GASTROEIVIZROLOGY
1990;99:967-994
Increased Risk of Preterm Birth for Women With Inflammatory Bowel Disease DONNA DAY BAIRD, M. NARENDRANATHAN, and ROBERT S. SANDLER Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina; and Division of Digestive Diseases and Nutrition, Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, North Carolina
The reproductive histories of 177 women with Crohn’s disease and 84 women with ulcerative colitis were compared with those of healthy control subjects. Inflammatory bowel disease was associated with reduced fertility as measured by number of pregnancies, but measures of childlessness, infertility, fecundability, and methods of birth control suggested that this reduced fertility was the patients’ choice rather than a consequence of disease-mediated biological impairments. There was no evidence of increased risk of pregnancy loss, but the risk of preterm birth was significantly elevated for patients with Crohn’s disease (odds ratio, 3.1; 95% confidence interval, 1.8-5.4) and for those with ulcerative colitis (odds ratio, 2.7; 95% confidence interval, 1.8-5.4). Several plausible biological mechanisms that could explain the link between preterm birth and inflammatory bowel disease are suggested. These results may be useful when counseling patients who desire pregnancy. Physicians can reassure patients about potential fertility problems but should also encourage close obstetrical monitoring during the third trimester of pregnancy.
M
any women with inflammatory bowel disease (IBD) are of reproductive age. The effect of the
disease on women’s fertility and pregnancies is a subject of controversy. Vender and Spiro (1) reviewed several descriptive reports that had been published before 1982 and noted the paucity of controlled studies. Three case-control studies have subsequently been published (2-4), all of which reported that most women with IBD reproduce successfully but may have an increased risk of problems. The one study that examined fertility showed an increased risk of subfertility, and all three studies found more preterm births in cases than in control subjects. However, infertility
was measured without consideration for whether women had tried to conceive. Furthermore, data on pregnancy outcomes were analyzed without any adjustment for factors, such as smoking, that might affect reproduction. To study reproductive characteristics of patients with IBD further, we included detailed reproductive questions in a case-control study of Crohn’s disease (CD] and ulcerative colitis (UC). This study compares subfertility, pregnancy loss, and preterm births in women with IBD (177 with CD and 84 with UC] and in healthy control subjects. Methods Study Subjects Potential study cases were identified from three North Carolina chapters of the National Foundation for Ileitis and Colitis (Charlotte, Greensboro, and RaleighDurham-Chapel Hill). Screening questionnaires were mailed to 1131 male and female subjects to determine whether they had IBD. Questionnaires were returned by 989 (87.4%) subjects, of whom 883 indicated that they had IBD. A self-administered questionnaire including details of reproductive history was mailed to each case. After two mailings and a phone call, data were available for 503 (74%) male and female cases, including 197 women with CD and 107 women with UC. The disease diagnosis was validated in a sample of 15% of these patients. Because 98% of these met the criteria for definite or probable IBD, we feel confident that virtually all of the cases in our study have IBD. The cases were asked to suggest one or two neighbors who were of the same sex, age [within 5 years], and race who might serve as control subjects. Control subjects were nominated by 95% of the cases. After two mailings and a phone call,
Abbreviations used in this paper: CD, Crohn’s disease; CI, confidence interval; OR, odds ratio. 0 1990 by the American Gastroenterological Association 0016-5065/90/$3.00
988
BAIRD ET AL.
data were available for 353 (74%) of the control subjects. Of 92 cases whose first controls declined to participate, 65 provided the names of second controls. Fifty-one of those responded, thus increasing the total number of control subjects to 404, including 245 women. Only data from the female respondents were used in these analyses. In an attempt to limit recall errors, women over 60 years old were excluded from analysis of the reproductive variables. This left 216 control subjects, 177 CD patients, and 84 UC patients for analysis.
