Maternal and fetal outcomes in patients with Crohn’s disease: a population-based cohort study

Introduction

Crohn’s disease is a chronic inflammatory bowel disease (IBD), with a relapsing and remitting pattern, which may affect any area of the gastrointestinal tract and may involve symptoms such as diarrhea, abdominal pain, rectal bleeding, weight loss, and fatigue [1]. Over time the incidence of Crohn’s disease has risen world-wide, with disease onset typically occurring in the second to fourth decade of life, therefore affecting many individuals of childbearing age [1], 2]. Most of the current literature pertaining to Crohn’s disease and pregnancy focuses on the effect of biologic medication on pregnancy outcomes, the effect of the pregnancy on the disease course, or pre-conception counselling for fertility issues associated with Crohn’s disease [2], [3], [4], [5]. Although some studies have published findings demonstrating increased risks for certain pregnancy outcomes, such as preterm delivery, cesarean sections, and low birthweight [6], [7], [8], [9], [10], our large population-based study aims to evaluate the risks of a broader range of adverse maternal and fetal/neonatal outcomes in patients with Crohn’s disease.

Materials and methods

Results

The unweighted HCUP-NIS sample consisted of a total of 5,671 patients diagnosed with Crohn’s disease out of a total of 4,337,612 individuals who gave birth between 2016 and 2021. Therefore, the overall unweighted prevalence of Crohn’s disease in this sample was 13.1 per 10,000 births. Figure 1 shows an upward slope in the prevalence of Crohn’s disease in pregnancy, from 10.2 per 10,000 deliveries in 2016 to 15.6 per 10,000 deliveries in 2021 (p<0.0001).

Figure 1:

Annual prevalence of Crohn’s disease in pregnancy in the HCUP-NIS between 2016–2021 (per 10,000 delivery admissions).

Table 1 lists the baseline characteristics and demographics identified for pregnant patients with and without Crohn’s disease. Compared to patients without Crohn’s disease in this sample, patients with the disease were more commonly older in age, Caucasian, had private insurance, and belonged to a higher income quartile. Patients with Crohn’s disease were also more likely to have thyroid disease and to use tobacco.

Table 2 shows the results of the multiple logistic regression analyses comparing the maternal outcomes in patients with and without Crohn’s disease. Pregnant patients with Crohn’s disease had a greater risk of developing preeclampsia in the antepartum period than did patients without the disease. In the intrapartum period, patients with Crohn’s disease had a statistically significant higher risk of chorioamnionitis, placental abruption, as well as cesarean section and instrumental vaginal deliveries. Patients with Crohn’s disease were at higher risk of developing PPH, sepsis, and VTE in the postpartum. Maternal death was included in the analysis but due to the very small number of cases, an odds ratio could not be computed.

The fetal/neonatal outcomes in patients with Crohn’s disease vs. those without this condition are displayed in Table 3. In our study population, offspring born to individuals with Crohn’s disease were significantly more likely to be born preterm, to have congenital anomalies, and to have experienced IUGR. There was no significant difference in intrauterine fetal death between the two groups.

Discussion

Crohn’s disease, which has increased in incidence over time, tends to be diagnosed in reproductive age individuals. This underscores the importance of determining the impact this disease has in pregnancy for both mother and baby. Further, previous studies were limited in the variety of obstetrical outcomes examined, and also, the majority of studies collectively examined Crohn’s disease with other IBDs. Hence, utilizing data from the HCUP-NIS database, we conducted a retrospective cohort study to examine the association between specifically Crohn’s disease in pregnancy and various obstetrical outcomes. Our study demonstrated that Crohn’s disease is associated with an increased risk of both adverse maternal and neonatal outcomes.

