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Ulcerative colitis: Female fecundity before diagnosis, during disease, and after surgery compared with a population sample
GASTROENTEROLOGY2002;122:15-19
CLINICAL RESEARCH Ulcerative Colitis: Female Fecundity Before Diagnosis, During Disease, and After Surgery Compared With a Population Sample KASPER ORDING OLSEN,* SVEND JUUL,~ INA BERNDTSSON,§ TOM (~)RESLAND,§ and SOREN LAURBERG* *Surgical Department L, Section AAS, Aarhus University Hospital, and ~Department of Epidemiology and Social Medicine, University of Aarhus, Aarhus, Denmark; and §Colorectal Unit, Sahlgrenska University Hospital/C)stra, Gothenburg, Sweden
See editorial on page 226. Background & Aims: Women with ulcerative colitis generally have normal fertility. The aim of this study was to compare patients' fecundability before and after restorative proctocolectomy with ileal pouch-anal anastomosis with the fecundabiiity of the general population. Methods: Historical follow-up was performed on 343 consecutive female patients aged 1 0 . 6 - 4 0 . 5 years at surgery and a reference population of 1 2 0 0 women aged 2 5 - 4 0 years. A total of 290 (85%) patients and 6 6 1 (55%) women in the reference population agreed to participate in a structured telephone interview concerning reproductive behavior and waiting times to pregnancy. Cox regression and Kaplan-Meier plots were used for analysis. Results: Surgery significantly reduced the ratio of patient to reference population fecundabiiity, which decreased to 0.20 (P < 0.0001). Before diagnosis and from diagnosis until colectomy, the fecundability of the patients was similar to that of the reference population. Conclusions: Female patients with ulcerative colitis have normal fecundity before surgical treatment. Surgery severely reduces female fecundity. Information about this reduction in fecundity should be given before surgery, and if a woman has an unfulfilled wish for pregnancy after surgery, early referral to a gynecologist is recommended.
tudies on women suffering from inflammatory bowel disease suggest that ulcerative colitis (UC) does not affect fertility. 1-4 UC is frequently treated by proctocolectomy with ileal pouch-anal anastomosis (IPAA). IPAA does not jeopardize pregnancy and childbirth, 5-1° but reports suggest that it could impair fertility. 11,~2 Hence, the number of births before surgery has been shown to match expectations; after IPAA, it has been shown to decrease to less than half of the expected number, and the frequency of in vitro fertilization (IVF)
S
has been shown to increase to a level 15 times higher than expected. 13 Therefore, it was concluded that these patients' fecundity was likely to be severely impaired after surgery. However, consistent data on fecundity (i.e., waiting times to pregnancy) and knowledge of UC patients' wishes in terms of pregnancy are not available. The primary aim of this study was to evaluate fecundity levels before diagnosis, from diagnosis until colectomy, and after IPAA in women with UC who underwent IPAA and to compare these data with those of a reference population. A secondary aim was to examine the frequency of IVF.
Patients and Methods Study Populations Patients. This study included all women with UC who underwent restorative proctocolectomy with IPAA between November 1982 and January 1998 and were 40 years old or younger at the time of stoma closure and older than 18 years of age at the time of the interview. A total of 343 subjects were studied from the 4 participating departments: 124 from the Swedish Colorectal Unit, Sahlgrenska University Hospital, Gothenburg; 89 from the Danish Surgical Department C, Rigshospitalet, Copenhagen; 88 from the Danish Surgical Department L, Aarhus University Hospital; and 42 from the Danish Surgical Department A, Odense University Hospital. A reference population of 1200 women aged 25-40 years was drawn at random from the national population registers, 600 in Denmark and 600 in Sweden. Concepts and definitions. The term fecundity describes the biological ability to conceive. Fecundity is estimated based on time periods of unprotected intercourse and Abbreviationsusedin this paper: FR, fecundabilityratio; IPAA, ileal pouch-anal anastomosis; IRA, ileorectal anastomosis; IVF, in vitro fertilization; TI'P, time to pregnancy. © 2002 by the American GastroenterologicalAssociation 0016-5085/02/$35.00 doi:10.1053/gast.2002.30345
16
OLSENETAL.
