Accepted Manuscript

Ectopic pregnancy in women with inflammatory bowel disease – a 22 yearnationwide cohort study

Punyanganie S. de Silva, MD, MPH, Helene H. Hansen, MSc, Sonja Wehberg,PhD, Sonia Friedman, MD, Bente M. Nørgård, MD, DMSc, PhD

PII: S1542-3565(17)30802-9DOI: 10.1016/j.cgh.2017.06.054Reference: YJCGH 55336

To appear in: Clinical Gastroenterology and HepatologyAccepted Date: 27 June 2017

Please cite this article as: de Silva PS, Hansen HH, Wehberg S, Friedman S, Nørgård BM, Ectopicpregnancy in women with inflammatory bowel disease – a 22 year nationwide cohort study, ClinicalGastroenterology and Hepatology (2017), doi: 10.1016/j.cgh.2017.06.054.

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Risk of Ectopic Pregnancy in Women with Inflammatory Bowel

Disease – a 22-year Nationwide Cohort Study

Short title: Ectopic pregnancy in IBD

Punyanganie S. de Silva MD, MPH1, Helene H. Hansen MSc2, Sonja Wehberg PhD2,

Sonia Friedman MD1,2, Bente M. Nørgård MD, DMSc, PhD 1,2

1) Center for Crohn’s and Colitis, Brigham and Women’s Hospital, Harvard Medical

School, Boston, Massachusetts, USA

2) Center for Clinical Epidemiology, Odense University Hospital, and Research Unit

of Clinical Epidemiology, University of Southern Denmark, Odense, Denmark

Grant Support: The study was supported by a Crohn’s & Colitis Foundation of

America Senior CCFA Research Award Number 112544.

Abbreviations:

assisted reproductive technology (ART)

confidence intervals (95% CI)

Crohn’s disease (CD)

ectopic pregnancies (EP)

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International Classification of Diseases (ICD)

inflammatory bowel disease (IBD)

National Patient Registry (NPR)

odds ratio (OR)

pelvic inflammatory disease (PID),

ulcerative colitis (UC)

Correspondence:

Punyanganie S. de Silva, MD, MPH

Center for Crohn’s and Colitis,

Division of Gastroenterology, Hepatology & Endoscopy

Brigham & Women’s Hospital

Boston, MA, 02115, USA

Email: pdesilva@bwh.harvard.edu

Tel: +1 617 838 5352

Fax: +1617 732 9198

Disclosures: The authors have no disclosures

Writing Assistance: None

Author Contributions:

PSdS: funding, conception, design, assistance with data analysis, interpretation of

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results, manuscript writing and editing, approved the final version. HHH: data

collection, data analysis, interpretation of results, manuscript editing, approved the

final version. SW: data collection, data analysis, interpretation of results, manuscript

editing, approved the final version. SF: funding, conception, interpretation of results,

manuscript writing and editing, approved the final version. BMN: funding,

conception, design, data collection, assistance with data analysis, interpretation of

results, manuscript writing and editing, approved the final version.

Word count (including references and table legends): 3993

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Abstract: Background & Aims: Few data are available on adverse events of pregnancy in

women with inflammatory bowel diseases (IBD), such as ectopic pregnancy. We assessed the risk of ectopic pregnancy in pregnancies of women in Denmark with IBD compared to those without IBD over a 22-year period. We also examined the disease-specific risks of ectopic pregnancies in pregnancies of women with ulcerative colitis (UC) or Crohn’s disease (CD) who underwent IBD-related surgical procedures.

Methods: We performed a retrospective study of all women of child-bearing age

(15–50 years old) registered in the Danish National Patient Registry (NPR) with at least 1 pregnancy during the period of January 1994 through December 2015. We collected data on all women with an ectopic pregnancy, hydatiform mole, miscarriages (spontaneous and other abortions, including abnormal pregnancy products, missed abortion, and pregnancy without a fetus), induced abortions, and births in women with and without IBD. Our study population included 7548 pregnancies in women with UC, 6731 pregnancies in women with CD, and 1,832,732 pregnancies in women with pregnancies without IBD. We controlled for multiple covariates, including pelvic and abdominal surgery.

