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Infertility among daughters either exposed or not exposed to diethylstilbestrol
Infertility among daughters either exposed or not exposed to diethylstilbestrol Elizabeth K. Senekjian, MD, Ronald K. Potkul, MD, Keith Frey, BA, and Arthur L. Herbst, MD Chicago, Illinois Infertility was examined among 343 diethylstilbestrol-exposed and 303 unexposed daughters whose mothers participated in an evaluation of diethylstilbestrol use during pregnancy 35 years ago. Of the married individuals who were not using contraception and who were actively trying to conceive, a greater proportion of diethylstilbestrol-exposed women than unexposed subjects experienced primary infertility (33% versus 14%, p < 0.001 ). Among those with primary infertility, abnormal hysterosalpingograms were observed in 46% of the diethylstilbestrol-exposed group and in none of the unexposed group (p < 0.02), while tubal abnormalities were found in 42% of the exposed and in none of the unexposed (p = 0.02). First pregnancies were achieved by 40 (58%) women exposed to diethylstilbestrol and 18 (64%) unexposed subjects. Twenty-four (60%) of the exposed women and 15 (83%) of the unexposed individuals who conceived had a live-born infant who survived. The estimated cumulative rate of first pregnancy was 16% for the exposed group and 36% for the unexposed group at 12 months after the diagnosis of primary infertility (p < 0.05). (AM J 0BSTET GYNECOL 1988;158:493-8.)
Key words: Infertility, diethylstilbestrol exposure, abnormal hysterosalpingogram, pregnancy among infertile diethylstilbestrol-exposed women
The infertility experience among 796 female offspring of mothers who participated in a double-blind controlled study of diethylstilbestrol (DES) use during pregnancy at the Chicago Lying-In Hospital in 1951 and 1952 was reviewed. Previous analysis of the study group by Bibbo et al.' in 1977 demonstrated a history of pregnancy in only 18% of 229 DES-exposed women as compared with 33% of 136 unexposed subjects. In 1981 Herbst et al. 2 reevaluated this population and found infertility to be present in a greater proportion of DES-exposed women (n = 53, 26%) than in unexposed subjects (n = 19, I 0% ). Furthermore, among the married women who were not always protected with contraceptives, 75% of the exposed group, as compared with 92% of the unexposed group, had achieved pregnancy.2 This study augments and extends the previous investigations of the original Chicago Lying-In Hospital population by including additional cases of infertility and examining specific risk factors potentially contributing to infertility. In addition, first conception rates and time to conception among DES-exposed and unexFrom the Department of Obstetrics and Gynecology, University of Chicago, Pritzker School of Medicine. Supported in part by American Cancer Society Clinical Career Development Award No. 85-38 (to E. K. S.) and the Mothers' Aid Research Fund of the Chicago Lying-In Hospital. Received for publication April 16, 1987; revised October 14, 1987; accepted November 6, 1987. Reprint requests: Elizabeth K. Senekjian, MD, Department of Obstetrics and Gynecology, Chicago Lying-In Hospital, 5841 South Maryland Ave., Box 446, Chicago, IL 60637.
posed women with primary and/or secondary infertility were analyzed. Material and methods
In the original double-blind study, 840 pregnant women were given DES and 806 were given placebo. The drug was taken from the first prenatal visit, from 6 to 23 weeks after the onset of the last menstrual period, in conformity with a standard dosage schedule.' Since 1974 an effort has been made to contact the 408 DES-exposed and the 388 unexposed live-born daughters and to obtain follow-up medical histories. Gynecologic examinations, which included cytologic smears and colposcopy, and infertility evaluations were offered at the Chicago Lying-In Hospital. For su~jects living outside the Chicago area analogous examinations by specialists were performed. The findings at the first physical examination, at which time the average age for the group was 23.5 years, have been reported previously.' Health-history questionnaires were completed at follow-up clinic visits, by mail, and through telephone interviews. Questionnaires included inquiries pertaining to contraception, history of pelvic inflammatory disease, infertility, and pregnancies achieved. Records concerning diagnostic infertility evaluations and treatment, as well as other significant medical conditions, were requested. Data were recorded on standard forms and entered into a confidential computer tile. Infertility is defined as the inability to conceive after at least I year of actively attempting to achieve preg-
493
494
Senekjian et al.
March 1988 Am J Obstet Gynecol
Table I. Infertility among DES-exposed and unexposed women DES-exposed women Total no. of live-born female infants born to mothers in study No. of women responding to questionnaire No. married Not at risk, never pregnant At risk No. reporting difficulty conceiving Primary infertility Secondary infertility *Total number at secondary as well as tTotal number at secondary as well as
Unexposed women
408
388
343 266 59 207 92 69 (33%) 39* (23%)
303 236 33 203 45 28 (14%) 28t (15%)
p Value
<0.001 <0.05
risk includes 170 DES-exposed women who have achieved at least one pregnancy; 16 exposed women had primary infertility. risk includes 193 unexposed subjects who have achieved at least one pregnancy; 11 unexposed subjects had primary infertility.