expressed as fecundability (the probability of becoming pregnant per month with unprotected intercourse). 14 Information about intervals of unprotected intercourse was collected from the participants, and intervals not leading to pregnancy were treated statistically as censored observations, as were time intervals resulting in pregnancy after IVF. This decision reflects the assumption that without the interference of IVF treatment, the duration of the interval of unprotected intercourse would at least have matched the observed interval. We calculated the actual time (in months) for each interval of unprotected intercourse leading or not leading to pregnancy. These intervals are hereafter referred to as time to pregnancy (TTP), irrespective of the outcome. We compared TTPs in the patient and reference populations to estimate the fecundability ratio (FR). D a t a collection. Data were collected by telephone interviews conducted by thoroughly instructed and trained female interviewers. A highly structured interview form, designed to ensure uniformity in interviewing the participating women, was developed and validated by pilot testings. For each patient we defined 3 time windows of interest: before diagnosis of UC (before diagnosis), from diagnosis until colectomy (before colectomy), and from stoma closure until the date of interview (after IPAA). For each woman in the reference population, 4 time windows were defined by age: 15-24, 25-29, 30-34, and 35-39 years. This enabled age-stratified comparisons between patients and the reference population. Participants were asked in detail about the first interval of unprotected intercourse starting within each time/age window. Thus reference women 25 years old or older might give information in 2 or more age windows. The main contents of the interview form were: reproductive history, starting and ending dates (or duration) for the first interval of unprotected intercourse in each time window, intent to become pregnant (planning), and exposures around the starting date of this first time interval. All intervals could be expressed in weeks, months, or years. Potential participants were contacted once by letter containing written information about the project and a stamped, addressed envelope to allow the potential participant to communicate her written consent or refusal to participate. Nonresponders whose telephone numbers could be found in the directory were contacted by telephone and invited to participate. No further contact was made to nonresponders with no easily identifiable telephone numbers. All interviews were performed between May 1998 and April 2000 (in Denmark, May-December 1998; in Sweden, December 1998-April 2OOO). A copy of the interview form (Danish, Swedish, and nonvalidated English) is available on request from one of the authors (K.~D.O.). Statistical methods. Time intervals were recorded as weeks, months, or years and analyzed according to the passage of time. An interval could end with a pregnancy or as a censored observation. Censoring occurred if cohabitation ended, if contraception was resumed, if the woman was still trying to conceive at the time of the interview, if the woman
GASTROENTEROLOGY Vol. 122, No. 1
became pregnant after IVF treatment, or (patients only) if the woman changed status (from unoperated to operated). The TTP was calculated for the first interval of unprotected intercourse in each time/age window. The cumulative incidence of pregnancy was described by Kaplan-Meier plots, and comparisons of TTPs between groups were made by use of the Cox proportional hazards model adjusting for age and country at the beginning of the time interval of unprotected intercourse. This corresponds to comparing, e.g., a Danish patient who was 27 years old at the beginning of the interval of unprotected intercourse with the reference population information for Danish women aged 25-29 years at the beginning of the interval of unprotected intercourse. Analyses were made for each country separately and for the pooled data. In all Cox regression analyses, the reference population served as base for the comparisons. The term fecundability ratio was used for the Cox regression coefficients. We included 1 TTP from each time window, thus allowing for more than 1 TTP per woman. We made no statistical corrections for interdependence of observations. The average number of live births among participants and nonparticipants was compared using data from the national birth registers. 15,16 Data entry was performed using the SPSS Data Entry Builder (SPSS, Chicago, IL)lV; double entry for a 15% random sample showed no discrepancies. Analyses were performed using SPSS 10.018 for Windows. Ethics. The study protocol, interview form, and procedures for contacting potential participants were all approved by local research ethics committees in Denmark and Sweden.
Results The 290 participating patients gave information on 98 T T P s before diagnosis, 84 before colectomy, and 149 after I P A A ; the 661 participating w o m e n from the reference population gave information on a total of 914 TTPs. The main finding of this study was that the fecundability levels of w o m e n with UC were equal to or slightly higher than those seen in the reference g r o u p up to the time of surgery (before diagnosis, FR 1.46, P = 0.002; before colectomy, FR 1.01, P = NS) but very low (FR 0.20, P < 0.0001) after I P A A (Table 1, Figure 1). Table 2 shows the cumulative incidence of pregnancy as determined from the K a p l a n - M e i e r life table. R u n n i n g the analyses after selecting only those who had a wish for pregnancy at the beginning of the T T P did not alter the main results (data not shown). N o statistically significant differences in FR were observed between the 2 countries in any of the groups analyzed, but the frequency of IVF treatment after I P A A was m u c h higher in Swedish than in Danish patients (P < 0.001). Background information and data from questions concerning each w o m a n ' s first pregnancy are shown in Table 3. Swedish patients received help and IVF treatments before the first pregnancy (P < 0.02) more frequently than Danish patients. The Swedish patients and reference
January 2002
ULCERATIVE COLITIS AND FEMALE FECUNDITY 17
Table 1. Age-Adjusted FR Denmark
Reference population Patients before diagnosis Patients before colectomy Patients after IPAA
Pooled data a
Sweden
FR (95% Cl)
nb
FR (95% CI)
nb
FR (95% Cl)
nb
1 1.33 (0.98-1.79) 1.01 (0.71-1.42) 0.25 (0.17-0.37)
511 63 46 92
1 1.75 (1.18-2.56) 1.04 (0.71-1.51) 0.14 (0.08-0.25)
403 35 38 57
1 1,46 (1.16-1.85) 1,01 (0.79-1.31) 0,20 (0.15-0.28)
914 98 84 149
P 0.002 0.92 <0.001
Analyses adjusting for smoking status changed ratios only in the second digit and therefore are not shown. 95% Cl, 95% confidence interval. aAdjusted for age and country. bNumber of periods observed (El'P).
population reported significantly more pelvic/genital infections than their Danish counterparts (P < 0.02). In Denmark, a larger proportion of the reference population had been pregnant, were smoking at first pregnancy, or reported pelvic/genital infections than among the Danish patients (P < 0.05). The same differences in incidence of smoking and pelvic/genital infections between patients and reference population were seen in Sweden. Lack of preoperative TTP was ascribed by 27.6% of the patients to a conscious choice because of the disease. After IPAA, 36.4% of the patients who had no TTP attributed the lack of TTP to disease and surgery. Table 4 shows the age of patients at onset of UC, at diagnosis, at colectomy, and at stoma closure as well as the time from diagnosis to surgery. Participation rates were 85% (Denmark, 87%; Sweden, 81%) for the patients and 55% (Denmark, 62%; Sweden, 48%) for the reference population. The proportions of nonresponders excluded because no telephone numbers could be identified were 12% for Danish patients, 20% for Swedish patients, 22% for the Danish reference population, and 38% for the Swedish reference population. There was no difference in age or average number of births between participating and nonparticipating patients in Denmark, whereas in Sweden the average num-
ber of births was 1.37 for participating and 1.0 for nonparticipating patients, and the participants' mean age was 1.9 years lower than that of nonparticipants. The Danish and Swedish reference populations were not different in terms of age, but both countries had a slightly higher average number of births among participants (Denmark, 1.08; Sweden, 1.42) than among nonparticipants (Denmark, 0.88; Sweden, 1.29).