Results: Women with CD had a greater risk of ectopic pregnancy, per pregnancy,

than women without IBD (odds ratio [OR], 1.23; 95% CI, 1.01–1.49), whereas women with UC did not (OR, 0.98; 95% CI, 0.80–1.20). In pregnancies of women with CD or UC who underwent IBD-related surgery before pregnancy, there was a non-specific increase in risk of ectopic pregnancy compared to pregnancies in women with IBD who did not have surgery (OR, 1.49; 95% CI, 0.91–2.44 for CD and OR, 1.17; 95% CI, 0.54–2.52 for UC ).

Conclusion: We found a statistically significant increased risk of ectopic

pregnancy in pregnancies of women with CD compared to pregnancies of women without IBD. Surgery for IBD before pregnancy increased risk of ectopic pregnancy, though this increase was not statistically significant.

KEY WORDS: epidemiology; chronic inflammation; risk; outcome

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BACKGROUND & AIMS

Ulcerative colitis (UC) and Crohn’s disease (CD) are chronic debilitating

autoimmune diseases that characteristically affect younger individuals during their

peak reproductive years.1 The diseases cause systemic inflammation, which may

affect fertility and lead to early adverse pregnancy outcomes. In addition, a

significant proportion of women with inflammatory bowel disease (IBD) undergo

IBD-related abdominal and pelvic surgery and the effect of these procedures on

future pregnancies is not well studied.

The prevalence of ectopic pregnancy (EP) among women who go to an emergency

department with first trimester bleeding, pain, or both ranges from six to sixteen

percent.2 The overall incidence of EP increased during the mid twentieth century,

plateauing at approximately almost 20 per 1000 pregnancies in the early 1990s in

the USA.3 The risk factors for EP are well recognized and include conditions that can

increase adhesions such as pelvic inflammatory disease (PID), endometriosis, pelvic

infection, prior pelvic and fallopian tube surgery, assisted reproductive technology

(ART), smoking and increasing age. Women with IBD often have common EP risk

factors such as previous abdominal and pelvic surgery or recurrent pelvic abscesses

with intra-abdominal adhesions. Pelvic infection (salpingitis, chlamydia, gonorrhea)

is a major cause of tubal pathology leading to altered tubal function, tubal

obstruction and pelvic adhesive disease and, therefore, increases the incidence of EP

by odds ratios of 2.1-4.5.4,5 Tubal surgery such as prior sterilization, bipolar

coagulation of tubes and tubal reconstructive surgery are also well recognized risk

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factors.6,7 Excessive ovarian response during in vitro fertilization has also been

associated with an increased risk of EP.8 In addition, caesarian section has been

identified as an independent risk factor for EP,9,10 and a meta-analysis of

appendectomies revealed a two-fold increased risk of EP.11 There is also a suggested

association between endometriosis (a well-recognized risk factor for EP),12 and

IBD.13

To date, studies regarding EP in IBD are severely limited due to small sample size,

and large population based cohort studies are therefore needed. The Danish

national registries contain the pregnancy outcome data of all women in Denmark

with and without IBD. We therefore aimed to assess the risk of EP in women with

IBD compared to all other pregnancies over a 22-year period of time. In addition, we

examined the association between IBD specific abdominal and pelvic surgery in

women with IBD prior to pregnancy and the risk of subsequent EP.

METHODS

Study population and setting

All citizens in Denmark (population approximately 5.6 million inhabitants, > 90%

Caucasians) have equal and free access to the tax-supported health care system, and

its uniform organization allowed us to use a nationwide population-based design.

The study population comprised of all women of child-bearing age (15-50 years),

with a valid civil registration number available for follow up in Denmark, registered

in the Danish National Patient Registry (NPR) with at least one pregnancy during

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the study period of 1 January 1994 – 31 December 2015. A woman could contribute

to the study population with several pregnancies. We included records of all EP,

hydatiform moles, miscarriages (consisting of spontaneous abortion; other

abortions - abnormal pregnancy products, missed abortion and pregnancy without

foetus), induced abortions, and births in women with and without IBD, during the

study period.

