8% ). Endometriosis was the most frequent factor identified, and had a preclinical abortion rate of 0.9%, which was not different from any of the other categories. In women subsequently found to have luteal phase inadequacy, the preclinical abortion rate was 3.6%, although this frequency did not achieve statistical significance because of the small number of patients.

c 0 0

(!)

0

~

5

Days Prior To Anticipated Menstrual Period

Figure 1 Serum hCG concentrations during the 5 days prior to the anticipated menstrual period. The hCG concentrations are depicted for: term pregnancies (e) with bar indicating the mean concentration; clinical abortions (c); preclinical abortions (p); and an ectopicpregnancy (e).

tation and trophoblastic activity. In 200 women with documented tubal blockage, hCG concentrations were all< 5 niiU/ml, indicating a false-positive rate of <0.5%. A preclinical pregnancy was defined by two criteria: (1) {1-hCG concentrations between ~5 and ~100 miU/ml, and (2) menses occurring no more than 7 days after the anticipated day of onset. Fisher's exact test was used to analyze the data and a P value ~0.05 was considered significant.

DISCUSSION

We examined late luteal phase hCG concentrations in serum to investigate whether preclinical abortions were increased in women with untreated endometriosis. To accomplish this objective, serum samples were obtained prospectively during the course of an infertility evaluation and later assigned to a group according to whether endometriosis was present and then according to the most significant fertility factor identified. In general, we examined therapy-independent pregnancies for the prevalence of preclinical abortions. However, in women who did not ovulate or in husbands who had

RESULTS

Figure 1 shows the hCG concentrations for 24 women with ter~ deliveries, 6 women with a cliniTable 1

Pregnancy Outcome According to Infertility Classification Pregnancy

Factor

Patients

Term

Premature

Clinical abortions

4 0 3 5 0 0 0 0 0 11

0 0 0 0 0 0 0 0 0 0

2b 0 1 2 0 1 1 0 0 0

2 1 1 1 0 0 1 0 0 0

24

0

7b

6 (0.8)

Preclinical abortions"

(%)

Endometriosis Tubal Male Ovulation Unexplained Uterine Luteal phase defect Adhesions Cervical Undetermined

232 145 128 90 39 37 28 14 9 63

Total

786 (101)

(30) (19) (16) (11) (5) (5) (4) (2) (1) (8)

(%)

Percent of patients with preclinical abortions. bOne ectopic pregnancy.

a

222

Pittaway et al.

Preclinical abortions and endometriosis

(0.9)< (0.7) (0.8) (1.1) (0) (0) (3.6) (0) (0) (0)

' Not statistically different from any other factor.

Fertility and Sterility

azoospermia or severe oligospermia, therapy had to be initiated for any possibility of pregnancy to occur, and to be included in the study. Nonetheless, these subgroups comprised a relatively small proportion of the study, and the clinical pregnancy rate of3.9% (31 of786) was in the range ofprevious studies reporting between 2.3 and 6.3%. 10- 13 Another confounding factor in the study was the group of 63 couples (8%) who did not have a completed evaluation (11 because of achieving a normal pregnancy during their workup}. This "undetermined" category precludes any conclusions about the proportion of term pregnancies, clinical abortions, and preclinical abortions within any of the groups since the 11 term pregnancies that occurred cannot be assigned to any of the diagnostic categories. Nevertheless, the frequencies of the preclinical abortions would not be significantly affected by the failure to identify the cause of infertility since no preclinical abortions were observed in this group. The method selected to detect pregnancy was a single serum sample assayed by a sensitive radioimmunoassay. None of the 31 clinical pregnancies went undetected when the samples were obtained no earlier than 5 days before the anticipated menstrual period, an.d we have not h!ld a false-negative result in nearly 3 years of experience using 5 miU I ml or greater. Conversely, we have no way of confirming an implanted pregnancy in the six preclinical abortions or whether we were observing a rare random false-positive elevation in hCG, although the false-positive rate is less than 0.5%, as we have determined in women with blocked or absent fallopian tubes. However, a single determination may have missed preclinical abortions in which the hCG concentration fell to below 5 miU /ml on the day of the sampling. Thus, the 0.8% frequency of preclinical abortions observed in this study should be considered as low estimates for an infertile population, but is not dissimilar from the 1.9% observed in another smaller series that used a single serum hCGY Also, the proportion of preclinical pregnancy losses to total pregnancies observed in this study (6 of 37 pregnancies or 16%) is similar to other studies using sensitive testing in an infertile population (2 of 6 pregnancies or 33%} 11 and in

Vol. 49, No.2, February 1988

fertile populations (8 14 and 19% 15 ). Consequently, we would conclude that increased rates of postimplantation failure are not a cause of infertility in general and not in women with endometriosis in particular. However, this study and the report of Cline 16 suggest that women with luteal phase inadequacy may have higher rates of preclinical abortions, although our data are insufficient to address this question adequately.

REFERENCES 1. Pittaway DE, Wentz AC: Endometriosis and corpus luteum function. Is there a relationship? J Reprod Med 29:712, 1984 2. Naples JD, Batt RE, Sadigh A: Spontaneous abortion rate in patients with endometriosis. Obstet Gynecol 57:509, 1981 3. Olive DL, Franklin RR, Gratkins LV: The association between endometriosis and spontaneous abortion. J Reprod Med 27:333, 1982 4. Wheeler JM, Johnston BM, Malinak LR: The relationship of endometriosis to spontaneous abortion. Fertil Steril 39:656, 1983 5. Groll M: Endometriosis and spontaneous abortion. Fertil Steril 41:933, 1984 6. Metzger DA, Olive DL, Stohs GF, Franklin RR: Association of endometriosis and spontaneous abortion: effect of control group selection. Fertil Steril 45:18, 1986 7. FitzSimmons J, Stahl R, Gocial B, Shapiro SS: Spontaneous abortion and endometriosis. Fertil Steril47:696, 1987 8. Pittaway DE, Vernon C, Fayez JA:. Spontaneous abortions in women with endometriosis. Fertil Steril. In press 9. Hull ME, Moghissi KS, Magyar DF, Hayes MF: Comparison of different treatment modalities of endometriosis in infertile women. Fertil Steril 47:40, 1987 10. Sulewski JM, Ward SP, McGaffic W: Endometrial biopsy during a cycle of conception. Fertil Steril 34:548, 1980 11. Cumming DC, Honore LH, Scott JZ, Williams KP: The late luteal phase in infertile women: comparison o~ simultaneous endometrial biopsy and progesterone levels. Fertil Steril 43:715, 1985 12. Wentz AC, Herbert CM iii, Maxson WS, Hill GA, Pittaway DE: Cycle of conception endometrial biopsy. Fertil Steril 46:196, 1986 13. Wild RA, $anfilippo J~, Toledo AA: Endometrial biopsy in the infertility investigation. J Reprod Med 31:954, 1986 14. Whittaker PG, Taylor A, LindT: Unsuspected pregnancy loss in healthy women. Lancet 1:11:26, 1983 15. Wilcox AJ, Weinberg CR, Wehmann RE, Armstrong EG, Canfield RE, Nisula BC: Measuring early pregnancy loss: laboratory and field methods. Fertil Steril 44:366, 1985 16. Cline DL: Unsuspected subclinical pregnancies in patients with luteal phase defects. Am J Obstet Gynecol 134:438, 1979

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