Discussion The present study is the first to systematically compare TTPs of women suffering from UC with those of a reference population. The main finding was that the fecundability of women with UC was unaffected up to the time of surgical treatment but became significantly reduced after IPAA compared with the reference population. This finding is in keeping with our previous study, which showed that the number of children born before surgery matched expectations and that it was significantly reduced after surgery33 Other studies and reviews have reported normal fertility rates for patients with UC, 1-4 a finding that is supported for the preoperative stage of the disease by our
Table 2, Cumulative Incidences of Pregnancy at 12, 24, and 6 0 M o n t h s Patients
08o~ '~
0.0-
"~
04 -
r - -
[
0.2-
12 mo 24 mo 60 mo
~ Reference l -Before diagnosis - - - Before surgery
0
12
24
36
48
After surgery
60
Time to pregnancy (months)
Figure 1. Cumulative incidence of pregnancy within 5 years. Patients and reference population.
Before diagnosis (n = 98)
Before colectomy (n = 84)
Reference After IPAA population (n = 149) (n = 914)
83% 90% 95%
78% 85% 90%
18% a 27% a 36% a
75% 82% 88%
0% 0% 0% 40%
0% 0% 0% 29%
30.0% a 14.3% a 52.0% a 17% a
1.3% 1.5% 1.0% 43%
Pregnancies after IVF treatment
Pooled Denmark Sweden Smokers
aSignificantly different from the reference population (P < 0.001).
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OLSEN ET AL.
GASTROENTEROLOGY Vol. 122, No. 1
Table 3. Background Information for Patients and Reference Population Patients
Background Single at time of interview Percentage who have been pregnant Mean number of live births Mean number of pregnancies Median age at first menstruation (yr) Ever had pelvic/genital infection Median age at interview (yr) Information concerning first pregnancy Smokers at beginning of TTP, first pregnancy Help required to achieve first pregnancy First pregnancies after IVF treatment Median age at beginning of FiP before first pregnancy (yr)
Reference population
Denmark (n = 190)
Sweden (n = 100)
Pooled (n = 290)
Denmark (n = 372)
Sweden (n = 289)
Pooled (n = 661)
13.2% 65.8% a 1.08 1.39 13.0 26.8% a 34.1
13.0% 77.0% 1.38 1.93 13.0 43.0% 38.0
13.1% 69.7% 1.19 1.58 13.0 32.4% b 35.3
15.9% 75.0% 1.24 1.80 13.0 36.0% 32.2
13.8% 74.7% 1.44 2.06 13,0 51.9% 32.9
15.0% 74.9% 1.33 1.90 13.0 43.0% 32.4
32.8% b 7.2% 2.4%
41.6% 18.2% b 13.0% b
36.1% a 11.4% 6.4% °
46.6% 6.5% 1.7%
38.9% 5.6% 1.4%
43.2% 6.1% 1.6%
23.3
22.6
23.1
23.2
23.1
23.2
a'bDifferences between patients and reference population: ap < 0.05; bp < 0.01.
finding of preoperative fecundability among patients that is slightly better than that of the reference population. Reports on female fecundity after IPAA are scarce and i n c o n c l u s i v e r,11,le,19 or based only on the numbers of children born *3 and not on TTPs. Our findings may be influenced by the severity of the disease leading to surgical treatment, but it seems plausible that the reduction in fecundability is attributable mainly to the surgical procedure. Surgery for perforated appendicitis does not influence fertility rates2°; therefore, it is probably the extent and the location right to the pelvic floor of the IPAA surgery that cause severe reductions in fecundability. In a study of 21 women who underwent IPAA for UC, postoperative hysterosalpingography produced normal findings in only 7 patients.l* If this finding is applicable to larger groups of patients, postoperative fecundability could be severely reduced as a result of postoperative adhesions. In a similar study of women with familial adenomatous polyposis, 21 we also found fecundability to be substantially reduced after IPAA but completely normal
Table 4. Age of Patients at Event: Pooled Data
Median (yr)
Range (yr)
20.3 22.0 27.1 27.9 35.3
3.9-39.1 4.9-39.2 10.6-40.5 11.0-40.5 19.5-52,8
2.8 7.8
0-25.0 0.1-16,1
Age Onset of UC Diagnosis of UC Colectomy Closing of the stoma Interview Time span Diagnosis to colectomy Stoma closure to interview
Inclusion criteria: age 18 years or older at interview, 40 years or younger at stoma closure.