After obtaining information on gestational age at the time of each pregnancy

outcome we were then able to estimate the conception date for each pregnancy.

Estimated date of conception was determined by date of recorded pregnancy

outcome date as documented in the NPR minus the estimated gestational age.

Data

The NPR includes records of all discharges from Danish hospitals since 1977 and all

outpatient visits since 1994.14 It maintains up to date records of all women who

have a hospital delivery and the vast majority of home deliveries (approximately

1.2% of all deliveries),15 surgical or medical treatment for EP, miscarriage and

diagnosis of other pregnancy outcomes. The register was established in 1977 and

used International Classification of Diseases (ICD) 8 classifications until 1993. In

1994 the ICD-10 classification was introduced (ICD-9 was never used in Denmark).

The following ICD codes were used to identify reproductive outcomes: EP

(confirmed by either medical or surgical treatment; ICD-10 DO00*, where *

indicates all subcategories); hydatiform moles (ICD-10 DO01*); miscarriages

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(spontaneous abortion; other abortions - abnormal pregnancy products, missed

abortion and pregnancy without foetus (ICD-10 DO02*, DO03*)); induced abortions

(ICD-10 DO04*-DO06*); hospital births (ICD-10 DO60.0-DO84.9). From the study

population of pregnancies, all women with a diagnosis of IBD (UC or CD) were

identified using the following codes: for UC ICD-8 563.19, 569.04; ICD-10 DK51*

(except DK51.9 for unspecified disease) and for CD ICD-8 563.01; ICD-10 DK50*. In

order to ensure accurate identification of IBD diagnosis we utilized IBD diagnostic

codes dated from 1977 onwards.

Data on confounders

We selected covariates a priori. From the NPR we included data on comorbid

diseases according to Charlson index calculation.16 We computed the index based on

diagnoses recorded during all previous hospitalizations since 1977, and three index

levels were defined: no comorbidity (Charlson Index 0), intermediate comorbidity

(Charlson Index 1-2), high comorbidity (Charlson Index >3). The Charlson index is

calculated according to each pregnancy.

We included data on selected abdominal and pelvic surgical procedures performed

in all pregnancies before each estimated conception date. Codes were thus obtained

for surgical procedures that are common to all women with and without IBD, and

included operations of fallopian tube surgical procedures (excluding bilateral

salpingectomy) and fallopian tubal operations for infertility, appendectomy,

cholecystectomy, perforated peptic ulcer surgery and caesarean section. These

surgeries were identified as non-IBD surgeries (Supplementary Table 1). IBD

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related surgery was classified separately for UC and CD. For pregnancies of women

with UC we identified those who had undergone IBD surgery prior to the estimated

date of each conception. The identification was based upon possible surgeries

according to the new and former version of the “Nordic Classification of Surgical

Procedures”. A similar approach was taken for pregnancies of women with CD

(Supplementary Table 1).

We also obtained information from 1994 onwards of all medical diagnoses of

endometriosis (ICD-8 625.29 to 625.39, ICD-10 DN80*), PID (ICD-8 612*, 613*,

614*, 615.19, 616*, ICD-10 DN71*, DN72*, DN73* ) and diseases of the fallopian

tube including salpingitis, oophoritis and hydrosalpinx (DN70*) for all women in

our study population any date prior to the onset of their first estimated conception

date .

In addition, we obtained data for estimated age at time of each conception and

gravida (primigravida vs multigravida), in all included pregnancies. We divided the

calendar period of pregnancy into the following groups: 1994-1998, 1999-2003,

2004-2008, 2009-2013, 2014-2015.

For the pregnancies of women with IBD we also obtained data on estimated

duration of IBD (calculated from the time from first IBD diagnosis (either CD or UC

diagnoses) until the estimated date of conception)).

