Scandinavian Journal of Gastroenterology. 2014; 49: 302–308
ORIGINAL RESEARCH
Influence of medical treatment, smoking and disease activity on pregnancy outcomes in Crohn’s disease
METTE JULSGAARD1, METTE NØRGAARD2, CHRISTIAN LODBERG HVAS1, ANNE GROSEN1, SARA HASSERIIS2 & LISBET AMBROSIUS CHRISTENSEN1 1
Department of Hepatology & Gastroenterology V, Aarhus University Hospital, Aarhus, Denmark, and 2Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark
Abstract Objective. Little is known about predictors for adverse pregnancy outcomes among women with Crohn’s disease (CD). In this population-based study, we examined pregnancy outcomes in CD stratified by medical treatment and smoking status while accounting for disease activity. Methods. In two Danish regions with a population of 1.6 million, we identified 154 CD women who had given birth within a 6-year period. We combined questionnaire data, prescription data, data from medical records and population-based medical databases. We used logistic regression to estimate prevalence odds ratios (POR) for adverse pregnancy outcomes by different predictors. Results. Among 105 (80%) respondents, 55 (52%) reported taking medication during pregnancy. The majority (95%) were in disease remission. The children’s mean birth weight did not differ by maternal medical treatment. As expected, smoking was a predictor of low birth weight. Mean birth weight in children of smokers in medical treatment was significantly reduced by 274 g compared with children of non-smokers who received medical treatment. In children of women without medical treatment, this difference was 126 g between smokers and non-smokers. Women in medical treatment did not have an increased risk of preterm delivery (POR 0.71; 95% confidence interval (CI) 0.18–2.79), congenital malformations (POR 0.60; 0.10–3.76) or cesarean section (POR 1.40; 0.63–3.08). Conclusion. In CD, smoking was negatively associated with child birth weight. This association was most pronounced among women who received medical treatment. Maternal medical treatment for CD did not seem to be a risk factor for adverse pregnancy outcomes.
Key Words: Crohn’s disease, disease activity, inflammatory bowel disease, medical treatment, pregnancy, pregnancy outcome, smoking
Introduction The onset of Crohn’s disease (CD) most frequently occurs in the second or third decade of life, with most cases developing before the age of 30 [1]. The impact of CD and medical treatment for CD on pregnancy outcomes therefore remains a significant concern. Active disease at the time of conception may predispose the patient to adverse pregnancy outcomes [2]. In order to induce and maintain disease remission, medical treatment is often needed during both asymptomatic and symptomatic stages of the disease [3]. This also applies to pregnancy [4,5]. Non-specific
anti-inflammatory agents such as 5-aminosalicylic acid (5-ASA), corticosteroids and thiopurines, which are most often used to treat CD, all cross the placental barrier [3,6]. This is also the case for anti-tumour necrosis factor alpha antibodies (anti-TNF-a) antibodies, which are increasingly used to treat severe CD during pregnancy [7,8]. Preterm birth is an important risk factor for substantial neurocognitive, pulmonary and ophthalmologic morbidity [9]. Nørgaard et al. reported a more than threefold increased risk of preterm delivery in women with active CD during pregnancy compared with women without disease activity [10]. In a
Correspondence: Mette Julsgaard, MD, Department of Hepatology & Gastroenterology V, Aarhus University Hospital, Noerrebrogade 44, building 1C, 1st floor, DK-8000 Aarhus, Denmark. Tel: +45 7846 4266. Fax: +45 7846 2740. E-mail: [email protected]
(Received 20 November 2013; revised 19 December 2013; accepted 20 December 2013) ISSN 0036-5521 print/ISSN 1502-7708 online 2014 Informa Healthcare DOI: 10.3109/00365521.2013.879200
Pregnancy outcomes in Crohn’s disease recent meta-analysis, Cornish et al. reported an increased risk of prematurity, low birth weight and cesarean section (CS) among 1952 women with CD compared with a control group with no inflammatory bowel disease (IBD), but the impact of disease activity was not evaluated [11]. In general, the lack of combined adjustment for disease activity, smoking and medical treatment is an important shortcoming of the existing literature on the risk of adverse pregnancy outcomes in women with CD [4,11–13]. It is well documented that smoking during pregnancy reduces fetal growth [14]. To our knowledge, no clinical study has investigated whether medical treatment is a predictor of low birth weight in women with CD compared with an untreated CD control group when stratifying for smoking and disease activity. The aim of the present study was to investigate child birth weight according to maternal medical CD treatment and smoking status while accounting for disease activity. Further, we wished to investigate the risk of preterm delivery, small for gestational age (SGA), CS, congenital malformations and stillbirth among medical-treated and non-medical-treated women with CD stratified for potential confounders. Materials and methods Identification of women with CD Women with CD were identified through the regional Patient Administrative System. Established in 1977, this registry transfers data to the Danish National Patient Registry, which covers 99.4% of all discharges from Danish hospitals [15]. Visits at outpatient clinics