Table II. Cervicovaginal abnormalities detected at initial examination among DES-exposed women Initial exami11ation at CL/* or el1ewhere Ever preKnantf
Primary infertility
(n = 106)
(n = 53)
48 (77% ):j:
68 (64'lr):j:
42 (79%):j:
56 (65%):j:
38 (61'7c)§
41 (39%)§
36 (68%)§
35(41%)§
Primary infertility Ceniirovaginal abnormality Vaginal epithelial changes Cervicovaginal ridges
Initial examination at CL/
(n = 62)
I
Ever preKrlantt
I
(n = 86)
*CL! = Chicago Lying-In Hospital. tSubjects were married, had at least one pregnancy. and never reported infertility. :j:p
nancy. Subjects with primary infertility have never conceived while those with secondary infertility have had one or more previous pregnancies. A complete diagnostic infertility investigation includes the documentation of ovulation, semen analysis, postcoital test, hysterosalpingography, and laparoscopy and/or laparotomy with testing of tubal patency. A diagnosis of ovulatory dysfunction includes a history of irregular menstrual cycles with intervals exceeding 35 days and was established by the assessment of basal body temperature curves, progesterone levels, and/or by the histologic evidence of delayed maturation of the endometrium (luteal phase defect). Seminal deficiency was defined as a score of >5 utilizing the Eliasson scoring system." A postcoital test was designated as abnormal when there were < 10 motile sperm per high-power microscopic field. Cervical stenosis was defined as a significant narrowing of the endocervical canal or a pinpoint cervical os. Uterine structural alterations were demonstrated by hysterosalpingography. The presence of tubal defects or endometriosis was assessed by the direct inspection of pelvic viscera. x" Statistics and t tests were used to compare variables of interest. Pregnancy patterns were analyzed by the Mantel-Haenszel statistic' and by a standard actuarial life-table method.''
Results
Baseline health data were available for 343 (84%) of the DES-exposed daughters and 303 (78%) of the unexposed individuals (Table I). Two hundred seven (60%) of the 266 married DES-exposed women and 203 (67%) of the 236 married unexposed subjects were not using contraception regularly and were at risk for pregnancy. As of February I 986 primary infertility was reported by 69 (33%) of the 207 DES-exposed women and 28 (14%) of the 203 unexposed subjects (p < 0.001). Infertility was not reported in the unmarried group. Table II demonstrates the prevalence of cervicovaginal abnormalities detected at the initial gynecologic examination (performed in the mid- l 970s) among DES-exposed women with primary infertility and among exposed subjects who were married, had been pregnant, and had never reported infertility. Cervicovaginal ridges (p < 0.00 I) and vaginal epithelial changes (adenosis and physiologic squamous metaplasia) were found in a greater proportion of individuals with primary infertility. No significant differences with regard to the age pregnancy was first attempted or in the time interval to the primary infertility evaluation were observed between women exposed to DES (means of 24.7 and 2.2 years) and unexposed subjects (means of 24.5 and 2.0
Infertility experience among DES daughters 495
Volume 158 Nurnher 3, Part I
Table III. Factors contributing to primary infertility DES-exposed (n
= 69)
I
%
No.
38 24 63 46 42 21
Factor
No.
Ovulatory factor Male factor Cervical factor Abnormal hysterosalpingogram Tubal factor Endometriosis
23/61 9/37 12*/l 9 11124 IOt/24 5/24
Unexposed (n
= 28)
I
%
p Value
15/27 3/14 2/8
56 21 25
019 019 419
44
NS NS 0.07,NS <0.02 0.02 NS
NS = not significant (p > 0.05). *Includes six cases of cervical stenosis. tlncludes seven cases of adnexal adhesions, and two cases of both adhesions and endometriosis.
years). The total DES dose for exposed women with primary infertility ranged from 10,744 to 12,582 mg (mean of 12,241 mg) and for fertile exposed women from 4817 to 12,582 mg (mean of 12,189 mg). A comparable proportion of DES-exposed women (59%) and unexposed individuals (57%) underwent primary infertility evaluation. Although ovulatory disorders were diagnosed less often in DES-exposed women (38%) than in unexposed subjects (56% ), the difference was not statistically significant (Table Ill). Abnormalities in the semen were demonstrated in a similar proportion of the male partners of exposed and unexposed women. No significant difference was found in the frequency of cervical factors in the exposed group as compared with the unexposed group. Of the six DES-exposed subjects with cervical stenosis, two had undergone previous cervical cauterization. None of the unexposed subjects who underwent hysterosalpingographic study had uterine abnormalities. Uterine defects including a T-shaped or hypoplastic cavity, a septate uterus, intrauterine synechiae, or irregular uterine margins were documented in 46% of DES-exposed women with primary infertility. Tubal abnormalities (including adnexal adhesions, tubal occlusion, and congenital or surgical tubal absence) were diagnosed at laparoscopy or laparotomy in 10 of 24 (42%) exposed and none of nine unexposed women. In six DES-exposed women the findings were consistent with pelvic inflammatory disease. Endometriosis was diagnosed less frequently in the exposed group. A smaller proportion of DES-exposed women with primary infertility (n = 40, 58%) than of control subjects (n = 18, 64%) achieved first pregnancies. Twentyfour women (60%) in the exposed group and 15 subjects (83%) in the unexposed group who eventually conceived had a live birth of an infant who survived. Among individuals who achieved first pregnancies, adverse pregnancy outi:omes (including spontaneous abortion, ectopic pregnancy, and perinatal death) occurred more often among DES-exposed women
(n
= 15, 38%) than among unexposed individuals
(n = 3, 17% ). None of these differences were statisti-
cally significant. Hysterosalpingographic findings were not predictive of conception rates among DES-exposed women with primary infertility. Pregnancies occurred in six of 13 (46%) DES-exposed women with normal hysterosalpingograms and in five of 11 (45%) DES-exposed individuals with abnormal studies. Four of I 0 DES-exposed women with tubal defects conceived. Treatment for primary infertility (prescribed medications, artificial insemination, or surgery) was administered at least once to a similar proportion of the exposed (n = 28,41%)andtheunexposed(n = 12,43%) groups. Among those who eventually conceived, pregnancies occurred independent of treatment in 29 of 40 (73%) women exposed to DES as compared with 10 of 18 (56%) unexposed subjects. The secondary infertility experience of the exposed and control groups was also examined. Thirty-nine (23%) of 170 DES-exposed women and 28 (15%) of 193 unexposed subjects who were at risk and ever pregnant reported secondary infertility (p < 0.05 ). Sixteen of the exposed women and 11 of the unexposed subjects experienced both primary and secondary infertility. When those with primary infertility were excluded, the difference was no longer statistically significant. The total DES dose ranged from I 0,850 to 12,582 mg (mean of 12,298 mg) for those who were exposed in utero and had secondary infertility and from 4817 to 12,582 mg (mean of 12,188 mg) for fertile exposed women without primary or secondary infertility. A similar proportion of exposed (54%) and unexposed (46%) subjects underwent secondary infertility evaluation. Each risk factor was analyzed and no significant differences were detected between the exposed and unexposed groups with regard to the presence of ovulatory, male, or cervical factors. Of the 13 exposed women who underwent hysterosalpingographic study, five (38%) had uterine defects. Although tubal abnormalities were more common in exposed individuals
496
Senekjian et al.