From the Danish ART registry, we retrieved information regarding prior ART

treatment to all pregnancies among women with IBD and without IBD. The Danish

ART registry is a mandatory registry and was established in January 1994 and

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includes data on all ART treatments in both public and private sectors. Information

on ART includes in vitro fertilisation, with or without fertilisation with

intracytoplasmic sperm injection, and transfer of frozen-thawed embryos.

We had data from all sources unambiguously linked on an individual level using the

unique civil registration number (assigned to all Danish residents at birth from the

Central Personal Registration system) and used in all Danish healthcare registries.

We used the period from 1990-1993 as a run in period to ensure that we had

accurately identified any first (primigravida) pregnancies from1994 onwards.

Exposed cohort

Our exposed cohort consisted of all eligible pregnancies of women who had a

discharge history of either UC or CD from any hospital in Denmark before the

estimated date of conception. If a woman with UC had a former diagnosis of CD in

the NPR she was only included as having UC if the latest given diagnosis was UC. If a

woman with a CD diagnosis had a former diagnosis of UC she was only included as

having CD if the latest given diagnosis was CD. Pregnancies before the IBD diagnosis

were allocated to the non-IBD group. Pregnancies that occurred after the women

were diagnosed with IBD were allocated to either the UC or CD group.

Unexposed cohort

The unexposed cohort comprised all pregnancies of women from the study

population, without a diagnosis of UC or CD at the time of estimated date of

conception.

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Outcome

The outcome consisted of a diagnosis of EP as coded in the NPR (this diagnosis was

supported by codes specifying either medical or surgical treatment for an EP).

Statistical Analysis

We used logistic regression with robust cluster analysis for pregnancy outcomes to

compute crude and adjusted odds ratio estimates for EP (odds ratio [OR] with 95%

confidence intervals [95% CI]) for each pregnancy in women with UC and CD,

relative to women without IBD. The observation unit was the pregnancy. The model

accounted for multiple pregnancies for each woman. Adjustment was made for

woman’s age at time of conception, Charlson index, calendar period, prior ART and

abdominal and pelvic surgery prior to each conception (including IBD specific

surgery). We also adjusted for diagnoses of endometriosis, PID and salpingitis made

prior to first estimated conception date.

In addition, we performed sub-analyses of the impact of IBD-specific abdominal and

pelvic surgical procedures on the risk of EP. The ORs for EP were calculated for

pregnancies of women with UC who had undergone IBD-specific surgery and

compared to those pregnancies of women with UC who had not had IBD-specific

surgery, adjusting for age at estimated conception, non-IBD surgery, endometriosis,

salpingitis, PID, prior ART, Charlson index and calendar period. A similar approach

was taken for pregnancies of women with CD.

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In a sensitivity analysis, we ran the analyses including unspecified UC (K51.9).

The study was approved by the Danish Data Protection Agency (j.nr. 2014-41-

3466).

RESULTS

There were 7,548 pregnancies of women with UC, 6,731 pregnancies of women with

CD, and 1,832,732 pregnancies of women without IBD (Table 1).

The median age at conception was 30.0 years (mean 30.5, SD 5.1) in pregnancies of

women with UC, 29.0 years (mean 29.6, SD 5.2) in pregnancies of women with CD,

and 29.0 years (mean 20.0, SD 5.6) in pregnancies of women without IBD. The

median duration of IBD prior to each pregnancy in women with UC was 5.0 years

(SD 5.3), and 5.0 years (SD 4.7) in women with CD. The majority of women in the

study had no other co-morbidities during pregnancy (pregnancies in UC 88.1%,

pregnancies in CD 83.6%, pregnancies in non-IBD 93.2%) (Table 1). Endometriosis

was more prevalent in the pregnancies of women with IBD compared to the

pregnancies of women without IBD (CD 2.0 %, UC 2.2%, non-IBD 1.0%).