after subtotal colectomy with ileorectal anastomosis (IRA); a finding that may call for a revival of IRA for UC in young female patients who have no children, but further studies are needed to establish if this difference between IPAA and IRA applies in patients with UC. The duration of T T P was undoubtedly subject to some uncertainty because the time span to recall ranged from 0 months to more than 20 years. However, this uncertainty does not invalidate the use of T T P as a sensitive marker of reproductive function, even with long recall, 22,23 and we had no reason to assume the presence of any differential recall problems. Therefore, we are confident that any T T P recall problem in the present study would be nondifferential. Nondifferential recall problems act as n o i s e , 24 making differences look smaller than they are, and therefore will not exaggerate the differences between the groups. The strength of this study was that T T P was assessed directly based on systematically collected information from a highly structured interview form, and the fecundability estimate was thus based only on patients whose reproductive behavior allowed pregnancy to occur. The single most obvious weakness was the low participation rate (5 5%) in the reference population, which we believe to be a matter of motivation. This may influence the results because participants had a larger average number of children than nonparticipants, but this is not believed to seriously affect the main conclusion. Fewer patients than reference subjects reported pelvic/ genital infection (Table 3); thus, pelvic infection cannot explain the lower postoperative fecundability among patients. The variation between countries was largely attributable to a large number of Swedish women reporting uncomplicated vaginal fungal disease. The dissimi-
January 2002
larity in smoking habits (Table 3) does not explain the reduced postoperative fecundability of the patients. The elevated frequency of IVF treatment among Swedish patients in the postoperative period reflects surgeons' increased awareness of the possibility of gynecologic and fertility problems after surgery. This awareness arises from a study of changes in the female pelvis after restorative proctocolectomy carried out in Gothenburg. 11 In addition, there has been a more liberal attitude toward IVF in the Gothenburg region of Sweden for most of the observation period compared with that in Denmark. Longer sequences with ongoing IVF treatment may prevent spontaneous pregnancies from occurring and thus the postoperative FR of the Swedish patients may be biased and appear lower than it really is (Table 1). In our study, the cumulative incidence of pregnancy after a T T P of 12 months or less (Table 2) was comparable to that reported in other studies of fecundability, 14"25 except for the postoperative period. W e are not able to suggest or explain why patients had a significantly better preoperative fecundability than the reference population. In conclusion, we found normal fecundability among women with UC up to the time of surgery. Fecundability was severely reduced after IPAA for UC; therefore, we may conclude that its negative effect on female fecundability is a clinical problem. This serious side effect must be made clear to women of reproductive age who plan to have children after surgery. W e recommend that women who cannot get pregnant after surgery be referred early to a gynecologist to allow for investigations and the possibility of IVF.
References 1. Willoughby CP, Truelove SC. Ulcerative colitis and pregnancy. Gut 1980;21:469-474. 2. Korelitz BI. Inflammatory bowel disease and pregnancy. Gastroenterol Clin North Am 1998;27:213-224. 3. Jarnerot G. Fertility, sterility and pregnancy in chronic inflammatory bowel disease. Scand J Gastroenterol 1 9 8 2 ; 1 7 : 1 - 4 . 4. Vender RJ, Spiro HM. Inflammatory bowel disease and pregnancy. J Clin Gastroenterol 1982;4:231-249. 5. Pezim ME. Successful childbirth after restorative proctocolectomy with pelvic ileal reservoir. Br J Surg 1984;71:292. 6. Metcalf A, Dozois RR, Beart RW Jr, Wolff BG. Pregnancy following ileal pouch-anal anastomosis. Dis Colon Rectum 1 9 8 5 ; 2 8 : 8 5 9 861. 7. Metcalf AM, Dozois RR, Kelly KA. Sexual function in women after proctocolectomy. Ann Surg 1 9 8 6 ; 2 0 4 : 6 2 4 - 6 2 7 . 8. Nelson H, DozoJs RR, Kelly KA, Malkasian GD, Wolff BG, Ilstrup DM. The effect of pregnancy and delivery on the ileal pouch-anal anastomosis functions. Dis Colon Rectum 1 9 8 9 ; 3 2 : 3 8 4 - 3 8 8 . 9. Juhasz ES, Fozard B, Dozois RR, IIstrup DM, Nelson H. Ileal pouch-anal anastomosis function following childbirth. An extended evaluation. Dis Colon Rectum 1 9 9 5 ; 3 8 : 1 5 9 - 1 6 5 . 10. Scott HJ, McLeod RS, Blair J, O'Connor B, Cohen Z. Ileal pouch-
ULCERATIVE COLITIS AND FEMALE FECUNDITY 19
11.
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anal anastomosis: pregnancy, delivery and pouch function. Int J Colorectal Dis 1 9 9 6 ; 1 1 : 8 4 - 8 7 . Oresland T, Palmblad S, EIIstrom M, Berndtsson I, Crona N, Hulten L. Gynaecological and sexual function related to anatomical changes in the female pelvis after restorative proctocolectomy. Int J Colorectal Dis 1 9 9 4 ; 9 : 7 7 - 8 1 . Counihan TC, Roberts PL, Schoetz DJ Jr, Coller JA, Murray JJ, Veidenheimer MC. Fertility and sexual and gynecologic function after ileal pouch-anal anastomosis. Dis Colon Rectum 1994;37: 1126-1129. Olsen K, Joelsson M, Laurberg S, Oresland T. Fertility after ileal pouch-anal anastomosis in women with ulcerative colitis. Br J Surg 1 9 9 9 ; 8 6 : 4 9 3 - 4 9 5 . Karmaus W, Juul S, European Infertility and Subfecundity Study Group. Infertility and subfecundity in population-based samples from Denmark, Germany, Italy, Poland and Spain. Eur J Public Health 1 9 9 9 ; 9 : 2 2 9 - 2 3 5 . Knudsen L8, Olsen J. The Danish Medical Birth Registry. Dan Med Bull 1 9 9 8 ; 4 5 : 3 2 0 - 3 2 3 . Cnattingius S, Ericson A, Gunnarskog J, Kalien BA. Quality study of a medical birth registry. Scand J Soc Med 1990;18:143-148. SPSS Inc. SPSS Data Entry Builder 1.0.5. Chicago, IL, SPSS, 1999 SPSS. SPSS/Windows 10.0.5. Chicago, IL, SPSS, 1999. Tiainen J, Matikainen M, Hiltunen KM. Ileal J-pouch-anal anastomosis, sexual dysfunction, and fertility. Scand J Gastroenterol 1999;34:185-188. Andersson R, Lambe M, Bergstrom R. Fertility patterns after appendicectomy: historical cohort study. BMJ 1 9 9 9 ; 3 1 8 : 9 6 3 967. Olsen KO, Juul S, BOIow S, J~rvinen HJ, Bakka A, Bj6rk J, Oresland T, Laurberg S. Female fecundity before and after surgery for familial adenomatous polyposis (FAP). Ann Surg (in press). Joffe M, Viliard L, Li Z, Plowman R, Vessey MA. Time to pregnancy questionnaire designed for long term recall: validity in Oxford, England. J Epidemiol Community Health 1 9 9 5 ; 4 9 : 3 1 4 - 3 1 9 . Joffe M, Villard L, Li Z, Plowman R, Vessey M. Long-term recall of time-to-pregnancy. Fertil Steril 1 9 9 3 ; 6 0 : 9 9 - 1 0 4 . Rothman KJ, Greenland S. Precision and validity in epidemiologic studies. In: Rothman KJ, Greenland S, eds. Modern epidemiology. Philadelphia, PA: Lippincott-Raven, 1998:115--134. Juul S, Karmaus W, Olsen J. Regional differences in waiting time to pregnancy: pregnancy-based surveys from Denmark, France, Germany, Italy and Sweden. The European Infertility and Subfecundity Study Group. Hum Reprod 1 9 9 9 ; 1 4 : 1 2 5 0 - 1 2 5 4 .