March 1988 Am J Obstet Gynecol
1.01c: >0 0 c: as 0 c:
-
... a. O> 0 Q) ...... Q.. Q..
-
"O
c:
as Q) >
-"' E
w
~-d'
.6
.s:; 0
<(
/
~-o--o-~
6
I
I
.5
24\{
.4
• Exposed, n=69
er -
I
.2
0
•
~56
I
.3
.I I
I
/
O>
Q)
I
7
.7
~
Control, n•28
I I
2
3
4
5
7
6
8
9
10
Years Post Diagnosis Fig. 1. Estimated cumulative annual rate of first pregnancies among DES-exposed and unexposed women with primary infertility.
I.OJ. .8
c: >0 0 c: as 0 c:
-... a.
O>
... a: 0
Q)
Q..
-
"O
O>
c: as > Q) E .s:; Q)
Cl)
w
0 <(
7
.7
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0-~-0-~
.6 .5 .4
••--e• Exposed, n=39
.3
<>- -
~
Control, n=28
.2 .l
0
2
3
4
5
6
7
8
9
10
Years Post Diagnosis Fig. 2. Estimated cumulative annual rate of pregnancies among DES-exposed and unexposed women with secondary infertility.
(eight of 12, 67%) than in unexposed subjects (one of seven, 14%), the data are limited and do not permit a meaningful statistical comparison. An equivalent proportion of DES-exposed women (n = 23, 59%) and unexposed subjects (n = 16, 57%) achieved pregnancies after the diagnosis of secondary
infertility. Among those who eventually conceived, a significantly smaller proportion in the exposed group (n = 11, 48%) as compared with the unexposed group (n = 13, 81 %) had a live birth of an infant who survived
Volume 158 !'\umber 3, Part I
first pregnancies only among exposed and unexposed individuals with primary infertility is shown in Fig. 1. After infertility was reported the estimated cumulative pregnancy rates for the exposed group versus the unexposed group were 16% and 36% (p < 0.05) at 12 months, 33% and 43% at 24 months, and 45% and 63% at 36 months. Fig. 2 illustrates the estimated cumulative annual rate of pregnancies among exposed and unexposed individuals with secondary infertility. Among those with primary infertility the mean time to the first conception for exposed untreated women (2.7 years) was significantly longer than for untreated control women ( 1.8 years, p < 0.03). Although the difference in mean time to conception was even greater among those treated for primary infertility, 4.0 years for DES-exposed women versus 2.8 years for control women, this difference was not statistically significant. Comparison of the times to pregnancies achieved over 10 years by DES-exposed and control women after the diagnosis of primary or secondary infertility, by the Mantel-Haenszel method, demonstrated no statistically significant differences (Figs. 1 and 2).