Analysis
of Data
Given that matching was used as a convenient method for generating a demographically similar comparison group and none of the matching variables was important for analysis, an unmatched analysis was performed using all cases and controls for whom data were available (51. The control subjects for the CD and UC cases were pooled to form a single control group. Specific analyses have fewer cases and/or controls because of missing data on individual variables. Variables for analysis were derived from data collected on a self-administered questionnaire. Women were asked if they had ever tried to conceive for more than 1 year. Women who had tried to conceive for more than 1 year but remained childless were classified as “involuntarily childless.” Women with one or more children who later tried for at least 1 year to conceive again but were unsuccessful were classified as “secondarily infertile.” Women were classified as “voluntarily childless” if they reported having no fertility problems but had never been pregnant. A “pregnancy loss” was defined as a pregnancy ending in the loss of an embryo or a fetus for reasons other than by induced abortion. Stillbirths were considered pregnancy losses. A “preterm birth” was defined as a singleton livebirth before 37 weeks’ gestation, as determined by the reported length of pregnancy in weeks. Race was dichotomized to white and nonwhite. Religion was dichotomized to Catholic and non-Catholic. Education was measured by number of years in school. Variables for each subject’s age (~30 or 230 years), gravidity (0, 1, or >l prior pregnancy], number of prior pregnancy losses (0, 1, or >l), and smoking (smoker or nonsmoker) at the time of each pregnancy were derived from appropriate questionnaire items on pregnancy and smoking histories. To test for time trends, four variables were created for the decade during which the pregnancy occurred (before 1960, 1960s 197Os, 1980s). To examine the effects of disease on reproductive characteristics, the pregnancies of women identified as cases were categorized in relation to time of onset of disease symptoms. Pregnancies before symptom onset were defined as “predisease pregnancies.” Pregnancies after onset of symptoms were defined as “disease pregnancies.” A disease pregnancy may have been symptom-free. We do not have adequate data to evaluate disease activity and severity during individual disease pregnancies. For multivariate modeling, each of a woman’s pregnancies was included in analysis as an independent event. Possible effects of IBD on fertility were examined by estimating relative fecundability, the probability of achiev-
GASTROENTEROLOGY
Vol. 99. No. 4
ing pregnancy in any given menstrual cycle for women with IBD relative to controls (6). Data on time to pregnancy (the number of menstrual cycles before conception in which no contraception was practiced] were fit as the dependent variables in a Cox proportional-hazard model (7) using the PHGLM procedure of SAS (SAS Institute, Gary, NC). Final results were confirmed using a discrete form of the Cox model, the more appropriate model for time-to-pregnancy data (8). The proportional-hazard analysis is a method used to identify factors that influence the time to some event (in this case, time to pregnancy). The coefficient associated with a factor in the proportional-hazard model provides an estimate of that factor’s influence on how quickly women get pregnant. The IBD status can be included as one of the factors in the model. When the coefficient associated with IBD is exponentiated, the resultant value provides an estimate of the probability of becoming pregnant in any given menstrual cycle for patients with IBD compared with control subjects. This estimate is called the fecundability ratio. A fecundability ratio near 1.0 indicates that the probability of getting pregnant is about the same for women with IBD as for control subjects. A fecundability ratio cl.0 indicates reduced fertility. Fecundability ratios for CD and UC were adjusted for age, gravidity, and smoking status. Each of the other variables for which we had data was individually added to this basic model, but none changed the fecundability ratio associated with disease in significant ways. Possible effects of IBD on pregnancy loss and preterm birth were estimated with logistic regression using the LOGIST procedure of SAS. Because both adverse pregnancy outcomes are dichotomous dependent variables, logistic regression is the preferred method (9). The status of IBD can be included as one of the independent variables in the regression model. The regression coefficient associated with IBD status is exponentiated and the resultant value provides an estimate of the odds ratio [OR) associated with disease [the odds of having an adverse pregnancy outcome for women with IBD divided by the odds for control women), controlling for other factors in the model. An OR close to 1.0 indicates that the risk of adverse pregnancy outcome is nearly the same for women with IBD as for control subjects. An OR >l.O indicates an elevated risk of pregnancy loss or preterm birth among women with IBD. Factors other than IBD status that might influence pregnancy outcomes were controlled in analysis. When analyzing pregnancy loss, the patient’s age, history of previous spontaneous abortion, and smoking status were included in all the models. Additional variables were tested individually to assess their influence on the relationship between IBD and pregnancy loss and were found not to change the relationship significantly. When analyzing preterm birth, pregnancies ending in multiple births were excluded. Age, gravidity, and smoking status were included in all the preterm birth models. Additional variables were tested individually and found not to change the relationship between IBD and preterm birth. All the variables in final models were checked by adding interaction terms to the model one at a time to make sure that the association of the dependent variable with IBD status did not differ significantly among subsets of the population. For
October 1990
PREGNANCY AND INFLAMMATORY BOWEL DISEASE
Table 1. Characteristics of the Study Subjects at Time of
The dominant religious affiliation in was Protestant. The median age of symptoms was 23 years, and the diagnosis was 26 years in both disease
Study as Reported by Self-Administered Questionnaire Controls (N = 216) (N :77] Race (%) White
Nonwhite Age(%I t20 yr 20-29 yr 30-39 yr 40-49 yr 50-60 yr
all three groups onset of disease median age of groups.