at all hospitals have been included since 1995. The data include dates of admission and discharge diagnoses, which are classified according to the International Classification of Diseases 10th revision (ICD-10) [16]. The code K 50 served to identify patients with CD. The diagnosis was confirmed by contact to the treating doctor. Identification of pregnant women and birth outcome data We identified all singletons born to women with CD through the Danish Medical Birth Registry, which contains information on all births in Denmark since 1 January 1973 recorded by the attending midwives or doctors [17]. From the registry, we retrieved information on gestational age (based on ultrasound or, if not available, last menstrual period), stillbirth (delivery of a dead fetus after 28 weeks of gestation), birth weight, body length, sex of the child, mode of delivery and maternal age at delivery. SGA was defined as a child with a birth weight more than 2 standard deviations
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(SD) below the mean for all children of similar gestational age, according to the reference curve of estimated fetal growth [18]. We defined preterm birth as a live birth before 36 weeks of gestation [19]. For live born children, the data on congenital malformations diagnosed during the first year of life were collected from the patient administrative system. The codes for congenital malformations were Q0.00– Q89 in ICD-10 [16]. The diagnoses of congenital dislocation of the hip (Q65.0–6) and undescended testis (Q53) were not included because of expected poor validity [20]. Chromosomal abnormalities (Q90–99) were also excluded. Study population We conducted this prevalence study in two Danish regions with a population of approximately 1.6 million. The study included all women who gave birth to a singleton between 1 January 2000 and 31 December 2005 and who were diagnosed with CD at least 1 year prior to their date of conception. Multiple births were not included because women who are pregnant with more than one fetus may have more complicated pregnancies than mothers of one child [21]. Therefore, pregnancy outcome in these women may be different because of the pregnancy itself. If a woman gave birth more than once during the study period, only the first birth was included. All eligible women with CD were asked to complete a postage-prepaid questionnaire. Self-reported data from women with CD To obtain information on medical treatment, disease activity, lifestyle factors and birth outcome, we developed a questionnaire. Details concerning birth, weight, length and sex of the offspring were obtained from the Danish Medical Birth Registry and printed in the individual questionnaire to confirm the relevant pregnancy and for the women to confirm the correctness of the data. All women were specifically asked if they experienced relapse in CD during pregnancy. Women who answered no to this question were classified as being in remission. The medical records of each patient answering yes were reviewed to verify relapse in CD. The Harvey–Bradshaw index (HBI) was used to assess CD activity during pregnancy [22]. CD was considered to be inactive if HBI was £4 points. Increase in disease activity (HBI ‡5) with duration of at least 1 week occurring during pregnancy was considered a relapse. Mild, moderate and severe activity in CD was equivalent with an HBI of 5–7, 8–16 and >16, respectively [22]. The women were asked to state their smoking status. In women who
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stopped smoking during pregnancy, the exact date of smoking cessation was not stated. Therefore, we defined smoking status as status prior to pregnancy. All study participants received the questionnaire by postal mail. Reminders were sent twice to each patient. We entered all data from the questionnaires into a database and verified the data by double entry.
(one or more than one) and maternal smoking (yes/ no). We constructed a two-sample t-test for the birth weight of children born to mothers who had medical treated or untreated CD. We calculated 95% CIs assuming a binomial distribution. The data analysis was performed using Stata version 11.0 (StataCorp LP, College Station, TX, USA).
Prescription database at Aarhus University
Results
To assess the validity of the self-reported use of medication, we retrieved data from the Aarhus University Prescription Database [23]. In Denmark, the National Health Service provides tax-supported healthcare for all inhabitants including refunds of a part of the costs of most prescription drugs. All pharmacies in the Central and North Denmark regions are equipped with electronic accounting systems that track data on all prescriptions for reimbursable medicines. The data include the patient’s Civil Personal Registration (CPR) number, the type of drug prescribed according to the anatomical therapeutic chemical (ATC) classification system and the date the prescription was redeemed. The data are transferred from these accounting systems to the prescription database at Aarhus University. For each of the included women, we identified all prescriptions for medicine used to treat CD (ATC-codes: A07EC01–04, L04AX01, L01BB02, A07EA01–02, A07EA06, H02AB06–07, P01AB01 and J01MA02) redeemed from 6 months before conception until date of giving birth. The unique 10-digit CPR number, which is assigned to all Danish citizens shortly after birth, was used to link all data.