Comment In the present study primary infertility was found to be significantly more common among women at risk for pregnancy who were exposed to DES (33%) than among control women (14%). These data conflict with findings by Barnes et al." and Cousins et al.,' who did not detect differences in fertility rates between DESexposed women and unexposed subjects. However, in three studies without controls, Schmidt et al.," Berger and Goldstein," and Kaufman et al. 10 reported infertility in approximately one third of DES-exposed women managed in specialty clinics. Cervicovaginal ridges were detected significantly more frequently at the initial examination in married DES-exposed women with primary infertility than in married DES-exposed women who conceived (Table II). Therefore structural abnormalities of the cervix and vagina present at the initial examination may be associated with the subsequent occurrence of primary infertility. These cervicovaginal structural changes have been correlated with the time DES was begun in pregnancy and the total dose received. 11 The complete regression of cervicovaginal ridges has been described by Antonioli et al. 12 in 28% of 123 patients and by Herbst et al.' in 57% of 102 cases. Regardless of the rate of regression, it seems that ridges will disappear over time in many DES-exposed women. Therefore the absence of a ridge at any given pelvic examination does not necessarily indicate that a ridge was never present. Ovulatory defects, male factors, and endometriosis do not seem to contribute to the excess of primary infertility found in DES-exposed women. Although a
Infertility experience among DES daughters 497
cervical factor may play a role, the difference between the exposed and unexposed groups does not attain statistical significance. The number of postcoital tests performed was small and abnormal tests were not always repeated; the results presented are based on the best available data. Among those with primary infertility who underwent evaluation, abnormal hysterosalpingograms and tubal defects were the factors found significantly more often in DES-exposed women than in control women. Tubal abnormalities compatible with previous pelvic inflammatory disease were more common in those exposed to DES, but the numbers are small and preclude a statistically meaningful analysis. Although differences in patterns of sexual practice may contribute to the occurrence of pelvic inflammatory disease, detailed data regarding sexual histories are not available. DES-exposed women who present with symptoms suggestive of acute salpingitis may benefit from laparoscopy in order to confirm the clinical suspicion and/or the administration of aggressive antibiotic therapy. The sexual partners of affected patients should also be evaluated and treated in order to decrease the risk of successive episodes of sexually transmitted diseases. Among high-risk DES-exposed women, routine interval cultures may identify and allow treatment of asymptomatic carriers of sexually transmitted organisms. Two studies have evaluated the risk factors among exposed and unexposed women attending infertility clinics. In one study, Berger and Alper'" noted a statistically significant increase in endometriosis among 50 infertile DES-exposed women (64%) as compared with 50 infertile unexposed, age-matched women (40%) and a significant decrease in the occurrence of pelvic inflammatory disease among exposed women as compared with unexposed subjects (6% versus 26%). Stillman and Miller'' found endometriosis at laparoscopy and/or laparotomy in 10 of 20 (50%) infertile women exposed to DES in utero in comparison with 39% of 377 infertile unexposed women. This latter difference was not statistically significant. Both studies were susceptible to bias since patients were selected from infertility clinics and were not participants in a single cohort study as in this report. Kaufman et al."' detected uterine structural abnormalities by hysterosalpingograms in 59% of 632 DESexposed women. Abnormal hysterosalpingographic studies were found in an equivalent proportion ofDESexposed women who had conceived within 1 year as compared with infertile exposed women. Therefore uterine abnormalities as a group were not associated with an increase in the occurrence of infertility. However, Kaufman et al. 10 did note a significant association between the presence of an upper uterine cavity con-
498
Senekjian et al.
striction and an inability to conceive. In addition, consistent with the results of this study, there did not appear to be a correlation between the ability of infertile exposed women to eventually achieve pregnancy and hysterosalpingographic abnormalities. Only first pregnancies occurring within I 0 years after the diagnosis of primary infertility were analyzed in the present study. The estimated cumulative rate of first pregnancies at 36 months was lower in DES-exposed women (45%) than in control women (63%). However, the overall difference between the two groups was not statistically significant. These findings are not dissimilar to reported cumulative pregnancy rates of 51 % and 59% at 36 months among infertile couples in general.''· 16 Although fewer pregnancies of all types as well as live births of surviving infants were achieved among DES-exposed women than among unexposed subjects, the differences were not statistically significant. Of those who ultimately conceived, unfavorable pregnancy outcomes occurred more often in women exP.osed to DES than in unexposed subjects. These findings are in agreement with other studies that demonstrate adverse pregnancy outcomes to be more frequent among DES-exposed women as compared with unexposed women. 2 • 6 · 7 Data are available for only a portion of the total number of subjects with infertility, and therefore there may be bias with regard to the different rates of risk factors contributing to the infertility experience in the exposed and unexposed groups. Nevertheless, among those with primary infertility, tubal defects including those compatible with a diagnosis of pelvic inflammatory disease were found more often in women exposed to DES than in control women. This suggests that a high index of suspicion and intensive therapy for this condition may increase the likelihood of preserving fertility in DES-exposed women. REFERENCES 1. Bibbo M, Gill WB, Azizi F, et al. Follow-up study of male and female offspring of DES-exposed mothers. Obstet Gynecol 1977;49:1.
March 1988 Am J Obstet Gynecol
2. Herbst AL, Hubby MM, Azizi F, Makii MM. Reproductive and gynecologic surgical experience in diethylstilbestrolexposed daughters. AM J OBSTET GYNECOL 1981; 141:1019. 3. Eliasson LR. Analysis of semen. In: Behrman SJ, Kistner RW, eds. Progress in infertility. 2nd ed. Boston: Little Brown, 1975:691-713. 4. Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 1966;50: 163. 5. Cutter SJ, Ederer F. Maximum utilization of the life table method in analyzing survival. J Chronic Dis 1958;8:699. 6. Barnes AB, Colton T, Gundersen J, et al. Fertility and outcome of pregnancy in women exposed in utero to diethylstilbestrol. N Engl J Med I 980;302:609. 7. Cousins L, Karp W, Lacey C, Lucas WE. Reproductive outcome of women exposed to diethylstilbestrol in utero. Obstet Gynecol 1980;56:70. 8. Schmidt G, Fowler WC, Talbert LM, Edelman DA. Reproductive history of women exposed to diethylstilbestrol in utero. Fertil Steril 1980;33:21. 9. Berger MJ, Goldstein DP. Impaired reproductive performance in DES-exposed women. Obstet Gynecol 1980; 55:25. 10. Kaufman RH, Adam E, Noller K, Irwin JF, Gray M. Upper genital tract changes and infertility in diethylstilbestrol-exposed women. AM J OBSTET GYNECOL 1986; 154:1312. 11. Jefferies JA, Robboy SJ, O'Brien PC, et al. Structural anomalies of the cervix and vagina in women enrolled in the Diethylstilbestrol Adenosis (DESAD) Project. AMJ 08STET GYNECOL 1984;148:59. 12. Antonioli DA, Burke L, Friedman EA. Natural history of diethylstilbestrol-associated genital tract lesions: cervical ectopy and cervicovaginal hood. AM J 0BSTET GYNECOL 1980;137:847. 13. Berger MJ, Alper MM. Intractable primary infertility in women exposed to diethylstilbestrol in utero. J Reprod Med 1986;31:231. 14. Stillman JR, Miller LC. Diethylstilbestrol exposure in utero and endometriosis in infertile females. Fertil Steril 1984;41:369. 15. CollinsJA, Wrixon W,Janes LB, Wilson EH. Treatmentindependent pregnancy among infertile couples. N Engl J Med 1983;309:1201. 16. Katayama KP, Kap-Soon JU, Manuel M,Jones GS, Jones HW. Computer analysis of etiology and pregnancy rate in 636 cases of primary infertility. AM J 0BSTET GYNECOL 1979;135:207.