(N:84]
95
93
99
5
7
1
2 15 38 29 16
1
23 33 26 17
2 14 35 36 13
5 33 28 21 13
7 38 27 19 17
4 28 28 29 11
13 78 7 1
16 71 10 2
21 18
20 15
6 76 10 2 6 21 17
57 19 24
37 27 36
55 31 14
91 7 2
85 3 12
84
Education(%) cl2 yr 12 yr 13-15 yr 16 yr >16 yr Marital status (TO] Single Married Divorced Separated Widowed Median age at first marriage ( yr) Median years married Smoking status (%) Never Past Current Religion (%) Protestant Catholic Other
989
6 10
example, the association between IBD and pregnancy loss only in older women could be formally tested by adding a variable to the final model that would be coded “1” for pregnancies occurring in older women with IBD and coded “0” for all other pregnancies. If analysis showed significant elevation in the regression coefficient associated with this variable, it would suggest that older women with IBD were more likely to have adverse pregnancy outcomes, but that IBD had no significant adverse effect on younger women. Results In Table 1, we show social and demographic characteristics of the study groups at the time of data collection. As expected, the cases and controls did not differ substantially by race or age given the process by which controls were selected. The groups were also similar in marital history, although when compared with controls, fewer women with UC were single (6% vs. 13%) and more women in both disease groups were separated, divorced, or widowed (14% for CD and 18% for UC vs. 9% for controls). Compared with control subjects, more women with CD were current smokers, whereas fewer women with UC smoked.
Fertility Women whose first pregnancies occurred after the onset of disease symptoms had fewer total pregnancies than the control subjects, even after data were adjusted for age at the time of first pregnancy (Table 2). On the other hand, women whose first pregnancies occurred before the onset of symptoms had about the same number of total pregnancies as control subjects. When tested with logistic regression, the chance of having subsequent pregnancies (adjusted for age at the time of first pregnancy] was significantly reduced among women of both disease groups whose first pregnancy occurred after onset of disease symptoms (P < 0.05). No significant differences were seen between women whose first pregnancies were predisease and controls. Available data were used to evaluate whether the reduced number of pregnancies in women with disease symptoms was attributable to impaired fecundity [the biological ability to conceive] or voluntary fertility control (Table 3). Cases and controls were similar in the proportions of ever-married women who were involuntarily childless or secondarily infertile (2%4%). In addition, 15%-20% of each group had a pregnancy that required more than 1 year of trying to conceive before conception was achieved. Women who had become pregnant were asked to provide their time to pregnancy, defined as the number of menstrual cycles in which contraception was not practiced before pregnancy. These data were used to estimate the fecundability of cases compared with control subjects. The fecundability ratios for both disease groups are near 1.0, indicating no significant reduction in fecundability associated with IBD (Table 3). Other available data suggest that IBD cases might
Table 2. Mean Number of Pregnancies by Disease Status of the First Pregnancy Among Women Who Had Ever Been Pregnant No. of pregnancies Study sample
n
R
SD
Controls CD cases First pregnancy before onset of symptoms First pregnancy after onset of symptoms UC cases First pregnancy before onset of symptoms First pregnancy after onset of symptoms
160
2.6
1.3
69 50
2.6 2.1
1.6 1.6
32 25
2.9 1.9
1.6 0.7
NOTE. Values are adjusted for age at the time of first pregnancy.
990
BAIRD ET AL.
Table 3. Measures
GASTROENTEROLOGY
of Infertility
and Fecundability
Status
Control
Measure Involuntarily childless” (%) Secondarily infertile” (%,I Pregnancy after >l year of trying” [ %]
Fecundability (95% CI) n
by Disease
4 4 15
CD
UC
3 2 19
2 3 17
Predisease pregnancies
Disease pregnancies
Predisease pregnancies
(O.Z.5] 73
(O.Z.2] 86
(O.Z2] 50
Disease pregnancies
ratiob (‘1-9 268
Vol. 99, No. 4
“Among married women (181 control subjects, 146 CD cases, 76 UC cases]. bAmong women who had ever been pregnant, estimated by Cox proportional-hazard status.
have voluntarily limited their fertility more than control subjects (Table 4). Voluntary childlessness was higher in women with UC than in controls. Compared with control subjects, a larger proportion of cases reported that they were afraid to have children or were told not to have children, and CD cases were told more often that they might have difficulty having children. Choice of birth control before the first pregnancy also differed somewhat between controls and cases whose first pregnancies occurred after IBD symptoms began. Adjusting for age at the time of first pregnancy and limiting the data to first pregnancies that occurred in the 1970s and 1980s to avoid any bias created by availability of oral contraceptives, 45% of control subjects reported using oral contraceptives or IUDs before their first pregnancies. In contrast, 63% of women with CD disease pregnancies and 57% of women with UC disease pregnancies used oral contraceptives or IUDs before their first pregnancies [Table 4), supporting the notion that women sought to avoid pregnancy after disease onset.