Study population
Statistical analysis The redemption of a prescription of CD-specific medication registered in the prescription database was used as a reference standard in the validity analysis. We computed the positive predictive value (PPV) as the proportion of women reporting medical treatment who were also registered with a prescription in the prescription database. For this calculation, the numerator was the number of women who reported use of medication and filled a prescription, and the denominator was the number of women who reported receiving medication. We constructed frequency tables of major study variables for the population with CD. A logistic regression analysis was used to compute the crude and adjusted prevalence odds ratios (POR) as estimates of relative risk, with associated 95% confidence intervals (CIs) for preterm birth, SGA, CS, congenital malformation and stillbirth. We adjusted for parity
We identified a total of 154 women diagnosed with CD who gave birth to a singleton during the study period. No stillbirths were identified. We excluded 21 (14%) women because review of their medical records could not confirm a CD diagnosis. One woman had passed away for reasons unrelated to CD, leaving a study population of 132 women. Among these 132 women, 105 (80%) returned filled-in questionnaires. The mean age at time of delivery among primiparous women was 30.3 years (range 22.3–39.8). Characteristics of medical-treated and non-medical-treated pregnant CD women are summarized in Table I. Medical-treated women seemed more likely to be cigarette smokers than non-medical-treated women though the difference was not statistically significant (POR 1.67, 95% CI 0.77–3.63). Disease activity Five (4.8%) women stated relapse in CD during pregnancy. One woman had mild disease activity (HBI 5–7), while three had moderate disease activity (HBI 8–16) and one severe activity (HBI >16). One woman had moderate activity prior to conception and during pregnancy, whereas the remaining four women were in remission around conception. Validity of self-reported data Medical treatment was provided to 55 (52.4%) women with CD during pregnancy. Within the treated population, 48 filled a prescription for relevant medication according to the prescription database, yielding a PPV of 87.3% (95% CI, 75.5–94.7). Medical treatment during pregnancy 5-ASA treatment was provided to 28 (52.8%) women, and 16 (30.5%) women received immunosuppressants (thiopurines). Systemic or topical glucocorticoid was provided to nine (17.0%) women [5]. Moreover, four women (3.8%) stated that they had received treatment with infliximab prior to conception. Two women had
Pregnancy outcomes in Crohn’s disease Table I. Characteristics of the study population. Crohn’s disease medical treatment n (%) Total 55 (52.4) Maternal age at delivery £19 years 0 (0.0) 20–24 years 6 (10.9) 25–29 16 (29.1) 30–34 25 (45.5) ‡35 years 8 (14.6) Parity Primiparous 28 (50.9) Not primiparous 27 (49.1) Cigarette smoking Yes 28 (50.9) No 27 (49.1) Data missing 0– Body mass index (kg/m2) 1) and maternal smoking (yes/no), these estimates remained unchanged (data not shown). Infants born to mothers with CD who had received medical treatment during pregnancy seemed not at increased risk of preterm birth, SGA, congenital malformation or stillbirth when compared to infants born to untreated mothers with CD (Table II). The effect of smoking and medical treatment on birth weight Independently of medical treatment, there was a statistically significant difference in birth weight between children of CD non-smokers (3475 g; 95% CI, 3368–3581) and CD smokers (3257 g; 95% CI, 3137–3378), corresponding to a difference in mean birth weight of 218 g (p < 0.008). Among women with CD who received medical treatment, lower birth weight was significantly more common among children of mothers with CD who smoked. The difference in mean birth weight was 274 g (Table III). We found that women with CD who did not receive medical treatment but were smokers gave birth to children with a lower mean birth weight than women with CD who did not smoke (mean difference 126 g) (Table III). Furthermore, maternal medical treatment during pregnancy did not seem to have a negative influence on the child’s birth weight (Table III). Discussion A novel finding in this population-based study was that maternal medical treatment during pregnancy did not influence child birth weight among women with CD. In contrast to this, maternal smoking was negatively associated with child birth weight among women with CD, especially among women who received medical treatment. The study gains strength from its 80% response rate, which is among the highest reported in the IBD literature [24,25]. Further, there was a high concordance between self-reported medical treatment and the prescription database. Previous studies found that children born to mothers with CD had a lower birth weight than those born to mothers without CD [2,12,26,27]. In the present study, we only addressed women with CD
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Table II. Prevalence and crude prevalence odds ratios (POR) for adverse pregnancy outcomes among women with Crohn’s disease (CD) receiving medical treatment or no medical treatment during pregnancy. CD medical treatment n (%) Total Preterm Small for gestational age Cesarean section Congenital malformation Stillbirth
55 4 0 23 2 0
CD no medical treatment n (%)
Crude POR (95% CI)
50 (47.6) 5 (10.0) 1 (2.0) 17 (34.0) 3 (6.0) 0 (0.0)
0.71 (0.18–2.79) – 1.40 (0.63–3.08) 0.60 (0.10–3.76) –
(52.4) (7.3) (0.0) (41.8) (3.6) (0.0)
active disease, it may have been disease activity rather than medical treatment that caused these increased risks. Because most women in our study were in remission, our risk estimates most likely reflect the effect of medical treatment and not disease activity. A population-based cohort study, including 163 births by 111 CD women found that in cases of moderate to high CD activity, the risk of preterm birth was increased more than threefold [10]. Our study therefore underscores the international recommendations emphasizing the importance of remission in CD during pregnancy to minimize the potential risk of adverse pregnancy outcomes [3,34]. Previous bowel resection may be associated with preterm birth [27,35]. This also seemed to be the case in the present study although the numbers were small. More than half of the women giving birth preterm in our study had undergone bowel resection prior to conception. Still, none of these babies were born SGA. Similar to our study, a European consensus report stated that women with CD are substantially more likely to give birth by a CS than women without CD [34]. We did not have more detailed information about the indications for CS and are therefore unable to provide information regarding the reasons for this high prevalence. Medical treatment during pregnancy did not seem to increase the risk of congenital malformations. In particular, the 16 women exposed to thiopurines during pregnancy all gave birth to children without congenital malformations. These results are in accordance with those of previous studies [3,13,34]. A majority of women with mild to moderate CD will receive maintenance medical treatment with