Key words: Infertility, diethylstilbestrol exposure, abnormal hysterosalpingogram, pregnancy among infertile diethylstilbestrol-exposed women
The infertility experience among 796 female offspring of mothers who participated in a double-blind controlled study of diethylstilbestrol (DES) use during pregnancy at the Chicago Lying-In Hospital in 1951 and 1952 was reviewed. Previous analysis of the study group by Bibbo et al.' in 1977 demonstrated a history of pregnancy in only 18% of 229 DES-exposed women as compared with 33% of 136 unexposed subjects. In 1981 Herbst et al. 2 reevaluated this population and found infertility to be present in a greater proportion of DES-exposed women (n = 53, 26%) than in unexposed subjects (n = 19, I 0% ). Furthermore, among the married women who were not always protected with contraceptives, 75% of the exposed group, as compared with 92% of the unexposed group, had achieved pregnancy.2 This study augments and extends the previous investigations of the original Chicago Lying-In Hospital population by including additional cases of infertility and examining specific risk factors potentially contributing to infertility. In addition, first conception rates and time to conception among DES-exposed and unexFrom the Department of Obstetrics and Gynecology, University of Chicago, Pritzker School of Medicine. Supported in part by American Cancer Society Clinical Career Development Award No. 85-38 (to E. K. S.) and the Mothers' Aid Research Fund of the Chicago Lying-In Hospital. Received for publication April 16, 1987; revised October 14, 1987; accepted November 6, 1987. Reprint requests: Elizabeth K. Senekjian, MD, Department of Obstetrics and Gynecology, Chicago Lying-In Hospital, 5841 South Maryland Ave., Box 446, Chicago, IL 60637.
posed women with primary and/or secondary infertility were analyzed. Material and methods
In the original double-blind study, 840 pregnant women were given DES and 806 were given placebo. The drug was taken from the first prenatal visit, from 6 to 23 weeks after the onset of the last menstrual period, in conformity with a standard dosage schedule.' Since 1974 an effort has been made to contact the 408 DES-exposed and the 388 unexposed live-born daughters and to obtain follow-up medical histories. Gynecologic examinations, which included cytologic smears and colposcopy, and infertility evaluations were offered at the Chicago Lying-In Hospital. For su~jects living outside the Chicago area analogous examinations by specialists were performed. The findings at the first physical examination, at which time the average age for the group was 23.5 years, have been reported previously.' Health-history questionnaires were completed at follow-up clinic visits, by mail, and through telephone interviews. Questionnaires included inquiries pertaining to contraception, history of pelvic inflammatory disease, infertility, and pregnancies achieved. Records concerning diagnostic infertility evaluations and treatment, as well as other significant medical conditions, were requested. Data were recorded on standard forms and entered into a confidential computer tile. Infertility is defined as the inability to conceive after at least I year of actively attempting to achieve preg-
493
494
Senekjian et al.
March 1988 Am J Obstet Gynecol
Table I. Infertility among DES-exposed and unexposed women DES-exposed women Total no. of live-born female infants born to mothers in study No. of women responding to questionnaire No. married Not at risk, never pregnant At risk No. reporting difficulty conceiving Primary infertility Secondary infertility *Total number at secondary as well as tTotal number at secondary as well as
Unexposed women
408
388
343 266 59 207 92 69 (33%) 39* (23%)
303 236 33 203 45 28 (14%) 28t (15%)
p Value
<0.001 <0.05
risk includes 170 DES-exposed women who have achieved at least one pregnancy; 16 exposed women had primary infertility. risk includes 193 unexposed subjects who have achieved at least one pregnancy; 11 unexposed subjects had primary infertility.