model controlling
for
1.0 (0.9-1.2) 49
age, gravidity,
and smoking
The proportion of first pregnancies ending in loss does not seem significantly elevated among cases compared with control subjects (Table 5). However,
when data on all pregnancies were used in analyses, pregnancy loss seemed more frequent in CD disease pregnancies. When logistic regression analysis was used to control for history of pregnancy loss, age, and smoking status, CD pregnancies were found to be at a significantly increased risk of pregnancy loss [OR, 1.86; 95% confidence interval (CI), 1.05-3.291. No significant elevation in risk was found in women with UC. To understand the differences between rates of first pregnancy losses compared with all pregnancies for women with CD, we considered the possibility that selection bias might be creating the observed increase in risk seen in analyses using all pregnancies. If women based their decisions whether or not to become pregnant again on the outcomes of their previous pregnancies (lo), and selection for those women who continued to get pregnant occurred differentially in case and control subjects, the results of analyses using data from all pregnancies could be biased. The rates of subsequent pregnancies did vary in women depending on the outcomes of previous pregnancies. Women with pregnancy losses were more likely to become pregnant again than women with live births (94% of controls with first pregnancies ending in loss had second pregnancies, whereas 84% of controls with live births had second pregnancies). This selec-
Table 4. Differences
to Voluntary
Pregnancy
Loss
Among
Factor Voluntary childlessness” Afraid to have childrenb Told not to have childrenb Told might have difficulties having childrenb
Disease
Groups
in Factors
Related
Control
Control [%)
CD (%)
UC (%)
14 12 4
14 18 14
21 15 9
17
23 Predisease pregnancies
Used birth control pills or IUD before first pregnancy”
Fertility
45
45
15 Disease pregnancies 63
Predisease pregnancies 42
Disease pregnancies 57
“Among respondents who had ever been married (181controls, 146CD cases, 76 UC cases]. bAmong all respondents (216controls, 177CD cases, 84 UC cases). “Among respondents who had ever been pregnant (160 controls, 124 CD cases, 63 UC cases]; adjusted for age at time of first pregnancy.
PREGNANCY AND INFLAMMATORY
October 1990
BOWEL DISEASE
991
Table 5. Pregnancies Ending in Loss Categorized by Disease Status CD
11 12
First pregnancies (%) All pregnancies (%] g!io CI)
;19
n
376
Disease pregnancies
Predisease pregnancies
Control
UC
15 16
12 20
(O.&)
1.9 (1.0-3.31 127
146
Disease pregnancies
Predisease pregnancies
6 11
16 16 1.3 (0.5-3.3) 63
(O.E.9) 50
“Controlling for history of pregnancy loss, age, and smoking status.
tion for those who had additional pregnancies was more marked in the IBD cases than in the control subjects, especially after the second pregnancy (i.e., women with CD were more likely than controls to stop reproducing after a live birth]. After two pregnancies, 52% of control subjects with one or two live births became pregnant again, whereas only 38% of CD cases with one or two live births continued to third pregnancies. Yet for those with no live births after two pregnancies, both control subjects and CD cases had high continuation rates of 80% and 83%) respectively. Differences between groups in the type of women who contributed multiple pregnancies to the pool of all pregnancies had the effect of increasing the apparent rate of loss for the cases. Cases at low risk of pregnancy loss tended to drop out of the reproducing population after one or two pregnancies, whereas those with high risk of loss tended to continue and thus overcontribute to the number of pregnancy losses when all gravidity categories were included. Therefore, the apparent increase in pregnancy loss in CD disease pregnancies is probably an artifact of selection bias.
Preterm
Birth
Women with CD or UC generally showed increased rates of preterm birth (Table 6). Each group of IBD cases was compared with control subjects using logistic regression to control for gravidity, age, and Table 6. Distribution
of Live Singleton
Births That
smoking status. All case groups showed a twofold to threefold elevated risk, although it was not statistically significant in the smallest study sample, the UC disease pregnancy group (Table 6). Because the risk of preterm birth was increased in both predisease and disease pregnancies, we looked for a time trend in the proportion of preterm births relative to onset of disease symptoms. Figure 1 shows the percentage of preterm births at different time intervals from onset of disease symptoms. Women with pregnancies occurring more than 10 years after the onset of symptoms had the highest percentage of preterm births for both disease groups, although nearly all time periods, including times before onset of disease symptoms, were elevated in comparison with the control group. When a variable for the time interval between the onset of disease symptoms and the time of pregnancy is included in logistic models, it is not significantly predictive of preterm birth, confirming that there is no strong time trend even adjusting for gravidity, age, and smoking status. When combining predisease and disease pregnancies, the relative odds of preterm birth is significantly elevated in both IBD groups. For CD the OR is 3.1 (95% CI, 1.8-5.4). For UC, the OR is 2.7 (95% CI, 1.4-5.3). Gestational age at delivery was used to assess preterm birth, but these data can lead to misclassification because of errors both in prediction of the due date determined from the last menstrual period and in recall by the mother years later as she filled out the
Were Preterm ft37 Weeks’ Gestation) CD
Controls First pregnancies (%) All pregnancies (%)
;:;o CI) n
11 10
;!I 273
“Controlling for gravidity, age, and smoking status.