and were able to stratify data according to maternal medical treatment and smoking status. Because the vast majority of women (95.2%) were in remission during their pregnancy, our observed differences could not be explained by differences in disease activity. The causal relationship between cigarette smoking and fetal growth restriction has previously been documented, and our results are in agreement with these data [14]. Further, it has been shown that smoking is associated with more complicated CD [28]. The need for steroids and immunosuppressants has been found to be higher in CD smokers compared with CD non-smokers [29]. However, our results indicate that when counseling medical-treated women with CD, it is important to stress that smoking cessation is of utmost importance because the risk of lower birth weight is even more pronounced among the medical-treated women who smoke. Several studies have investigated the impact of CD medication on pregnancy outcomes such as preterm birth, SGA, congenital malformations or stillbirth. In the majority of these studies, women with CD were compared with populations of non-IBD women [11]. Few studies have addressed the safety of medical treatment comparing pregnant women with CD with untreated women with CD. Our finding that the risk of these adverse pregnancy outcomes was unrelated to maternal medical treatment is in accordance with most previous studies [13,30,31]. On the other hand, two epidemiological studies reported increased risks of preterm birth and stillbirth in CD women who had medical treatment compared with untreated women [32,33]. As stated by the authors, disease activity was not assessed in these studies. Therefore, if medical treatment was associated with
Table III. Birth weight among infants born to women with Crohn’s disease. Medical treatment during pregnancy Characteristic Non-smoker Smoker
n = 50* 24 26
Mean (g) a,b
3504 3230a,d
95% CI 3372–3636 3072–3341
*Data are missing for five women and **Data are missing for one woman. a p = 0.002 and b,c,dp > 0.05.
No medical treatment during pregnancy n = 49** 29 20
Mean (g) c,b
3450 3324c,d
95% CI 3281–3619 3097–3550
Pregnancy outcomes in Crohn’s disease thiopurines, glucocorticoids or 5-ASAs during pregnancy [4,13,36], which emphasizes the clinical relevance of our study. In recent years, anti-TNF-a therapy has been introduced as treatment of severe CD during pregnancy. In the present study, two women had received infliximab infusion due to a relapse during the period 6 months prior to conception. Both women gave birth to healthy children without any adverse pregnancy outcome. Treatment with anti-TNF-a seems safe in pregnancy, but future population-based studies are warranted [7,8]. A potential bias due to differential patient recruitment was avoided in this study by applying a population-based design. The study was also strengthened by the highly organized nature of the Danish Health Care system. A previous study found that the quality of the CD diagnosis in the Regional Patient Administrative System reached 97% [37]. The data quality in the Danish Medical Birth Registry is also reported to be high [38,39]. Furthermore, to minimize the influence of short disease duration, the patient diagnosis had to be established at least 1 year prior to conception [40]. As the questionnaire-based data collection was performed retrospectively, possible recall bias should be taken into account; however, we found only approximately 13% discrepancy between selfreported medical treatment and the Danish prescription database. We therefore do not expect recall bias regarding medical treatment to have major effect on the results of the present study. After review of the medical records, we found all cases of self-reported relapse during pregnancy to be valid. Misclassification of smoking status could bias our results. We defined smoking status as the status prior to pregnancy because the women did not state when smoking cessation occurred during pregnancy. Women who stopped smoking at conception or very early in pregnancy may therefore be misclassified as smokers. Yet, such a bias would lead us to underestimate the negative association between smoking and birth weight. Although this study was conducted in two Danish regions equivalent to a third of the Danish population, the precision of our risk estimates remains low due to the low prevalence of adverse pregnancy outcomes. This was amplified by the relatively low number of CD women who had given birth within a 6-year period. The low number of births remains a general challenge in the study of rare outcomes in relatively rare diseases such as CD. In conclusion, our data indicate that smoking, and not medical treatment, is a risk factor for lower birth weight among infants born to women with CD. We observed, however, the largest difference in mean birth weight of the child between smokers and non-smokers
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among mothers who received medical treatment. We found it reassuring that medical treatment did not seem to be associated with preterm birth, SGA, congenital malformations or stillbirth among women with CD where the vast majority of women were in remission. Our findings underline that prior to conception and during pregnancy, smoking cessation and remission in CD, most often induced by medical treatment, are important parameters to ensure the best possible outcome of pregnancy among women with CD.
Acknowledgments The authors gratefully acknowledge the physicians at the hospitals involved. Declaration of interest: Dr. Mette Julsgaard has served as a speaker for AbbVie A/S. Dr. Christian Lodberg Hvas has served as a speaker for AbbVie A/S and MSD A/S. Dr. Lisbet Ambrosius Christensen has served as a speaker for Ferring A/S, MSD A/S, and AbbVie A/S and is a member of the advisory board for MSD A/S. The remaining authors declare no conflicts of interest. This study was funded in part by the Danish Colitis-Crohn association and the A.P. Moeller Foundation of the Advancement of Medical Science. The Danish Ministry of Health has financially supported Dr. Mette Julsgaard. The funding has in no way affected the study design, data collection, analysis and interpretation of the data or the writing of the report.