Table II. Cervicovaginal abnormalities detected at initial examination among DES-exposed women Initial exami11ation at CL/* or el1ewhere Ever preKnantf
Primary infertility
(n = 106)
(n = 53)
48 (77% ):j:
68 (64'lr):j:
42 (79%):j:
56 (65%):j:
38 (61'7c)§
41 (39%)§
36 (68%)§
35(41%)§
Primary infertility Ceniirovaginal abnormality Vaginal epithelial changes Cervicovaginal ridges
Initial examination at CL/
(n = 62)
I
Ever preKrlantt
I
(n = 86)
*CL! = Chicago Lying-In Hospital. tSubjects were married, had at least one pregnancy. and never reported infertility. :j:p
nancy. Subjects with primary infertility have never conceived while those with secondary infertility have had one or more previous pregnancies. A complete diagnostic infertility investigation includes the documentation of ovulation, semen analysis, postcoital test, hysterosalpingography, and laparoscopy and/or laparotomy with testing of tubal patency. A diagnosis of ovulatory dysfunction includes a history of irregular menstrual cycles with intervals exceeding 35 days and was established by the assessment of basal body temperature curves, progesterone levels, and/or by the histologic evidence of delayed maturation of the endometrium (luteal phase defect). Seminal deficiency was defined as a score of >5 utilizing the Eliasson scoring system." A postcoital test was designated as abnormal when there were < 10 motile sperm per high-power microscopic field. Cervical stenosis was defined as a significant narrowing of the endocervical canal or a pinpoint cervical os. Uterine structural alterations were demonstrated by hysterosalpingography. The presence of tubal defects or endometriosis was assessed by the direct inspection of pelvic viscera. x" Statistics and t tests were used to compare variables of interest. Pregnancy patterns were analyzed by the Mantel-Haenszel statistic' and by a standard actuarial life-table method.''
Results
Baseline health data were available for 343 (84%) of the DES-exposed daughters and 303 (78%) of the unexposed individuals (Table I). Two hundred seven (60%) of the 266 married DES-exposed women and 203 (67%) of the 236 married unexposed subjects were not using contraception regularly and were at risk for pregnancy. As of February I 986 primary infertility was reported by 69 (33%) of the 207 DES-exposed women and 28 (14%) of the 203 unexposed subjects (p < 0.001). Infertility was not reported in the unmarried group. Table II demonstrates the prevalence of cervicovaginal abnormalities detected at the initial gynecologic examination (performed in the mid- l 970s) among DES-exposed women with primary infertility and among exposed subjects who were married, had been pregnant, and had never reported infertility. Cervicovaginal ridges (p < 0.00 I) and vaginal epithelial changes (adenosis and physiologic squamous metaplasia) were found in a greater proportion of individuals with primary infertility. No significant differences with regard to the age pregnancy was first attempted or in the time interval to the primary infertility evaluation were observed between women exposed to DES (means of 24.7 and 2.2 years) and unexposed subjects (means of 24.5 and 2.0
Infertility experience among DES daughters 495
Volume 158 Nurnher 3, Part I
Table III. Factors contributing to primary infertility DES-exposed (n
= 69)
I
%
No.
38 24 63 46 42 21
Factor
No.
Ovulatory factor Male factor Cervical factor Abnormal hysterosalpingogram Tubal factor Endometriosis
23/61 9/37 12*/l 9 11124 IOt/24 5/24
Unexposed (n
= 28)
I
%
p Value
15/27 3/14 2/8
56 21 25
019 019 419
44
NS NS 0.07,NS <0.02 0.02 NS
NS = not significant (p > 0.05). *Includes six cases of cervical stenosis. tlncludes seven cases of adnexal adhesions, and two cases of both adhesions and endometriosis.
years). The total DES dose for exposed women with primary infertility ranged from 10,744 to 12,582 mg (mean of 12,241 mg) and for fertile exposed women from 4817 to 12,582 mg (mean of 12,189 mg). A comparable proportion of DES-exposed women (59%) and unexposed individuals (57%) underwent primary infertility evaluation. Although ovulatory disorders were diagnosed less often in DES-exposed women (38%) than in unexposed subjects (56% ), the difference was not statistically significant (Table Ill). Abnormalities in the semen were demonstrated in a similar proportion of the male partners of exposed and unexposed women. No significant difference was found in the frequency of cervical factors in the exposed group as compared with the unexposed group. Of the six DES-exposed subjects with cervical stenosis, two had undergone previous cervical cauterization. None of the unexposed subjects who underwent hysterosalpingographic study had uterine abnormalities. Uterine defects including a T-shaped or hypoplastic cavity, a septate uterus, intrauterine synechiae, or irregular uterine margins were documented in 46% of DES-exposed women with primary infertility. Tubal abnormalities (including adnexal adhesions, tubal occlusion, and congenital or surgical tubal absence) were diagnosed at laparoscopy or laparotomy in 10 of 24 (42%) exposed and none of nine unexposed women. In six DES-exposed women the findings were consistent with pelvic inflammatory disease. Endometriosis was diagnosed less frequently in the exposed group. A smaller proportion of DES-exposed women with primary infertility (n = 40, 58%) than of control subjects (n = 18, 64%) achieved first pregnancies. Twentyfour women (60%) in the exposed group and 15 subjects (83%) in the unexposed group who eventually conceived had a live birth of an infant who survived. Among individuals who achieved first pregnancies, adverse pregnancy outi:omes (including spontaneous abortion, ectopic pregnancy, and perinatal death) occurred more often among DES-exposed women
(n
= 15, 38%) than among unexposed individuals
(n = 3, 17% ). None of these differences were statisti-