Pregnancies in women with CD had the highest proportion of concomitant PID

(7.9%) (Table 1). A significantly higher number of women with CD pregnancies had

undergone non-IBD surgeries prior to conception (CD 26.3 %, UC 19.8 %, non-IBD

16.0%). More women with CD pregnancies (15.0%) had IBD surgery compared to

women with UC pregnancies (5.3%). Women with UC pregnancies had the highest

proportion of prior ART (2.8%) compared to women with CD pregnancies (2.6%)

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and women without IBD pregnancies (1.5%)(Table1). In total we identified 240 EP

among pregnancies of women with IBD (Table 2). The prevalence of EP among

pregnancies in women with UC was 1.5% (112/7548), and 1.9% (128/6731) among

pregnancies in women with CD. Among women without IBD, the prevalence of EP

was 1.4 % (25,584/1,832,732).

Table 2 shows the crude and adjusted OR for EP in pregnancies of women with IBD

compared with pregnancies of women without IBD. For pregnancies in women with

IBD in general, the adjusted OR was 1.10 (95% CI 0.96-1.27). For pregnancies of

women with a UC diagnosis, adjusted OR for EP was 0.98 (95% CI 0.80-1.20), and

for pregnancies of women with a CD diagnosis the adjusted OR was 1.23 (95% CI

1.01-1.49).

Table 3 shows crude and adjusted OR for EP in the cohort of pregnancies in women

with IBD who had undergone surgery prior to estimated date of conception,

compared with EP in pregnancies in women with IBD who had not undergone

surgery. Although pregnancies in women with UC and CD who underwent IBD-

specific surgery had an increased risk of EP, the results were not statistically

significant.

When we included unspecified diagnostic codes for UC (DK51.9) in the sensitivity

analysis we found similar results and none of our conclusions changed (data not

shown).

DISCUSSION

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In this national cohort study, we found that pregnancies in women with CD were at

a higher relative risk of EP than pregnancies in women without IBD. This difference

was not noted in pregnancies in women with UC. One explanation for this is that

women with CD may be more likely than women with UC to have perforating or

fistulising pathology with subsequent adhesions, a risk factor for EP. Pregnancies in

women with UC or CD who had undergone IBD-related surgery did have increased

risk of EP occurrence compared to pregnancies in women with UC or CD who did

not have IBD-related surgery, but the results were not statistically significant. The

prevalence of EP in the non-IBD cohort was consistent with that of previously published

literature.2,3

This is the first study, based on nationwide data, analysing the risk of EP in

pregnancies of women with IBD and it provides useful information for physicians

who are treating women of reproductive age who have IBD. Prior studies reporting

EP in women with IBD are extremely limited and consist of two smaller case

series.17,18 While late pregnancy complications and birth outcomes have been

extensively studied,19-22 as far as we are aware, this is the only cohort study to date

that has aimed to specifically investigate the risk of a very early adverse outcome

such as EP in women with IBD.

Our study has several strengths. We provide data on a very large national cohort.

We have complete follow up for our study cohorts, and the outcome, EP, was studied

independently of exposure status, thereby preventing selection and information

bias. In addition, we were able to take into account a number of important

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confounders such as PID, endometriosis, ART and abdominal and pelvic surgeries

including reconstruction of the fallopian tubes.

There is a high degree of completeness and validity in Danish healthcare registry

data assessing the exposure (IBD diagnosis). It has previously been demonstrated

that there is high (94%) concordance between patients with a confirmed diagnosis

of UC or CD within the Danish pathology system, and those included in the NPR. 23

The diagnosis of UC and CD included obligatory registration from both hospitals and

outpatient visits, and when the validity of diagnosis in the NPR was assessed for

patients diagnosed in specialised departments, the positive predictive value was

94% for UC and 97% for CD.23

The study also has limitations. We were unable to obtain data on medication use,

disease activity/severity as this is a national register-based study, and we did not

have access to individual chart review. Even if we had had access to such

information it is questionable whether such factors would exert any confounding

effects as no studies have indicated them to be risk factors for EP. Another limitation

is that smoking data are not available in the dataset for either the IBD or non-IBD

women. Although smoking is a recognized risk factor for EP 24, since we did not have

smoking data, we were unable to test the theory whether women with IBD who

smoke have a higher risk of EP than women without IBD who smoke. While we did

adjust for diagnoses of endometriosis based on ICD classification, there is a

possibility that this may have been over-called in women with GI symptoms and

dysmenorrhea. However we used established registry data with confirmed ICD 10

codes for endometriosis, and these same codes have previously been used in other

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registry-based studies regarding women with endometriosis.25 A limitation of our

study is that miscarriages that never need medical or surgical treatment are not

captured in the registry so there is the possibility that we underestimated the

prevalence of EP in both exposed and unexposed cohorts.