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ORIGINAL RESEARCH
Influence of medical treatment, smoking and disease activity on pregnancy outcomes in Crohn’s disease
METTE JULSGAARD1, METTE NØRGAARD2, CHRISTIAN LODBERG HVAS1, ANNE GROSEN1, SARA HASSERIIS2 & LISBET AMBROSIUS CHRISTENSEN1 1
Department of Hepatology & Gastroenterology V, Aarhus University Hospital, Aarhus, Denmark, and 2Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark
Abstract Objective. Little is known about predictors for adverse pregnancy outcomes among women with Crohn’s disease (CD). In this population-based study, we examined pregnancy outcomes in CD stratified by medical treatment and smoking status while accounting for disease activity. Methods. In two Danish regions with a population of 1.6 million, we identified 154 CD women who had given birth within a 6-year period. We combined questionnaire data, prescription data, data from medical records and population-based medical databases. We used logistic regression to estimate prevalence odds ratios (POR) for adverse pregnancy outcomes by different predictors. Results. Among 105 (80%) respondents, 55 (52%) reported taking medication during pregnancy. The majority (95%) were in disease remission. The children’s mean birth weight did not differ by maternal medical treatment. As expected, smoking was a predictor of low birth weight. Mean birth weight in children of smokers in medical treatment was significantly reduced by 274 g compared with children of non-smokers who received medical treatment. In children of women without medical treatment, this difference was 126 g between smokers and non-smokers. Women in medical treatment did not have an increased risk of preterm delivery (POR 0.71; 95% confidence interval (CI) 0.18–2.79), congenital malformations (POR 0.60; 0.10–3.76) or cesarean section (POR 1.40; 0.63–3.08). Conclusion. In CD, smoking was negatively associated with child birth weight. This association was most pronounced among women who received medical treatment. Maternal medical treatment for CD did not seem to be a risk factor for adverse pregnancy outcomes.
Key Words: Crohn’s disease, disease activity, inflammatory bowel disease, medical treatment, pregnancy, pregnancy outcome, smoking
Introduction The onset of Crohn’s disease (CD) most frequently occurs in the second or third decade of life, with most cases developing before the age of 30 [1]. The impact of CD and medical treatment for CD on pregnancy outcomes therefore remains a significant concern. Active disease at the time of conception may predispose the patient to adverse pregnancy outcomes [2]. In order to induce and maintain disease remission, medical treatment is often needed during both asymptomatic and symptomatic stages of the disease [3]. This also applies to pregnancy [4,5]. Non-specific
anti-inflammatory agents such as 5-aminosalicylic acid (5-ASA), corticosteroids and thiopurines, which are most often used to treat CD, all cross the placental barrier [3,6]. This is also the case for anti-tumour necrosis factor alpha antibodies (anti-TNF-a) antibodies, which are increasingly used to treat severe CD during pregnancy [7,8]. Preterm birth is an important risk factor for substantial neurocognitive, pulmonary and ophthalmologic morbidity [9]. Nørgaard et al. reported a more than threefold increased risk of preterm delivery in women with active CD during pregnancy compared with women without disease activity [10]. In a
Correspondence: Mette Julsgaard, MD, Department of Hepatology & Gastroenterology V, Aarhus University Hospital, Noerrebrogade 44, building 1C, 1st floor, DK-8000 Aarhus, Denmark. Tel: +45 7846 4266. Fax: +45 7846 2740. E-mail: [email protected]
(Received 20 November 2013; revised 19 December 2013; accepted 20 December 2013) ISSN 0036-5521 print/ISSN 1502-7708 online 2014 Informa Healthcare DOI: 10.3109/00365521.2013.879200
Pregnancy outcomes in Crohn’s disease recent meta-analysis, Cornish et al. reported an increased risk of prematurity, low birth weight and cesarean section (CS) among 1952 women with CD compared with a control group with no inflammatory bowel disease (IBD), but the impact of disease activity was not evaluated [11]. In general, the lack of combined adjustment for disease activity, smoking and medical treatment is an important shortcoming of the existing literature on the risk of adverse pregnancy outcomes in women with CD [4,11–13]. It is well documented that smoking during pregnancy reduces fetal growth [14]. To our knowledge, no clinical study has investigated whether medical treatment is a predictor of low birth weight in women with CD compared with an untreated CD control group when stratifying for smoking and disease activity. The aim of the present study was to investigate child birth weight according to maternal medical CD treatment and smoking status while accounting for disease activity. Further, we wished to investigate the risk of preterm delivery, small for gestational age (SGA), CS, congenital malformations and stillbirth among medical-treated and non-medical-treated women with CD stratified for potential confounders. Materials and methods Identification of women with CD Women with CD were identified through the regional Patient Administrative System. Established in 1977, this registry transfers data to the Danish National Patient Registry, which covers 99.4% of all discharges from Danish hospitals [15]. Visits at outpatient clinics at