Received March 21, 2001. Accepted August 30, 2001. Address requests for reprints to: Kasper Ording Olsen, M.D., Surgical Department L, AFD 900, Aarhus University Hospital, Tage Hansensgade 2, DK-8000 Aarhus C, Denmark. e-mail: [email protected]; fax: (45) 89497709. Supported by grants or equipment from the Institute of Experimental Clinical Research, University of Aarhus, Denmark; the Colitis-Crohn Association of Denmark (Colitis-Crohn Foreningen); the FERRING Grant of Gastroenterology 1998, Ferring Laegemidler A/S, Denmark; the Vibeke Binder and Poul Riis Foundation; and the Swedish Medical Research Council. Study Group of Ulcerative Colitis and Female Fertility: Tom Oresland, Ina Berndtsson, Eva Persson, Colorectal Unit, Sahlgrenska University Hospital/Ostra, Gothenburg, Sweden; Lars Bo Svendsen, Surgical Department C, Rigshospitalet, Copenhagen, Denmark; Kasper ~rding Olsen, Soren Laurberg, Surgical Department L, Section AAS, Aarhus University Hospital, Aarhus, Denmark; Niels Qvist, Surgical Department A, Odense University Hospital, Odense, Denmark; Svend Juul, Department of Epidemiology and Social Medicine, University of Aarhus, Aarhus, Denmark.
CLINICAL RESEARCH Ulcerative Colitis: Female Fecundity Before Diagnosis, During Disease, and After Surgery Compared With a Population Sample KASPER ORDING OLSEN,* SVEND JUUL,~ INA BERNDTSSON,§ TOM (~)RESLAND,§ and SOREN LAURBERG* *Surgical Department L, Section AAS, Aarhus University Hospital, and ~Department of Epidemiology and Social Medicine, University of Aarhus, Aarhus, Denmark; and §Colorectal Unit, Sahlgrenska University Hospital/C)stra, Gothenburg, Sweden
See editorial on page 226. Background & Aims: Women with ulcerative colitis generally have normal fertility. The aim of this study was to compare patients' fecundability before and after restorative proctocolectomy with ileal pouch-anal anastomosis with the fecundabiiity of the general population. Methods: Historical follow-up was performed on 343 consecutive female patients aged 1 0 . 6 - 4 0 . 5 years at surgery and a reference population of 1 2 0 0 women aged 2 5 - 4 0 years. A total of 290 (85%) patients and 6 6 1 (55%) women in the reference population agreed to participate in a structured telephone interview concerning reproductive behavior and waiting times to pregnancy. Cox regression and Kaplan-Meier plots were used for analysis. Results: Surgery significantly reduced the ratio of patient to reference population fecundabiiity, which decreased to 0.20 (P < 0.0001). Before diagnosis and from diagnosis until colectomy, the fecundability of the patients was similar to that of the reference population. Conclusions: Female patients with ulcerative colitis have normal fecundity before surgical treatment. Surgery severely reduces female fecundity. Information about this reduction in fecundity should be given before surgery, and if a woman has an unfulfilled wish for pregnancy after surgery, early referral to a gynecologist is recommended.
tudies on women suffering from inflammatory bowel disease suggest that ulcerative colitis (UC) does not affect fertility. 1-4 UC is frequently treated by proctocolectomy with ileal pouch-anal anastomosis (IPAA). IPAA does not jeopardize pregnancy and childbirth, 5-1° but reports suggest that it could impair fertility. 11,~2 Hence, the number of births before surgery has been shown to match expectations; after IPAA, it has been shown to decrease to less than half of the expected number, and the frequency of in vitro fertilization (IVF)
S
has been shown to increase to a level 15 times higher than expected. 13 Therefore, it was concluded that these patients' fecundity was likely to be severely impaired after surgery. However, consistent data on fecundity (i.e., waiting times to pregnancy) and knowledge of UC patients' wishes in terms of pregnancy are not available. The primary aim of this study was to evaluate fecundity levels before diagnosis, from diagnosis until colectomy, and after IPAA in women with UC who underwent IPAA and to compare these data with those of a reference population. A secondary aim was to examine the frequency of IVF.