We do not know what the biological mechanism is for women with CD

demonstrating an increased risk of EP. We could speculate that it has some

association with IL-6 or changes in the gut flora. It has recently been shown that

women with EP are more prone to higher levels of circulating IL-6.26 IL-6 is a

pleiotropic cytokine which influences immune responses by both its pro- and anti-

inflammatory properties.27,28 Women with higher levels of serum IL-6 have been

shown to have a higher OR for new onset CD and increased disease activity.29,

Therefore, although speculative, it is possible that CD may predispose women to an

IL-6 mediated process that promotes EP pathogenesis.

IBD also leads to changes in the gut microbiome.30 Lactobacillus crispatus is an

organism found in the human gut flora, and associated with active colonic

inflammation in animal models.31 It is also known to dominate the vaginal

microbiota of healthy reproductive-age women and protects the genitourinary tract

from attack by several infectious agents including Chlamydia trachomatis, which in

turn can lead to PID and subsequent EP.32 It is possible that IBD therapies can cause

changes in the levels of these organisms in the microbiome. Another possible

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explanation of the differences seen in UC and CD may be due to the variability in

microbial composition noted between the two phenotypes.33

Many patients are concerned and sometimes fearful of their IBD diagnosis and its

implications on future pregnancy, and our study provides very useful information

for physicians who are treating women of reproductive age who have IBD. Although

we did demonstrate an increased relative risk of EP in pregnancies of women with

CD, the overall absolute risk of EP remains low. This is useful for physicians treating

reproductive age women with CD and heightens awareness of the possibility of

ectopic complications in this patient group. Our study suggested an increased risk of

EP in pregnancies of women with UC or CD who had former IBD- related surgery

compared to pregnancies of women with IBD who had not had IBD-related surgery,

though these results were not statistically significant. In general, women with IBD

should be educated about risk factors for EP such as pelvic infections and ART.

These first results, based on large cohorts, on the risk of EP in women with IBD, are

reassuring but our results should be confirmed in other settings. Future analyses

including supplementary clinical details would be welcome.

Acknowledgements: Pia V. Larsen: data collection

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33. Tyler AD, Kirsch R, Milgrom R et al. Microbiome Heterogeneity Characterizing

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TABLE1:

Descriptive characteristics of study cohorts of women with IBD and without IBD for all pregnancies during the study

period of 1 January 1994 through December 31, 2015.

IBD Cohort Non IBD cohort

UC (%) CD (%)

Pregnancies 7,548� 6,731� 1,832,732�

Ectopic pregnancy

(yes)

112 (1.5) 128 (1.9) 25,584 (1.4)

Distribution of

other reproductive outcomes:

7,436 (98.5) 6,603 (98.1) 1,807,148 (98.6)

Birth 5,437 (72.0) 4,666 (69.3) 1,257,800 (68.6)

Molar pregnancy* 15 (0.2) 4 (0.1) 1,737 (0.1)

Other abortions ** 499 (6.6) 466 (6.9) 107,048 (5.8)

Spontaneous abortions *** 451 (6.0) 416 (6.2) 109,436 (6.0)

Induced abortions**** 1,034 (13.7) 1,051 (15.6) 331,127 (18.1)

Calendar Period

1994-1998 934 (12.4) 738 (11.0) 413,195 (22.5)

1999-2003 1,514 (20.1) 1,248 (18.5) 451,877 (24.7) 2004-2008 2,005 (26.6) 1,836 (27.3) 442,617 (24.2)