all hospitals have been included since 1995. The data include dates of admission and discharge diagnoses, which are classified according to the International Classification of Diseases 10th revision (ICD-10) [16]. The code K 50 served to identify patients with CD. The diagnosis was confirmed by contact to the treating doctor. Identification of pregnant women and birth outcome data We identified all singletons born to women with CD through the Danish Medical Birth Registry, which contains information on all births in Denmark since 1 January 1973 recorded by the attending midwives or doctors [17]. From the registry, we retrieved information on gestational age (based on ultrasound or, if not available, last menstrual period), stillbirth (delivery of a dead fetus after 28 weeks of gestation), birth weight, body length, sex of the child, mode of delivery and maternal age at delivery. SGA was defined as a child with a birth weight more than 2 standard deviations
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(SD) below the mean for all children of similar gestational age, according to the reference curve of estimated fetal growth [18]. We defined preterm birth as a live birth before 36 weeks of gestation [19]. For live born children, the data on congenital malformations diagnosed during the first year of life were collected from the patient administrative system. The codes for congenital malformations were Q0.00– Q89 in ICD-10 [16]. The diagnoses of congenital dislocation of the hip (Q65.0–6) and undescended testis (Q53) were not included because of expected poor validity [20]. Chromosomal abnormalities (Q90–99) were also excluded. Study population We conducted this prevalence study in two Danish regions with a population of approximately 1.6 million. The study included all women who gave birth to a singleton between 1 January 2000 and 31 December 2005 and who were diagnosed with CD at least 1 year prior to their date of conception. Multiple births were not included because women who are pregnant with more than one fetus may have more complicated pregnancies than mothers of one child [21]. Therefore, pregnancy outcome in these women may be different because of the pregnancy itself. If a woman gave birth more than once during the study period, only the first birth was included. All eligible women with CD were asked to complete a postage-prepaid questionnaire. Self-reported data from women with CD To obtain information on medical treatment, disease activity, lifestyle factors and birth outcome, we developed a questionnaire. Details concerning birth, weight, length and sex of the offspring were obtained from the Danish Medical Birth Registry and printed in the individual questionnaire to confirm the relevant pregnancy and for the women to confirm the correctness of the data. All women were specifically asked if they experienced relapse in CD during pregnancy. Women who answered no to this question were classified as being in remission. The medical records of each patient answering yes were reviewed to verify relapse in CD. The Harvey–Bradshaw index (HBI) was used to assess CD activity during pregnancy [22]. CD was considered to be inactive if HBI was £4 points. Increase in disease activity (HBI ‡5) with duration of at least 1 week occurring during pregnancy was considered a relapse. Mild, moderate and severe activity in CD was equivalent with an HBI of 5–7, 8–16 and >16, respectively [22]. The women were asked to state their smoking status. In women who
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stopped smoking during pregnancy, the exact date of smoking cessation was not stated. Therefore, we defined smoking status as status prior to pregnancy. All study participants received the questionnaire by postal mail. Reminders were sent twice to each patient. We entered all data from the questionnaires into a database and verified the data by double entry.
(one or more than one) and maternal smoking (yes/ no). We constructed a two-sample t-test for the birth weight of children born to mothers who had medical treated or untreated CD. We calculated 95% CIs assuming a binomial distribution. The data analysis was performed using Stata version 11.0 (StataCorp LP, College Station, TX, USA).
Prescription database at Aarhus University
Results
To assess the validity of the self-reported use of medication, we retrieved data from the Aarhus University Prescription Database [23]. In Denmark, the National Health Service provides tax-supported healthcare for all inhabitants including refunds of a part of the costs of most prescription drugs. All pharmacies in the Central and North Denmark regions are equipped with electronic accounting systems that track data on all prescriptions for reimbursable medicines. The data include the patient’s Civil Personal Registration (CPR) number, the type of drug prescribed according to the anatomical therapeutic chemical (ATC) classification system and the date the prescription was redeemed. The data are transferred from these accounting systems to the prescription database at Aarhus University. For each of the included women, we identified all prescriptions for medicine used to treat CD (ATC-codes: A07EC01–04, L04AX01, L01BB02, A07EA01–02, A07EA06, H02AB06–07, P01AB01 and J01MA02) redeemed from 6 months before conception until date of giving birth. The unique 10-digit CPR number, which is assigned to all Danish citizens shortly after birth, was used to link all data.