Predisease pregnancies 21 24
(1.::.6) 94
UC Disease pregnancies
Predisease pregnancies
Disease pregnancies
29 25
23 22
10 15
(l.Zl] 84
(lE7.1, 56
(O.Z.9) 41
992 BAIRD ET AL.
GASTROENTEROLOGY
Vol. 99. No. 4
Discussion Predisease
Pregnancies
Disease Pregnancies
Fertility LZ2 CD I
>lO
UC
6-10
1990;99:967-994
Increased Risk of Preterm Birth for Women With Inflammatory Bowel Disease DONNA DAY BAIRD, M. NARENDRANATHAN, and ROBERT S. SANDLER Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina; and Division of Digestive Diseases and Nutrition, Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, North Carolina
The reproductive histories of 177 women with Crohn’s disease and 84 women with ulcerative colitis were compared with those of healthy control subjects. Inflammatory bowel disease was associated with reduced fertility as measured by number of pregnancies, but measures of childlessness, infertility, fecundability, and methods of birth control suggested that this reduced fertility was the patients’ choice rather than a consequence of disease-mediated biological impairments. There was no evidence of increased risk of pregnancy loss, but the risk of preterm birth was significantly elevated for patients with Crohn’s disease (odds ratio, 3.1; 95% confidence interval, 1.8-5.4) and for those with ulcerative colitis (odds ratio, 2.7; 95% confidence interval, 1.8-5.4). Several plausible biological mechanisms that could explain the link between preterm birth and inflammatory bowel disease are suggested. These results may be useful when counseling patients who desire pregnancy. Physicians can reassure patients about potential fertility problems but should also encourage close obstetrical monitoring during the third trimester of pregnancy.
M
any women with inflammatory bowel disease (IBD) are of reproductive age. The effect of the
disease on women’s fertility and pregnancies is a subject of controversy. Vender and Spiro (1) reviewed several descriptive reports that had been published before 1982 and noted the paucity of controlled studies. Three case-control studies have subsequently been published (2-4), all of which reported that most women with IBD reproduce successfully but may have an increased risk of problems. The one study that examined fertility showed an increased risk of subfertility, and all three studies found more preterm births in cases than in control subjects. However, infertility
was measured without consideration for whether women had tried to conceive. Furthermore, data on pregnancy outcomes were analyzed without any adjustment for factors, such as smoking, that might affect reproduction. To study reproductive characteristics of patients with IBD further, we included detailed reproductive questions in a case-control study of Crohn’s disease (CD] and ulcerative colitis (UC). This study compares subfertility, pregnancy loss, and preterm births in women with IBD (177 with CD and 84 with UC] and in healthy control subjects. Methods Study Subjects Potential study cases were identified from three North Carolina chapters of the National Foundation for Ileitis and Colitis (Charlotte, Greensboro, and RaleighDurham-Chapel Hill). Screening questionnaires were mailed to 1131 male and female subjects to determine whether they had IBD. Questionnaires were returned by 989 (87.4%) subjects, of whom 883 indicated that they had IBD. A self-administered questionnaire including details of reproductive history was mailed to each case. After two mailings and a phone call, data were available for 503 (74%) male and female cases, including 197 women with CD and 107 women with UC. The disease diagnosis was validated in a sample of 15% of these patients. Because 98% of these met the criteria for definite or probable IBD, we feel confident that virtually all of the cases in our study have IBD. The cases were asked to suggest one or two neighbors who were of the same sex, age [within 5 years], and race who might serve as control subjects. Control subjects were nominated by 95% of the cases. After two mailings and a phone call,
Abbreviations used in this paper: CD, Crohn’s disease; CI, confidence interval; OR, odds ratio. 0 1990 by the American Gastroenterological Association 0016-5065/90/$3.00
988
BAIRD ET AL.
data were available for 353 (74%) of the control subjects. Of 92 cases whose first controls declined to participate, 65 provided the names of second controls. Fifty-one of those responded, thus increasing the total number of control subjects to 404, including 245 women. Only data from the female respondents were used in these analyses. In an attempt to limit recall errors, women over 60 years old were excluded from analysis of the reproductive variables. This left 216 control subjects, 177 CD patients, and 84 UC patients for analysis.