cally significant. Hysterosalpingographic findings were not predictive of conception rates among DES-exposed women with primary infertility. Pregnancies occurred in six of 13 (46%) DES-exposed women with normal hysterosalpingograms and in five of 11 (45%) DES-exposed individuals with abnormal studies. Four of I 0 DES-exposed women with tubal defects conceived. Treatment for primary infertility (prescribed medications, artificial insemination, or surgery) was administered at least once to a similar proportion of the exposed (n = 28,41%)andtheunexposed(n = 12,43%) groups. Among those who eventually conceived, pregnancies occurred independent of treatment in 29 of 40 (73%) women exposed to DES as compared with 10 of 18 (56%) unexposed subjects. The secondary infertility experience of the exposed and control groups was also examined. Thirty-nine (23%) of 170 DES-exposed women and 28 (15%) of 193 unexposed subjects who were at risk and ever pregnant reported secondary infertility (p < 0.05 ). Sixteen of the exposed women and 11 of the unexposed subjects experienced both primary and secondary infertility. When those with primary infertility were excluded, the difference was no longer statistically significant. The total DES dose ranged from I 0,850 to 12,582 mg (mean of 12,298 mg) for those who were exposed in utero and had secondary infertility and from 4817 to 12,582 mg (mean of 12,188 mg) for fertile exposed women without primary or secondary infertility. A similar proportion of exposed (54%) and unexposed (46%) subjects underwent secondary infertility evaluation. Each risk factor was analyzed and no significant differences were detected between the exposed and unexposed groups with regard to the presence of ovulatory, male, or cervical factors. Of the 13 exposed women who underwent hysterosalpingographic study, five (38%) had uterine defects. Although tubal abnormalities were more common in exposed individuals
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March 1988 Am J Obstet Gynecol
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(eight of 12, 67%) than in unexposed subjects (one of seven, 14%), the data are limited and do not permit a meaningful statistical comparison. An equivalent proportion of DES-exposed women (n = 23, 59%) and unexposed subjects (n = 16, 57%) achieved pregnancies after the diagnosis of secondary
infertility. Among those who eventually conceived, a significantly smaller proportion in the exposed group (n = 11, 48%) as compared with the unexposed group (n = 13, 81 %) had a live birth of an infant who survived
Volume 158 !'\umber 3, Part I
first pregnancies only among exposed and unexposed individuals with primary infertility is shown in Fig. 1. After infertility was reported the estimated cumulative pregnancy rates for the exposed group versus the unexposed group were 16% and 36% (p < 0.05) at 12 months, 33% and 43% at 24 months, and 45% and 63% at 36 months. Fig. 2 illustrates the estimated cumulative annual rate of pregnancies among exposed and unexposed individuals with secondary infertility. Among those with primary infertility the mean time to the first conception for exposed untreated women (2.7 years) was significantly longer than for untreated control women ( 1.8 years, p < 0.03). Although the difference in mean time to conception was even greater among those treated for primary infertility, 4.0 years for DES-exposed women versus 2.8 years for control women, this difference was not statistically significant. Comparison of the times to pregnancies achieved over 10 years by DES-exposed and control women after the diagnosis of primary or secondary infertility, by the Mantel-Haenszel method, demonstrated no statistically significant differences (Figs. 1 and 2).
Comment In the present study primary infertility was found to be significantly more common among women at risk for pregnancy who were exposed to DES (33%) than among control women (14%). These data conflict with findings by Barnes et al." and Cousins et al.,' who did not detect differences in fertility rates between DESexposed women and unexposed subjects. However, in three studies without controls, Schmidt et al.," Berger and Goldstein," and Kaufman et al. 10 reported infertility in approximately one third of DES-exposed women managed in specialty clinics. Cervicovaginal ridges were detected significantly more frequently at the initial examination in married DES-exposed women with primary infertility than in married DES-exposed women who conceived (Table II). Therefore structural abnormalities of the cervix and vagina present at the initial examination may be associated with the subsequent occurrence of primary infertility. These cervicovaginal structural changes have been correlated with the time DES was begun in pregnancy and the total dose received. 11 The complete regression of cervicovaginal ridges has been described by Antonioli et al. 12 in 28% of 123 patients and by Herbst et al.' in 57% of 102 cases. Regardless of the rate of regression, it seems that ridges will disappear over time in many DES-exposed women. Therefore the absence of a ridge at any given pelvic examination does not necessarily indicate that a ridge was never present. Ovulatory defects, male factors, and endometriosis do not seem to contribute to the excess of primary infertility found in DES-exposed women. Although a
Infertility experience among DES daughters 497
cervical factor may play a role, the difference between the exposed and unexposed groups does not attain statistical significance. The number of postcoital tests performed was small and abnormal tests were not always repeated; the results presented are based on the best available data. Among those with primary infertility who underwent evaluation, abnormal hysterosalpingograms and tubal defects were the factors found significantly more often in DES-exposed women than in control women. Tubal abnormalities compatible with previous pelvic inflammatory disease were more common in those exposed to DES, but the numbers are small and preclude a statistically meaningful analysis. Although differences in patterns of sexual practice may contribute to the occurrence of pelvic inflammatory disease, detailed data regarding sexual histories are not available. DES-exposed women who present with symptoms suggestive of acute