It was observed in our study that pregnant individuals with Crohn’s disease possessed a greater risk of preeclampsia during pregnancy. The association between preeclampsia and Crohn’s disease is mixed in the published literature, with some studies finding an increased incidence of preeclampsia among pregnant patients with IBD [12], [13], [14] and other studies finding no association [11], 15]. Despite these differences in results, it has been suggested by a recently convened Global Consensus Consortium, consisting of IBD experts and patient advocates, that pregnant individuals with IBD should take low-dose aspirin starting between 12 and 16 weeks’ gestation in order to minimize the risk of developing preeclampsia [16]. Further, in our study, gestational hypertension was more common among patients with Crohn’s disease compared to those without Crohn’s disease (7.9 % vs. 6.4 %, respectively); although the adjusted estimate was greater than 1.0, the results were inconclusive as the 95 % CI for the regression model included a lower limit of 1.0 and the p-value was 0.01. It is hypothesized that the increased risk of gestational hypertensive disorders in patients with Crohn’s disease is attributable to an elevated level of inflammatory cytokines associated with disease activity. These cytokines cause increased vasoreactivity, which, in turn, elevates the risk of hypertensive disorders [17]. In contrast, Clarke et al., which was a single-center cohort study, did not observe an association between IBD in pregnancy and hypertensive disorders [18]. Further research is required to study the potential association between specifically Crohn’s disease and gestational hypertension.

Gestational diabetes was observed to be of lower frequency among the patients with Crohn’s disease than among those without this condition (7.1 vs. 8.3 %, respectively). The reason for this finding is unknown. Nevertheless, the adjusted findings pertaining to the association between maternal Crohn’s disease and gestational diabetes were inconclusive in our study (OR 0.9, 95 % CI 0.8–1.0, p-value 0.01). Conversely, a meta-analysis conducted by Tandon et al., which was also presented in an umbrella review by Singh et al., showed an almost three-fold increased risk of gestational diabetes among patients with IBD (OR 2.96, 95 % CI 1.47–5.98) [11], 19]. However, it should be noted that the calculated summary effect estimate was based on three studies, of which only one study found a positive association between IBD and gestational diabetes, and the other two studies found a null association. A later study, not included in the meta-analysis by Tandon and colleagues, found a null association between specifically Crohn’s disease and gestational diabetes (OR 0.74, 95 % CI 0.37–1.46) [15]. Another study has specified that the use of corticosteroids to treat Crohn’s flares during pregnancy was associated with increased risk of gestational diabetes [4]. Recent studies have found that with the advancement of new medications to manage Crohn’s disease, such as biologics, there has been a concomitant decline in corticosteroid use in the management of Crohn’s disease [20], 21]. A study by Ahn et al., which included pregnant individuals with IBD and rheumatic diseases, found a reduced risk of gestational diabetes among subjects who used biologics, although its use was associated with other adverse events [22]. We hypothesize that this changing trend in medicinal management may have impacted the risk of gestational diabetes in patients with Crohn’s disease in our study population.

During the intrapartum, our study demonstrated a higher likelihood of chorioamnionitis and placental abruption in pregnant women with Crohn’s disease. Specifically, we observed a 1.3-fold greater risk of chorioamnionitis in Crohn’s disease patients compared to patients without this disease. As little research has examined the association between Crohn’s disease and chorioamnionitis in pregnancy, further research is warranted. We also observed a greater risk of placental abruption among individuals with Crohn’s disease. Risk factors for placental abruption include preeclampsia, PPROM, chorioamnionitis, and inflammatory states [23], all of which were found at higher rates in patients with Crohn’s disease in our study. Although PPROM was of greater incidence in the Crohn’s group, the association between Crohn’s disease and PPROM was inconclusive. Other studies found a greater risk of PPROM in patients with IBD or, specifically, in Crohn’s disease [12], 14]. Boyd et al. hypothesized that inflammatory cytokines associated with more severe Crohn’s disease activity may play a part in early membrane weakening, a process which normally occurs as the gestation approaches term, and hence, leading to early rupture of the amniotic membrane [14]. PPROM itself predisposes patients to developing chorioamnionitis [24] and likewise, chorioamnionitis can also cause PPROM through the activation of inflammatory mediators [25].