Patients and Methods Study Populations Patients. This study included all women with UC who underwent restorative proctocolectomy with IPAA between November 1982 and January 1998 and were 40 years old or younger at the time of stoma closure and older than 18 years of age at the time of the interview. A total of 343 subjects were studied from the 4 participating departments: 124 from the Swedish Colorectal Unit, Sahlgrenska University Hospital, Gothenburg; 89 from the Danish Surgical Department C, Rigshospitalet, Copenhagen; 88 from the Danish Surgical Department L, Aarhus University Hospital; and 42 from the Danish Surgical Department A, Odense University Hospital. A reference population of 1200 women aged 25-40 years was drawn at random from the national population registers, 600 in Denmark and 600 in Sweden. Concepts and definitions. The term fecundity describes the biological ability to conceive. Fecundity is estimated based on time periods of unprotected intercourse and Abbreviationsusedin this paper: FR, fecundabilityratio; IPAA, ileal pouch-anal anastomosis; IRA, ileorectal anastomosis; IVF, in vitro fertilization; TI'P, time to pregnancy. © 2002 by the American GastroenterologicalAssociation 0016-5085/02/$35.00 doi:10.1053/gast.2002.30345
16
OLSENETAL.
expressed as fecundability (the probability of becoming pregnant per month with unprotected intercourse). 14 Information about intervals of unprotected intercourse was collected from the participants, and intervals not leading to pregnancy were treated statistically as censored observations, as were time intervals resulting in pregnancy after IVF. This decision reflects the assumption that without the interference of IVF treatment, the duration of the interval of unprotected intercourse would at least have matched the observed interval. We calculated the actual time (in months) for each interval of unprotected intercourse leading or not leading to pregnancy. These intervals are hereafter referred to as time to pregnancy (TTP), irrespective of the outcome. We compared TTPs in the patient and reference populations to estimate the fecundability ratio (FR). D a t a collection. Data were collected by telephone interviews conducted by thoroughly instructed and trained female interviewers. A highly structured interview form, designed to ensure uniformity in interviewing the participating women, was developed and validated by pilot testings. For each patient we defined 3 time windows of interest: before diagnosis of UC (before diagnosis), from diagnosis until colectomy (before colectomy), and from stoma closure until the date of interview (after IPAA). For each woman in the reference population, 4 time windows were defined by age: 15-24, 25-29, 30-34, and 35-39 years. This enabled age-stratified comparisons between patients and the reference population. Participants were asked in detail about the first interval of unprotected intercourse starting within each time/age window. Thus reference women 25 years old or older might give information in 2 or more age windows. The main contents of the interview form were: reproductive history, starting and ending dates (or duration) for the first interval of unprotected intercourse in each time window, intent to become pregnant (planning), and exposures around the starting date of this first time interval. All intervals could be expressed in weeks, months, or years. Potential participants were contacted once by letter containing written information about the project and a stamped, addressed envelope to allow the potential participant to communicate her written consent or refusal to participate. Nonresponders whose telephone numbers could be found in the directory were contacted by telephone and invited to participate. No further contact was made to nonresponders with no easily identifiable telephone numbers. All interviews were performed between May 1998 and April 2000 (in Denmark, May-December 1998; in Sweden, December 1998-April 2OOO). A copy of the interview form (Danish, Swedish, and nonvalidated English) is available on request from one of the authors (K.~D.O.). Statistical methods. Time intervals were recorded as weeks, months, or years and analyzed according to the passage of time. An interval could end with a pregnancy or as a censored observation. Censoring occurred if cohabitation ended, if contraception was resumed, if the woman was still trying to conceive at the time of the interview, if the woman
GASTROENTEROLOGY Vol. 122, No. 1
became pregnant after IVF treatment, or (patients only) if the woman changed status (from unoperated to operated). The TTP was calculated for the first interval of unprotected intercourse in each time/age window. The cumulative incidence of pregnancy was described by Kaplan-Meier plots, and comparisons of TTPs between groups were made by use of the Cox proportional hazards model adjusting for age and country at the beginning of the time interval of unprotected intercourse. This corresponds to comparing, e.g., a Danish patient who was 27 years old at the beginning of the interval of unprotected intercourse with the reference population information for Danish women aged 25-29 years at the beginning of the interval of unprotected intercourse. Analyses were made for each country separately and for the pooled data. In all Cox regression analyses, the reference population served as base for the comparisons. The term fecundability ratio was used for the Cox regression coefficients. We included 1 TTP from each time window, thus allowing for more than 1 TTP per woman. We made no statistical corrections for interdependence of observations. The average number of live births among participants and nonparticipants was compared using data from the national birth registers. 15,16 Data entry was performed using the SPSS Data Entry Builder (SPSS, Chicago, IL)lV; double entry for a 15% random sample showed no discrepancies. Analyses were performed using SPSS 10.018 for Windows. Ethics. The study protocol, interview form, and procedures for contacting potential participants were all approved by local research ethics committees in Denmark and Sweden.