Analysis
of Data
Given that matching was used as a convenient method for generating a demographically similar comparison group and none of the matching variables was important for analysis, an unmatched analysis was performed using all cases and controls for whom data were available (51. The control subjects for the CD and UC cases were pooled to form a single control group. Specific analyses have fewer cases and/or controls because of missing data on individual variables. Variables for analysis were derived from data collected on a self-administered questionnaire. Women were asked if they had ever tried to conceive for more than 1 year. Women who had tried to conceive for more than 1 year but remained childless were classified as “involuntarily childless.” Women with one or more children who later tried for at least 1 year to conceive again but were unsuccessful were classified as “secondarily infertile.” Women were classified as “voluntarily childless” if they reported having no fertility problems but had never been pregnant. A “pregnancy loss” was defined as a pregnancy ending in the loss of an embryo or a fetus for reasons other than by induced abortion. Stillbirths were considered pregnancy losses. A “preterm birth” was defined as a singleton livebirth before 37 weeks’ gestation, as determined by the reported length of pregnancy in weeks. Race was dichotomized to white and nonwhite. Religion was dichotomized to Catholic and non-Catholic. Education was measured by number of years in school. Variables for each subject’s age (~30 or 230 years), gravidity (0, 1, or >l prior pregnancy], number of prior pregnancy losses (0, 1, or >l), and smoking (smoker or nonsmoker) at the time of each pregnancy were derived from appropriate questionnaire items on pregnancy and smoking histories. To test for time trends, four variables were created for the decade during which the pregnancy occurred (before 1960, 1960s 197Os, 1980s). To examine the effects of disease on reproductive characteristics, the pregnancies of women identified as cases were categorized in relation to time of onset of disease symptoms. Pregnancies before symptom onset were defined as “predisease pregnancies.” Pregnancies after onset of symptoms were defined as “disease pregnancies.” A disease pregnancy may have been symptom-free. We do not have adequate data to evaluate disease activity and severity during individual disease pregnancies. For multivariate modeling, each of a woman’s pregnancies was included in analysis as an independent event. Possible effects of IBD on fertility were examined by estimating relative fecundability, the probability of achiev-
GASTROENTEROLOGY
Vol. 99. No. 4
ing pregnancy in any given menstrual cycle for women with IBD relative to controls (6). Data on time to pregnancy (the number of menstrual cycles before conception in which no contraception was practiced] were fit as the dependent variables in a Cox proportional-hazard model (7) using the PHGLM procedure of SAS (SAS Institute, Gary, NC). Final results were confirmed using a discrete form of the Cox model, the more appropriate model for time-to-pregnancy data (8). The proportional-hazard analysis is a method used to identify factors that influence the time to some event (in this case, time to pregnancy). The coefficient associated with a factor in the proportional-hazard model provides an estimate of that factor’s influence on how quickly women get pregnant. The IBD status can be included as one of the factors in the model. When the coefficient associated with IBD is exponentiated, the resultant value provides an estimate of the probability of becoming pregnant in any given menstrual cycle for patients with IBD compared with control subjects. This estimate is called the fecundability ratio. A fecundability ratio near 1.0 indicates that the probability of getting pregnant is about the same for women with IBD as for control subjects. A fecundability ratio cl.0 indicates reduced fertility. Fecundability ratios for CD and UC were adjusted for age, gravidity, and smoking status. Each of the other variables for which we had data was individually added to this basic model, but none changed the fecundability ratio associated with disease in significant ways. Possible effects of IBD on pregnancy loss and preterm birth were estimated with logistic regression using the LOGIST procedure of SAS. Because both adverse pregnancy outcomes are dichotomous dependent variables, logistic regression is the preferred method (9). The status of IBD can be included as one of the independent variables in the regression model. The regression coefficient associated with IBD status is exponentiated and the resultant value provides an estimate of the odds ratio [OR) associated with disease [the odds of having an adverse pregnancy outcome for women with IBD divided by the odds for control women), controlling for other factors in the model. An OR close to 1.0 indicates that the risk of adverse pregnancy outcome is nearly the same for women with IBD as for control subjects. An OR >l.O indicates an elevated risk of pregnancy loss or preterm birth among women with IBD. Factors other than IBD status that might influence pregnancy outcomes were controlled in analysis. When analyzing pregnancy loss, the patient’s age, history of previous spontaneous abortion, and smoking status were included in all the models. Additional variables were tested individually to assess their influence on the relationship between IBD and pregnancy loss and were found not to change the relationship significantly. When analyzing preterm birth, pregnancies ending in multiple births were excluded. Age, gravidity, and smoking status were included in all the preterm birth models. Additional variables were tested individually and found not to change the relationship between IBD and preterm birth. All the variables in final models were checked by adding interaction terms to the model one at a time to make sure that the association of the dependent variable with IBD status did not differ significantly among subsets of the population. For
October 1990
PREGNANCY AND INFLAMMATORY BOWEL DISEASE
Table 1. Characteristics of the Study Subjects at Time of
The dominant religious affiliation in was Protestant. The median age of symptoms was 23 years, and the diagnosis was 26 years in both disease
Study as Reported by Self-Administered Questionnaire Controls (N = 216) (N :77] Race (%) White
Nonwhite Age(%I t20 yr 20-29 yr 30-39 yr 40-49 yr 50-60 yr
all three groups onset of disease median age of groups.
(N:84]
95
93
99
5
7
1
2 15 38 29 16
1
23 33 26 17
2 14 35 36 13
5 33 28 21 13
7 38 27 19 17
4 28 28 29 11
13 78 7 1
16 71 10 2
21 18
20 15
6 76 10 2 6 21 17
57 19 24
37 27 36
55 31 14
91 7 2
85 3 12
84
Education(%) cl2 yr 12 yr 13-15 yr 16 yr >16 yr Marital status (TO] Single Married Divorced Separated Widowed Median age at first marriage ( yr) Median years married Smoking status (%) Never Past Current Religion (%) Protestant Catholic Other
989
6 10
example, the association between IBD and pregnancy loss only in older women could be formally tested by adding a variable to the final model that would be coded “1” for pregnancies occurring in older women with IBD and coded “0” for all other pregnancies. If analysis showed significant elevation in the regression coefficient associated with this variable, it would suggest that older women with IBD were more likely to have adverse pregnancy outcomes, but that IBD had no significant adverse effect on younger women. Results In Table 1, we show social and demographic characteristics of the study groups at the time of data collection. As expected, the cases and controls did not differ substantially by race or age given the process by which controls were selected. The groups were also similar in marital history, although when compared with controls, fewer women with UC were single (6% vs. 13%) and more women in both disease groups were separated, divorced, or widowed (14% for CD and 18% for UC vs. 9% for controls). Compared with control subjects, more women with CD were current smokers, whereas fewer women with UC smoked.