Study population
Statistical analysis The redemption of a prescription of CD-specific medication registered in the prescription database was used as a reference standard in the validity analysis. We computed the positive predictive value (PPV) as the proportion of women reporting medical treatment who were also registered with a prescription in the prescription database. For this calculation, the numerator was the number of women who reported use of medication and filled a prescription, and the denominator was the number of women who reported receiving medication. We constructed frequency tables of major study variables for the population with CD. A logistic regression analysis was used to compute the crude and adjusted prevalence odds ratios (POR) as estimates of relative risk, with associated 95% confidence intervals (CIs) for preterm birth, SGA, CS, congenital malformation and stillbirth. We adjusted for parity
We identified a total of 154 women diagnosed with CD who gave birth to a singleton during the study period. No stillbirths were identified. We excluded 21 (14%) women because review of their medical records could not confirm a CD diagnosis. One woman had passed away for reasons unrelated to CD, leaving a study population of 132 women. Among these 132 women, 105 (80%) returned filled-in questionnaires. The mean age at time of delivery among primiparous women was 30.3 years (range 22.3–39.8). Characteristics of medical-treated and non-medical-treated pregnant CD women are summarized in Table I. Medical-treated women seemed more likely to be cigarette smokers than non-medical-treated women though the difference was not statistically significant (POR 1.67, 95% CI 0.77–3.63). Disease activity Five (4.8%) women stated relapse in CD during pregnancy. One woman had mild disease activity (HBI 5–7), while three had moderate disease activity (HBI 8–16) and one severe activity (HBI >16). One woman had moderate activity prior to conception and during pregnancy, whereas the remaining four women were in remission around conception. Validity of self-reported data Medical treatment was provided to 55 (52.4%) women with CD during pregnancy. Within the treated population, 48 filled a prescription for relevant medication according to the prescription database, yielding a PPV of 87.3% (95% CI, 75.5–94.7). Medical treatment during pregnancy 5-ASA treatment was provided to 28 (52.8%) women, and 16 (30.5%) women received immunosuppressants (thiopurines). Systemic or topical glucocorticoid was provided to nine (17.0%) women [5]. Moreover, four women (3.8%) stated that they had received treatment with infliximab prior to conception. Two women had
Pregnancy outcomes in Crohn’s disease Table I. Characteristics of the study population. Crohn’s disease medical treatment n (%) Total 55 (52.4) Maternal age at delivery £19 years 0 (0.0) 20–24 years 6 (10.9) 25–29 16 (29.1) 30–34 25 (45.5) ‡35 years 8 (14.6) Parity Primiparous 28 (50.9) Not primiparous 27 (49.1) Cigarette smoking Yes 28 (50.9) No 27 (49.1) Data missing 0– Body mass index (kg/m2) 1) and maternal smoking (yes/no), these estimates remained unchanged (data not shown). Infants born to mothers with CD who had received medical treatment during pregnancy seemed not at increased risk of preterm birth, SGA, congenital malformation or stillbirth when compared to infants born to untreated mothers with CD (Table II). The effect of smoking and medical treatment on birth weight Independently of medical treatment, there was a statistically significant difference in birth weight between children of CD non-smokers (3475 g; 95% CI, 3368–3581) and CD smokers (3257 g; 95% CI, 3137–3378), corresponding to a difference in mean birth weight of 218 g (p < 0.008). Among women with CD who received medical treatment, lower birth weight was significantly more common among children of mothers with CD who smoked. The difference in mean birth weight was 274 g (Table III). We found that women with CD who did not receive medical treatment but were smokers gave birth to children with a lower mean birth weight than women with CD who did not smoke (mean difference 126 g) (Table III). Furthermore, maternal medical treatment during pregnancy did not seem to have a negative influence on the child’s birth weight (Table III). Discussion A novel finding in this population-based study was that maternal medical treatment during pregnancy did not influence child birth weight among women with CD. In contrast to this, maternal smoking was negatively associated with child birth weight among women with CD, especially among women who received medical treatment. The study gains strength from its 80% response rate, which is among the highest reported in the IBD literature [24,25]. Further, there was a high concordance between self-reported medical treatment and the prescription database. Previous studies found that children born to mothers with CD had a lower birth weight than those born to mothers without CD [2,12,26,27]. In the present study, we only addressed women with CD
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Table II. Prevalence and crude prevalence odds ratios (POR) for adverse pregnancy outcomes among women with Crohn’s disease (CD) receiving medical treatment or no medical treatment during pregnancy. CD medical treatment n (%) Total Preterm Small for gestational age Cesarean section Congenital malformation Stillbirth
55 4 0 23 2 0
CD no medical treatment n (%)
Crude POR (95% CI)
50 (47.6) 5 (10.0) 1 (2.0) 17 (34.0) 3 (6.0) 0 (0.0)
0.71 (0.18–2.79) – 1.40 (0.63–3.08) 0.60 (0.10–3.76) –
(52.4) (7.3) (0.0) (41.8) (3.6) (0.0)
active disease, it may have been disease activity rather than medical treatment that caused these increased risks. Because most women in our study were in remission, our risk estimates most likely reflect the effect of medical treatment and not disease activity. A population-based cohort study, including 163 births by 111 CD women found that in cases of moderate to high CD activity, the risk of preterm birth was increased more than threefold [10]. Our study therefore underscores the international recommendations emphasizing the importance of remission in CD during pregnancy to minimize the potential risk of adverse pregnancy outcomes [3,34]. Previous bowel resection may be associated with preterm birth [27,35]. This also seemed to be the case in the present study although the numbers were small. More than half of the women giving birth preterm in our study had undergone bowel resection prior to conception. Still, none of these babies were born SGA. Similar to our study, a European consensus report stated that women with CD are substantially more likely to give birth by a CS than women without CD [34]. We did not have more detailed information about the indications for CS and are therefore unable to provide information regarding the reasons for this high prevalence. Medical treatment during pregnancy did not seem to increase the risk of congenital malformations. In particular, the 16 women exposed to thiopurines during pregnancy all gave birth to children without congenital malformations. These results are in accordance with those of previous studies [3,13,34]. A majority of women with mild to moderate CD will receive maintenance medical treatment with