Results The 290 participating patients gave information on 98 T T P s before diagnosis, 84 before colectomy, and 149 after I P A A ; the 661 participating w o m e n from the reference population gave information on a total of 914 TTPs. The main finding of this study was that the fecundability levels of w o m e n with UC were equal to or slightly higher than those seen in the reference g r o u p up to the time of surgery (before diagnosis, FR 1.46, P = 0.002; before colectomy, FR 1.01, P = NS) but very low (FR 0.20, P < 0.0001) after I P A A (Table 1, Figure 1). Table 2 shows the cumulative incidence of pregnancy as determined from the K a p l a n - M e i e r life table. R u n n i n g the analyses after selecting only those who had a wish for pregnancy at the beginning of the T T P did not alter the main results (data not shown). N o statistically significant differences in FR were observed between the 2 countries in any of the groups analyzed, but the frequency of IVF treatment after I P A A was m u c h higher in Swedish than in Danish patients (P < 0.001). Background information and data from questions concerning each w o m a n ' s first pregnancy are shown in Table 3. Swedish patients received help and IVF treatments before the first pregnancy (P < 0.02) more frequently than Danish patients. The Swedish patients and reference
January 2002
ULCERATIVE COLITIS AND FEMALE FECUNDITY 17
Table 1. Age-Adjusted FR Denmark
Reference population Patients before diagnosis Patients before colectomy Patients after IPAA
Pooled data a
Sweden
FR (95% Cl)
nb
FR (95% CI)
nb
FR (95% Cl)
nb
1 1.33 (0.98-1.79) 1.01 (0.71-1.42) 0.25 (0.17-0.37)
511 63 46 92
1 1.75 (1.18-2.56) 1.04 (0.71-1.51) 0.14 (0.08-0.25)
403 35 38 57
1 1,46 (1.16-1.85) 1,01 (0.79-1.31) 0,20 (0.15-0.28)
914 98 84 149
P 0.002 0.92 <0.001
Analyses adjusting for smoking status changed ratios only in the second digit and therefore are not shown. 95% Cl, 95% confidence interval. aAdjusted for age and country. bNumber of periods observed (El'P).
population reported significantly more pelvic/genital infections than their Danish counterparts (P < 0.02). In Denmark, a larger proportion of the reference population had been pregnant, were smoking at first pregnancy, or reported pelvic/genital infections than among the Danish patients (P < 0.05). The same differences in incidence of smoking and pelvic/genital infections between patients and reference population were seen in Sweden. Lack of preoperative TTP was ascribed by 27.6% of the patients to a conscious choice because of the disease. After IPAA, 36.4% of the patients who had no TTP attributed the lack of TTP to disease and surgery. Table 4 shows the age of patients at onset of UC, at diagnosis, at colectomy, and at stoma closure as well as the time from diagnosis to surgery. Participation rates were 85% (Denmark, 87%; Sweden, 81%) for the patients and 55% (Denmark, 62%; Sweden, 48%) for the reference population. The proportions of nonresponders excluded because no telephone numbers could be identified were 12% for Danish patients, 20% for Swedish patients, 22% for the Danish reference population, and 38% for the Swedish reference population. There was no difference in age or average number of births between participating and nonparticipating patients in Denmark, whereas in Sweden the average num-
ber of births was 1.37 for participating and 1.0 for nonparticipating patients, and the participants' mean age was 1.9 years lower than that of nonparticipants. The Danish and Swedish reference populations were not different in terms of age, but both countries had a slightly higher average number of births among participants (Denmark, 1.08; Sweden, 1.42) than among nonparticipants (Denmark, 0.88; Sweden, 1.29).
Discussion The present study is the first to systematically compare TTPs of women suffering from UC with those of a reference population. The main finding was that the fecundability of women with UC was unaffected up to the time of surgical treatment but became significantly reduced after IPAA compared with the reference population. This finding is in keeping with our previous study, which showed that the number of children born before surgery matched expectations and that it was significantly reduced after surgery33 Other studies and reviews have reported normal fertility rates for patients with UC, 1-4 a finding that is supported for the preoperative stage of the disease by our
Table 2, Cumulative Incidences of Pregnancy at 12, 24, and 6 0 M o n t h s Patients
08o~ '~
0.0-
"~
04 -
r - -
[
0.2-
12 mo 24 mo 60 mo
~ Reference l -Before diagnosis - - - Before surgery
0
12
24
36
48
After surgery
60
Time to pregnancy (months)
Figure 1. Cumulative incidence of pregnancy within 5 years. Patients and reference population.
Before diagnosis (n = 98)
Before colectomy (n = 84)
Reference After IPAA population (n = 149) (n = 914)
83% 90% 95%
78% 85% 90%
18% a 27% a 36% a
75% 82% 88%
0% 0% 0% 40%
0% 0% 0% 29%
30.0% a 14.3% a 52.0% a 17% a
1.3% 1.5% 1.0% 43%
Pregnancies after IVF treatment
Pooled Denmark Sweden Smokers
aSignificantly different from the reference population (P < 0.001).
18
OLSEN ET AL.
GASTROENTEROLOGY Vol. 122, No. 1
Table 3. Background Information for Patients and Reference Population Patients
Background Single at time of interview Percentage who have been pregnant Mean number of live births Mean number of pregnancies Median age at first menstruation (yr) Ever had pelvic/genital infection Median age at interview (yr) Information concerning first pregnancy Smokers at beginning of TTP, first pregnancy Help required to achieve first pregnancy First pregnancies after IVF treatment Median age at beginning of FiP before first pregnancy (yr)
Reference population
Denmark (n = 190)
Sweden (n = 100)
Pooled (n = 290)
Denmark (n = 372)
Sweden (n = 289)
Pooled (n = 661)
13.2% 65.8% a 1.08 1.39 13.0 26.8% a 34.1
13.0% 77.0% 1.38 1.93 13.0 43.0% 38.0
13.1% 69.7% 1.19 1.58 13.0 32.4% b 35.3
15.9% 75.0% 1.24 1.80 13.0 36.0% 32.2
13.8% 74.7% 1.44 2.06 13,0 51.9% 32.9
15.0% 74.9% 1.33 1.90 13.0 43.0% 32.4
32.8% b 7.2% 2.4%
41.6% 18.2% b 13.0% b
36.1% a 11.4% 6.4% °
46.6% 6.5% 1.7%
38.9% 5.6% 1.4%
43.2% 6.1% 1.6%
23.3
22.6
23.1
23.2
23.1
23.2
a'bDifferences between patients and reference population: ap < 0.05; bp < 0.01.