Fertility Women whose first pregnancies occurred after the onset of disease symptoms had fewer total pregnancies than the control subjects, even after data were adjusted for age at the time of first pregnancy (Table 2). On the other hand, women whose first pregnancies occurred before the onset of symptoms had about the same number of total pregnancies as control subjects. When tested with logistic regression, the chance of having subsequent pregnancies (adjusted for age at the time of first pregnancy] was significantly reduced among women of both disease groups whose first pregnancy occurred after onset of disease symptoms (P < 0.05). No significant differences were seen between women whose first pregnancies were predisease and controls. Available data were used to evaluate whether the reduced number of pregnancies in women with disease symptoms was attributable to impaired fecundity [the biological ability to conceive] or voluntary fertility control (Table 3). Cases and controls were similar in the proportions of ever-married women who were involuntarily childless or secondarily infertile (2%4%). In addition, 15%-20% of each group had a pregnancy that required more than 1 year of trying to conceive before conception was achieved. Women who had become pregnant were asked to provide their time to pregnancy, defined as the number of menstrual cycles in which contraception was not practiced before pregnancy. These data were used to estimate the fecundability of cases compared with control subjects. The fecundability ratios for both disease groups are near 1.0, indicating no significant reduction in fecundability associated with IBD (Table 3). Other available data suggest that IBD cases might
Table 2. Mean Number of Pregnancies by Disease Status of the First Pregnancy Among Women Who Had Ever Been Pregnant No. of pregnancies Study sample
n
R
SD
Controls CD cases First pregnancy before onset of symptoms First pregnancy after onset of symptoms UC cases First pregnancy before onset of symptoms First pregnancy after onset of symptoms
160
2.6
1.3
69 50
2.6 2.1
1.6 1.6
32 25
2.9 1.9
1.6 0.7
NOTE. Values are adjusted for age at the time of first pregnancy.
990
BAIRD ET AL.
Table 3. Measures
GASTROENTEROLOGY
of Infertility
and Fecundability
Status
Control
Measure Involuntarily childless” (%) Secondarily infertile” (%,I Pregnancy after >l year of trying” [ %]
Fecundability (95% CI) n
by Disease
4 4 15
CD
UC
3 2 19
2 3 17
Predisease pregnancies
Disease pregnancies
Predisease pregnancies
(O.Z.5] 73
(O.Z.2] 86
(O.Z2] 50
Disease pregnancies
ratiob (‘1-9 268
Vol. 99, No. 4
“Among married women (181 control subjects, 146 CD cases, 76 UC cases]. bAmong women who had ever been pregnant, estimated by Cox proportional-hazard status.
have voluntarily limited their fertility more than control subjects (Table 4). Voluntary childlessness was higher in women with UC than in controls. Compared with control subjects, a larger proportion of cases reported that they were afraid to have children or were told not to have children, and CD cases were told more often that they might have difficulty having children. Choice of birth control before the first pregnancy also differed somewhat between controls and cases whose first pregnancies occurred after IBD symptoms began. Adjusting for age at the time of first pregnancy and limiting the data to first pregnancies that occurred in the 1970s and 1980s to avoid any bias created by availability of oral contraceptives, 45% of control subjects reported using oral contraceptives or IUDs before their first pregnancies. In contrast, 63% of women with CD disease pregnancies and 57% of women with UC disease pregnancies used oral contraceptives or IUDs before their first pregnancies [Table 4), supporting the notion that women sought to avoid pregnancy after disease onset.