and were able to stratify data according to maternal medical treatment and smoking status. Because the vast majority of women (95.2%) were in remission during their pregnancy, our observed differences could not be explained by differences in disease activity. The causal relationship between cigarette smoking and fetal growth restriction has previously been documented, and our results are in agreement with these data [14]. Further, it has been shown that smoking is associated with more complicated CD [28]. The need for steroids and immunosuppressants has been found to be higher in CD smokers compared with CD non-smokers [29]. However, our results indicate that when counseling medical-treated women with CD, it is important to stress that smoking cessation is of utmost importance because the risk of lower birth weight is even more pronounced among the medical-treated women who smoke. Several studies have investigated the impact of CD medication on pregnancy outcomes such as preterm birth, SGA, congenital malformations or stillbirth. In the majority of these studies, women with CD were compared with populations of non-IBD women [11]. Few studies have addressed the safety of medical treatment comparing pregnant women with CD with untreated women with CD. Our finding that the risk of these adverse pregnancy outcomes was unrelated to maternal medical treatment is in accordance with most previous studies [13,30,31]. On the other hand, two epidemiological studies reported increased risks of preterm birth and stillbirth in CD women who had medical treatment compared with untreated women [32,33]. As stated by the authors, disease activity was not assessed in these studies. Therefore, if medical treatment was associated with
Table III. Birth weight among infants born to women with Crohn’s disease. Medical treatment during pregnancy Characteristic Non-smoker Smoker
n = 50* 24 26
Mean (g) a,b
3504 3230a,d
95% CI 3372–3636 3072–3341
*Data are missing for five women and **Data are missing for one woman. a p = 0.002 and b,c,dp > 0.05.
No medical treatment during pregnancy n = 49** 29 20
Mean (g) c,b
3450 3324c,d
95% CI 3281–3619 3097–3550
Pregnancy outcomes in Crohn’s disease thiopurines, glucocorticoids or 5-ASAs during pregnancy [4,13,36], which emphasizes the clinical relevance of our study. In recent years, anti-TNF-a therapy has been introduced as treatment of severe CD during pregnancy. In the present study, two women had received infliximab infusion due to a relapse during the period 6 months prior to conception. Both women gave birth to healthy children without any adverse pregnancy outcome. Treatment with anti-TNF-a seems safe in pregnancy, but future population-based studies are warranted [7,8]. A potential bias due to differential patient recruitment was avoided in this study by applying a population-based design. The study was also strengthened by the highly organized nature of the Danish Health Care system. A previous study found that the quality of the CD diagnosis in the Regional Patient Administrative System reached 97% [37]. The data quality in the Danish Medical Birth Registry is also reported to be high [38,39]. Furthermore, to minimize the influence of short disease duration, the patient diagnosis had to be established at least 1 year prior to conception [40]. As the questionnaire-based data collection was performed retrospectively, possible recall bias should be taken into account; however, we found only approximately 13% discrepancy between selfreported medical treatment and the Danish prescription database. We therefore do not expect recall bias regarding medical treatment to have major effect on the results of the present study. After review of the medical records, we found all cases of self-reported relapse during pregnancy to be valid. Misclassification of smoking status could bias our results. We defined smoking status as the status prior to pregnancy because the women did not state when smoking cessation occurred during pregnancy. Women who stopped smoking at conception or very early in pregnancy may therefore be misclassified as smokers. Yet, such a bias would lead us to underestimate the negative association between smoking and birth weight. Although this study was conducted in two Danish regions equivalent to a third of the Danish population, the precision of our risk estimates remains low due to the low prevalence of adverse pregnancy outcomes. This was amplified by the relatively low number of CD women who had given birth within a 6-year period. The low number of births remains a general challenge in the study of rare outcomes in relatively rare diseases such as CD. In conclusion, our data indicate that smoking, and not medical treatment, is a risk factor for lower birth weight among infants born to women with CD. We observed, however, the largest difference in mean birth weight of the child between smokers and non-smokers
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among mothers who received medical treatment. We found it reassuring that medical treatment did not seem to be associated with preterm birth, SGA, congenital malformations or stillbirth among women with CD where the vast majority of women were in remission. Our findings underline that prior to conception and during pregnancy, smoking cessation and remission in CD, most often induced by medical treatment, are important parameters to ensure the best possible outcome of pregnancy among women with CD.
Acknowledgments The authors gratefully acknowledge the physicians at the hospitals involved. Declaration of interest: Dr. Mette Julsgaard has served as a speaker for AbbVie A/S. Dr. Christian Lodberg Hvas has served as a speaker for AbbVie A/S and MSD A/S. Dr. Lisbet Ambrosius Christensen has served as a speaker for Ferring A/S, MSD A/S, and AbbVie A/S and is a member of the advisory board for MSD A/S. The remaining authors declare no conflicts of interest. This study was funded in part by the Danish Colitis-Crohn association and the A.P. Moeller Foundation of the Advancement of Medical Science. The Danish Ministry of Health has financially supported Dr. Mette Julsgaard. The funding has in no way affected the study design, data collection, analysis and interpretation of the data or the writing of the report.
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