2009-2013 2,311 (30.6) 2,096 (31.1) 399,487 (21.8)

2014-2015 784 (10.4) 813 (12.1) 125,556 (6.9)

Age at conception

(years)

15-24 849 (11.2) 1,154 (17.1) 389,685 (21.3)

25-34 5,059 (67.0) 4,380 (65.1) 1,141,202 (62.3)

35-50 1,640 (21.7) 1,197 (17.8) 301,845 (16.5)

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Duration IBD at

conception –

any pregnancy

outcome (years)

0-1 1,563 (20.7) 1,202 (17.9) 2-3 1,517 (20.1) 1,248 (18.5)

4-7 2,148 (28.5) 1,992 (29.6)

8≤ 2,320 (30.7) 2,289 (34.0)

Co-morbidity at

each pregnancy

None (0) 6,653 (88.1) 5,625 (83.6) 1,708,234 (93.2)

Some (1-2) 854 (11.3) 1,053 (15.6) 119,433 (6.5)

High (>=3) 41 (0.5) 53 (0.8) 5,065 (0.3)

Endometriosis

prior to

Conception

150 (2.0) 147 (2.2) 18,708 (1.0)

Pelvic

Inflammatory

Disease

or salpingitis prior

to conception

400 (5.3) 533 (7.9) 70,186 (3.8)

Any Surgery prior

to

conception (yes)

1,887 (25.0) 2,761 (41.0) 292,967 (16.0)

Distribution of surgeries: All abdominal and pelvic surgeries

1,491 (19.8) 1,770 (26.3) 292,967 (16.0)

All abdominal surgeries Δ 518 (6.9) 1,198 (17.8) 139,690 (7.6)

Caesarian sections 869 (11.5) 505 (7.5) 135,746 (7.4)

Fallopian tube surgical procedures &

Tubal operations for infertility

104 (1.4) 71 (1.1) 17,762 (1.0)

UC specific surgeries 399 (5.3)

CD specific surgeries 1,011 (15.0)

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Number of surgical

dates

prior to

conception∆

0 5,624 (74.5) 3,875 (57.6) 1,539,600 (84.0)

1 1,472 (19.5) 1,970 (29.3) 254,234 (13.9)

2-3 439 (5.8) 820 (12.2) 38,288 (2.1)

4≤ 13 (0.2) 66 (1.0) 610 (0.0)

ART within 6

months

prior to conception

(yes)

213 (2.8) 172 (2.6) 28,283 (1.5)

First (primi)

pregnancy (yes)

2,743 (36.3) 2,658 (39.5) 819,279 (44.7)

�Represents 4,166 women with UC, 3,542 women with CD and 840,377 women without IBD *Molar pregnancy DO01

** Other abortions DO02

*** Spontaneous abortions DO03

**** Induced abortions DO04-DO06 ∆

Appendectomy, cholecystectomy, perforated peptic ulcer surgeries

ART Assisted Reproductive Technology

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TABLE 2:

Crude and adjusted ORs, with 95% confidence intervals (CI), for ectopic

pregnancy in the study cohorts of women with IBD compared with women

without IBD (pregnancies from 1 January 1994 till December 31, 2015)

*Adjusted for Charlson comorbidity, age at conception date, all abdominal or pelvic surgery before

each conception (yes/no), prior ART (yes/no), prior endometriosis (yes/no), prior PID and

salpingitis (yes/no), and calendar period (1994-1998, 1999-2003, 2004-2008, 2009-2013, 2014-

2015)

All pregnancies Ectopic pregnancy

N (%)

Crude OR

(95% CI)

Adjusted OR*

(95% CI)

Non IBD 1,832,732 25,584 (1.4) 1 (Ref) 1 (Ref)

All IBD 14,279 240 (1.7) 1.21 (1.05–1.39) 1.10 (0.96–1.27)

CD 6,731 128 (1.9) 1.37 (1.13–1.66) 1.23 (1.01–1.49) UC 7,548 112 (1.5) 1.06 (0.87–1.30) 0.98 (0.80–1.20)