salpingitis may benefit from laparoscopy in order to confirm the clinical suspicion and/or the administration of aggressive antibiotic therapy. The sexual partners of affected patients should also be evaluated and treated in order to decrease the risk of successive episodes of sexually transmitted diseases. Among high-risk DES-exposed women, routine interval cultures may identify and allow treatment of asymptomatic carriers of sexually transmitted organisms. Two studies have evaluated the risk factors among exposed and unexposed women attending infertility clinics. In one study, Berger and Alper'" noted a statistically significant increase in endometriosis among 50 infertile DES-exposed women (64%) as compared with 50 infertile unexposed, age-matched women (40%) and a significant decrease in the occurrence of pelvic inflammatory disease among exposed women as compared with unexposed subjects (6% versus 26%). Stillman and Miller'' found endometriosis at laparoscopy and/or laparotomy in 10 of 20 (50%) infertile women exposed to DES in utero in comparison with 39% of 377 infertile unexposed women. This latter difference was not statistically significant. Both studies were susceptible to bias since patients were selected from infertility clinics and were not participants in a single cohort study as in this report. Kaufman et al."' detected uterine structural abnormalities by hysterosalpingograms in 59% of 632 DESexposed women. Abnormal hysterosalpingographic studies were found in an equivalent proportion ofDESexposed women who had conceived within 1 year as compared with infertile exposed women. Therefore uterine abnormalities as a group were not associated with an increase in the occurrence of infertility. However, Kaufman et al. 10 did note a significant association between the presence of an upper uterine cavity con-
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striction and an inability to conceive. In addition, consistent with the results of this study, there did not appear to be a correlation between the ability of infertile exposed women to eventually achieve pregnancy and hysterosalpingographic abnormalities. Only first pregnancies occurring within I 0 years after the diagnosis of primary infertility were analyzed in the present study. The estimated cumulative rate of first pregnancies at 36 months was lower in DES-exposed women (45%) than in control women (63%). However, the overall difference between the two groups was not statistically significant. These findings are not dissimilar to reported cumulative pregnancy rates of 51 % and 59% at 36 months among infertile couples in general.''· 16 Although fewer pregnancies of all types as well as live births of surviving infants were achieved among DES-exposed women than among unexposed subjects, the differences were not statistically significant. Of those who ultimately conceived, unfavorable pregnancy outcomes occurred more often in women exP.osed to DES than in unexposed subjects. These findings are in agreement with other studies that demonstrate adverse pregnancy outcomes to be more frequent among DES-exposed women as compared with unexposed women. 2 • 6 · 7 Data are available for only a portion of the total number of subjects with infertility, and therefore there may be bias with regard to the different rates of risk factors contributing to the infertility experience in the exposed and unexposed groups. Nevertheless, among those with primary infertility, tubal defects including those compatible with a diagnosis of pelvic inflammatory disease were found more often in women exposed to DES than in control women. This suggests that a high index of suspicion and intensive therapy for this condition may increase the likelihood of preserving fertility in DES-exposed women. REFERENCES 1. Bibbo M, Gill WB, Azizi F, et al. Follow-up study of male and female offspring of DES-exposed mothers. Obstet Gynecol 1977;49:1.
March 1988 Am J Obstet Gynecol
2. Herbst AL, Hubby MM, Azizi F, Makii MM. Reproductive and gynecologic surgical experience in diethylstilbestrolexposed daughters. AM J OBSTET GYNECOL 1981; 141:1019. 3. Eliasson LR. Analysis of semen. In: Behrman SJ, Kistner RW, eds. Progress in infertility. 2nd ed. Boston: Little Brown, 1975:691-713. 4. Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 1966;50: 163. 5. Cutter SJ, Ederer F. Maximum utilization of the life table method in analyzing survival. J Chronic Dis 1958;8:699. 6. Barnes AB, Colton T, Gundersen J, et al. Fertility and outcome of pregnancy in women exposed in utero to diethylstilbestrol. N Engl J Med I 980;302:609. 7. Cousins L, Karp W, Lacey C, Lucas WE. Reproductive outcome of women exposed to diethylstilbestrol in utero. Obstet Gynecol 1980;56:70. 8. Schmidt G, Fowler WC, Talbert LM, Edelman DA. Reproductive history of women exposed to diethylstilbestrol in utero. Fertil Steril 1980;33:21. 9. Berger MJ, Goldstein DP. Impaired reproductive performance in DES-exposed women. Obstet Gynecol 1980; 55:25. 10. Kaufman RH, Adam E, Noller K, Irwin JF, Gray M. Upper genital tract changes and infertility in diethylstilbestrol-exposed women. AM J OBSTET GYNECOL 1986; 154:1312. 11. Jefferies JA, Robboy SJ, O'Brien PC, et al. Structural anomalies of the cervix and vagina in women enrolled in the Diethylstilbestrol Adenosis (DESAD) Project. AMJ 08STET GYNECOL 1984;148:59. 12. Antonioli DA, Burke L, Friedman EA. Natural history of diethylstilbestrol-associated genital tract lesions: cervical ectopy and cervicovaginal hood. AM J 0BSTET GYNECOL 1980;137:847. 13. Berger MJ, Alper MM. Intractable primary infertility in women exposed to diethylstilbestrol in utero. J Reprod Med 1986;31:231. 14. Stillman JR, Miller LC. Diethylstilbestrol exposure in utero and endometriosis in infertile females. Fertil Steril 1984;41:369. 15. CollinsJA, Wrixon W,Janes LB, Wilson EH. Treatmentindependent pregnancy among infertile couples. N Engl J Med 1983;309:1201. 16. Katayama KP, Kap-Soon JU, Manuel M,Jones GS, Jones HW. Computer analysis of etiology and pregnancy rate in 636 cases of primary infertility. AM J 0BSTET GYNECOL 1979;135:207.