finding of preoperative fecundability among patients that is slightly better than that of the reference population. Reports on female fecundity after IPAA are scarce and i n c o n c l u s i v e r,11,le,19 or based only on the numbers of children born *3 and not on TTPs. Our findings may be influenced by the severity of the disease leading to surgical treatment, but it seems plausible that the reduction in fecundability is attributable mainly to the surgical procedure. Surgery for perforated appendicitis does not influence fertility rates2°; therefore, it is probably the extent and the location right to the pelvic floor of the IPAA surgery that cause severe reductions in fecundability. In a study of 21 women who underwent IPAA for UC, postoperative hysterosalpingography produced normal findings in only 7 patients.l* If this finding is applicable to larger groups of patients, postoperative fecundability could be severely reduced as a result of postoperative adhesions. In a similar study of women with familial adenomatous polyposis, 21 we also found fecundability to be substantially reduced after IPAA but completely normal
Table 4. Age of Patients at Event: Pooled Data
Median (yr)
Range (yr)
20.3 22.0 27.1 27.9 35.3
3.9-39.1 4.9-39.2 10.6-40.5 11.0-40.5 19.5-52,8
2.8 7.8
0-25.0 0.1-16,1
Age Onset of UC Diagnosis of UC Colectomy Closing of the stoma Interview Time span Diagnosis to colectomy Stoma closure to interview
Inclusion criteria: age 18 years or older at interview, 40 years or younger at stoma closure.
after subtotal colectomy with ileorectal anastomosis (IRA); a finding that may call for a revival of IRA for UC in young female patients who have no children, but further studies are needed to establish if this difference between IPAA and IRA applies in patients with UC. The duration of T T P was undoubtedly subject to some uncertainty because the time span to recall ranged from 0 months to more than 20 years. However, this uncertainty does not invalidate the use of T T P as a sensitive marker of reproductive function, even with long recall, 22,23 and we had no reason to assume the presence of any differential recall problems. Therefore, we are confident that any T T P recall problem in the present study would be nondifferential. Nondifferential recall problems act as n o i s e , 24 making differences look smaller than they are, and therefore will not exaggerate the differences between the groups. The strength of this study was that T T P was assessed directly based on systematically collected information from a highly structured interview form, and the fecundability estimate was thus based only on patients whose reproductive behavior allowed pregnancy to occur. The single most obvious weakness was the low participation rate (5 5%) in the reference population, which we believe to be a matter of motivation. This may influence the results because participants had a larger average number of children than nonparticipants, but this is not believed to seriously affect the main conclusion. Fewer patients than reference subjects reported pelvic/ genital infection (Table 3); thus, pelvic infection cannot explain the lower postoperative fecundability among patients. The variation between countries was largely attributable to a large number of Swedish women reporting uncomplicated vaginal fungal disease. The dissimi-
January 2002
larity in smoking habits (Table 3) does not explain the reduced postoperative fecundability of the patients. The elevated frequency of IVF treatment among Swedish patients in the postoperative period reflects surgeons' increased awareness of the possibility of gynecologic and fertility problems after surgery. This awareness arises from a study of changes in the female pelvis after restorative proctocolectomy carried out in Gothenburg. 11 In addition, there has been a more liberal attitude toward IVF in the Gothenburg region of Sweden for most of the observation period compared with that in Denmark. Longer sequences with ongoing IVF treatment may prevent spontaneous pregnancies from occurring and thus the postoperative FR of the Swedish patients may be biased and appear lower than it really is (Table 1). In our study, the cumulative incidence of pregnancy after a T T P of 12 months or less (Table 2) was comparable to that reported in other studies of fecundability, 14"25 except for the postoperative period. W e are not able to suggest or explain why patients had a significantly better preoperative fecundability than the reference population. In conclusion, we found normal fecundability among women with UC up to the time of surgery. Fecundability was severely reduced after IPAA for UC; therefore, we may conclude that its negative effect on female fecundability is a clinical problem. This serious side effect must be made clear to women of reproductive age who plan to have children after surgery. W e recommend that women who cannot get pregnant after surgery be referred early to a gynecologist to allow for investigations and the possibility of IVF.
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Received March 21, 2001. Accepted August 30, 2001. Address requests for reprints to: Kasper Ording Olsen, M.D., Surgical Department L, AFD 900, Aarhus University Hospital, Tage Hansensgade 2, DK-8000 Aarhus C, Denmark. e-mail: [email protected]; fax: (45) 89497709. Supported by grants or equipment from the Institute of Experimental Clinical Research, University of Aarhus, Denmark; the Colitis-Crohn Association of Denmark (Colitis-Crohn Foreningen); the FERRING Grant of Gastroenterology 1998, Ferring Laegemidler A/S, Denmark; the Vibeke Binder and Poul Riis Foundation; and the Swedish Medical Research Council. Study Group of Ulcerative Colitis and Female Fertility: Tom Oresland, Ina Berndtsson, Eva Persson, Colorectal Unit, Sahlgrenska University Hospital/Ostra, Gothenburg, Sweden; Lars Bo Svendsen, Surgical Department C, Rigshospitalet, Copenhagen, Denmark; Kasper ~rding Olsen, Soren Laurberg, Surgical Department L, Section AAS, Aarhus University Hospital, Aarhus, Denmark; Niels Qvist, Surgical Department A, Odense University Hospital, Odense, Denmark; Svend Juul, Department of Epidemiology and Social Medicine, University of Aarhus, Aarhus, Denmark.