model controlling
for
1.0 (0.9-1.2) 49
age, gravidity,
and smoking
The proportion of first pregnancies ending in loss does not seem significantly elevated among cases compared with control subjects (Table 5). However,
when data on all pregnancies were used in analyses, pregnancy loss seemed more frequent in CD disease pregnancies. When logistic regression analysis was used to control for history of pregnancy loss, age, and smoking status, CD pregnancies were found to be at a significantly increased risk of pregnancy loss [OR, 1.86; 95% confidence interval (CI), 1.05-3.291. No significant elevation in risk was found in women with UC. To understand the differences between rates of first pregnancy losses compared with all pregnancies for women with CD, we considered the possibility that selection bias might be creating the observed increase in risk seen in analyses using all pregnancies. If women based their decisions whether or not to become pregnant again on the outcomes of their previous pregnancies (lo), and selection for those women who continued to get pregnant occurred differentially in case and control subjects, the results of analyses using data from all pregnancies could be biased. The rates of subsequent pregnancies did vary in women depending on the outcomes of previous pregnancies. Women with pregnancy losses were more likely to become pregnant again than women with live births (94% of controls with first pregnancies ending in loss had second pregnancies, whereas 84% of controls with live births had second pregnancies). This selec-
Table 4. Differences
to Voluntary
Pregnancy
Loss
Among
Factor Voluntary childlessness” Afraid to have childrenb Told not to have childrenb Told might have difficulties having childrenb
Disease
Groups
in Factors
Related
Control
Control [%)
CD (%)
UC (%)
14 12 4
14 18 14
21 15 9
17
23 Predisease pregnancies
Used birth control pills or IUD before first pregnancy”
Fertility
45
45
15 Disease pregnancies 63
Predisease pregnancies 42
Disease pregnancies 57
“Among respondents who had ever been married (181controls, 146CD cases, 76 UC cases]. bAmong all respondents (216controls, 177CD cases, 84 UC cases). “Among respondents who had ever been pregnant (160 controls, 124 CD cases, 63 UC cases]; adjusted for age at time of first pregnancy.
PREGNANCY AND INFLAMMATORY
October 1990
BOWEL DISEASE
991
Table 5. Pregnancies Ending in Loss Categorized by Disease Status CD
11 12
First pregnancies (%) All pregnancies (%] g!io CI)
;19
n
376
Disease pregnancies
Predisease pregnancies
Control
UC
15 16
12 20
(O.&)
1.9 (1.0-3.31 127
146
Disease pregnancies
Predisease pregnancies
6 11
16 16 1.3 (0.5-3.3) 63
(O.E.9) 50
“Controlling for history of pregnancy loss, age, and smoking status.
tion for those who had additional pregnancies was more marked in the IBD cases than in the control subjects, especially after the second pregnancy (i.e., women with CD were more likely than controls to stop reproducing after a live birth]. After two pregnancies, 52% of control subjects with one or two live births became pregnant again, whereas only 38% of CD cases with one or two live births continued to third pregnancies. Yet for those with no live births after two pregnancies, both control subjects and CD cases had high continuation rates of 80% and 83%) respectively. Differences between groups in the type of women who contributed multiple pregnancies to the pool of all pregnancies had the effect of increasing the apparent rate of loss for the cases. Cases at low risk of pregnancy loss tended to drop out of the reproducing population after one or two pregnancies, whereas those with high risk of loss tended to continue and thus overcontribute to the number of pregnancy losses when all gravidity categories were included. Therefore, the apparent increase in pregnancy loss in CD disease pregnancies is probably an artifact of selection bias.
Preterm
Birth
Women with CD or UC generally showed increased rates of preterm birth (Table 6). Each group of IBD cases was compared with control subjects using logistic regression to control for gravidity, age, and Table 6. Distribution
of Live Singleton
Births That
smoking status. All case groups showed a twofold to threefold elevated risk, although it was not statistically significant in the smallest study sample, the UC disease pregnancy group (Table 6). Because the risk of preterm birth was increased in both predisease and disease pregnancies, we looked for a time trend in the proportion of preterm births relative to onset of disease symptoms. Figure 1 shows the percentage of preterm births at different time intervals from onset of disease symptoms. Women with pregnancies occurring more than 10 years after the onset of symptoms had the highest percentage of preterm births for both disease groups, although nearly all time periods, including times before onset of disease symptoms, were elevated in comparison with the control group. When a variable for the time interval between the onset of disease symptoms and the time of pregnancy is included in logistic models, it is not significantly predictive of preterm birth, confirming that there is no strong time trend even adjusting for gravidity, age, and smoking status. When combining predisease and disease pregnancies, the relative odds of preterm birth is significantly elevated in both IBD groups. For CD the OR is 3.1 (95% CI, 1.8-5.4). For UC, the OR is 2.7 (95% CI, 1.4-5.3). Gestational age at delivery was used to assess preterm birth, but these data can lead to misclassification because of errors both in prediction of the due date determined from the last menstrual period and in recall by the mother years later as she filled out the
Were Preterm ft37 Weeks’ Gestation) CD
Controls First pregnancies (%) All pregnancies (%)
;:;o CI) n
11 10
;!I 273
“Controlling for gravidity, age, and smoking status.
Predisease pregnancies 21 24
(1.::.6) 94
UC Disease pregnancies
Predisease pregnancies
Disease pregnancies
29 25
23 22
10 15
(l.Zl] 84
(lE7.1, 56
(O.Z.9) 41
992 BAIRD ET AL.
GASTROENTEROLOGY
Vol. 99. No. 4
Discussion Predisease
Pregnancies
Disease Pregnancies
Fertility LZ2 CD I
>lO
UC
6-10