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TABLE 3:

Crude and adjusted ORs, with 95% confidence interval (CI), for ectopic

pregnancy in the cohort of women with UC who had undergone surgery prior

to estimated date of conception, compared to women with UC who had not

undergone surgery; similar results for women with CD (pregnancy data from 1

January 1994 through December 31 2015)

UC pregnancies

Exposed cohort

(women with UC

who had prior

UC surgery)

(N= 399)

Unexposed

cohort (women

with UC who had

no prior UC

surgery)

(N=7149)

Crude OR

(95% CI)

Adjusted OR†

(95% CI)

Ectopic

pregnancy

Yes, N (%)

No, N (%)

8 (2.01)

391 (97.99)

104 (1.45) 7045 (98.55)

1.39 (0.67-2.87)

1.17 (0.54 –2.52)

CD pregnancies

Exposed cohort

(Women with CD

who had prior

CD surgery)

(N=1011)

Unexposed

cohort

(Women with CD

who had no

prior CD

surgery)

(N=5720)

Crude OR

(95% CI)

Adjusted OR†

(95% CI)

Ectopic

pregnancy

Yes, N (%)

No, N (%)

23 (2.27)

988 (97.73)

105 (1.84)

5615 (98.16)

1.24 (0.79 –1.96)

1.49 (0.91- 2-44)

† Adjusted for Charlson comorbidity, age at conception date, non IBD surgery (yes/no), prior ART

(yes/no), prior endometriosis (yes/no), prior PID and salpingitis (yes/no), and calendar period

(1994-1998, 1999-2003, 2004-2008, 2009-2013, 2014-2015)

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SUPPLEMENTARY TABLE 1

Surgical procedures used in the analysis

ICD 8 (1977-1995)

Ulcerative colitis surgeries

45020, 45060, 45080, 45840, 45880

Crohn’s Disease surgeries 43440, 43460, 43520, 43540, 43680,

43700, 43740, 43760, 43780,

43800, 43820, 43840, 43860, 43880, 44060, 44120, 44150, 44160,

44790, 44900, 44920,. 44940, 44960,

44980, 45020, 45060, 45080, 45100, 45120, 45200, 45240, 45320,

45480, 45690, 45840, 45860,

45880, 46290

Cholecystectomy

47360, 47365

Appendicectomy 43000, 43001, 43040, 43041

Perforated peptic ulcer surgery

41740, 41741, 43140, 43141, 44220,

42240, 42260, 42261, 41980, 42000,

42100, 42101

Fallopian tube surgical procedures (excluding salpingectomy) & Tubal operations for infertility

60501, 60520, 94400, 94420

Caesarian section

65190, 66020, 66040, 66060, 78000, 63620

Nordic Classification of Surgical Procedures

(since 1996):

Ulcerative colitis surgeries KJFH*

Crohn’s Disease surgeries

KJFB00, KJFB01, KJFB20, KJBF21, KJBF30,

KJBF31, KJFB33, KJFB34

KJFB40, KJFB41, KJFB43, KJFB44, KJFB46, KJFB47, KJFB50, KJFB51,

KJFB60, KJFB61, KJFB63, KJFB64,

KJFB96, KJFB97

KJFH00, KJFH01, KJFH10, KJFH11, KJFH20, KJFH96

KJGB00, KJGB01, KJGB10, KJGB11, KJGB30,

KJGB31 KJFA60

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Cholecystectomy KJKA20, KJKA21

Appendicectomy KJEA*, KJEW*

Perforated peptic ulcer surgery

KJDA60, KJDA61, KJDH70, KJDH71,

KJDC00, KJDC10, KJDC11, KJDC20, KJDC96,

KJDC97

KJDD96

Fallopian tube surgical procedures

(excluding salpingectomy) & Tubal operations for infertility

KLBA*, KLBB*

KLBF00, KLBF01, KLBF03, KLBF30, KLBF31

KLBF50, KLBF51

Caesarian section

KMCA00, KMCA10*, KMCA20, KMCA30