Crohn’s disease was also associated with mode of delivery. Specifically, our study showed that patients with Crohn’s disease were more likely to deliver by cesarean than by spontaneous vaginal delivery (OR 1.6, 95 % CI 1.5–1.7). The observed increased likelihood of cesarean delivery associated with Crohn’s disease was previously demonstrated in a 2007 meta-analysis by Cornish et al. (OR 1.65, 95 % CI 1.19–2.29) [7] and a more recent study [15]. Guidelines do recommend cesarean delivery in the care of Crohn’s disease associated with active perianal disease since vaginal delivery predisposes patients to 4th degree perineal lacerations and exacerbation of perianal disease [2], 26], 27]. In addition, previous intestinal or perianal surgery in patients with Crohn’s disease has also been associated with an increased risk of cesarean delivery [6], 8], 11]. All these situations may have potentially contributed to the observed greater frequency of cesarean sections among Crohn’s cases in our study. Crohn’s disease was also positively associated with instrumental vaginal deliveries (OR 1.3, 95 % CI 1.1–1.4), albeit to a lesser degree than for cesarean deliveries. A study by Payet et al. found that among patients with Crohn’s disease who delivered vaginally, 25 % required instrumental extraction [26] compared to 3.3 % for the general population [28].

Patients with Crohn’s disease had a greater likelihood of experiencing several postpartum complications in our study population. First, our study demonstrated that PPH was more common among pregnancies associated with Crohn’s. Other studies have made a similar conclusion. For instance, the study by Abdul Sultan found an adjusted odds ratio of 1.27 (95 % CI 1.04–1.55) for the association between Crohn’s disease and PPH, which is similar to the results of our study [15]. In addition, many of the other obstetrical complications observed in our study that characterize individuals with Crohn’s, including preeclampsia, placental abruption, instrumental delivery and cesarean sections, also places them at greater risk of experiencing PPH [29]. Health care providers should be aware of this greater risk of PPH in patients with Crohn’s disease and hence, monitor patients appropriately. Second, we observed a two-fold increased risk of postpartum sepsis in Crohn’s cases. To our knowledge no other study has examined the incidence of sepsis in pregnant women with Crohn’s disease. One explanation for this finding is the presence of active Crohn’s disease. It has been shown that 1 in 3 patients with Crohn’s disease experiences postpartum disease flares, which were usually preceded by increased disease activity in the third trimester [6]. Mucosal injury and inflammation during flares predispose patients to fistulas, abscesses, and bowel perforation, which can lead to sepsis [1]. Lastly, our study demonstrated a two-fold increased risk of VTE events. Other studies have described such an association among IBD cases. Namely, a Danish study estimated a relative risk between IBD and VTE of 2.10 (95 % CI 1.33–3.30) [30]. Similarly, a meta-analysis conducted by Kim et al. examining the risk of postpartum VTE among women with IBD in pregnancy, found an overall risk ratio estimate of 2.61 (95 % CI 1.84–3.69) [31]. Inflammation plays an important role in the formation of venous thromboses, putting patients with immune-mediated inflammatory disease such as IBD at increased risk for these events [32]. In fact, IBD has been identified as a risk factor for postpartum venous thromboembolic events by the Society of Obstetricians and Gynecologists of Canada (SOGC). Therefore, health care providers should be vigilant in monitoring Crohn’s patients for VTE in the postpartum and should consider offering thromboprophylaxis [33].

Our study also investigated outcomes for neonates born to mothers with Crohn’s disease. Neonates born to women with Crohn’s disease were more likely to be premature, a finding that has been shown previously (OR 1.42, 95 % CI 1.12–1.80) [15]. The higher incidence of preterm delivery in patients with Crohn’s is likely associated with higher disease activity [5], although information about disease severity, including flaring, was not available in the HCUP-NIS. Furthermore, another study found that prior surgery, including intestinal surgeries, with or without stomas, in patients with Crohn’s disease, predisposed them to increased risk of preterm birth [8]. Preterm delivery may also reflect the higher risk for preeclampsia and PPROM observed in pregnancies associated with Crohn’s disease.

It was observed that the offspring of individuals with Crohn’s disease were at greater risk of congenital abnormalities. This observation is supported by a study by Auger et al. that found a positive association between Crohn’s disease and abdominal wall defects among their offspring, including gastroschisis, omphalocele, and diaphragmatic hernia [34]. This finding is strongly correlated to the presence of disease flares, especially in the first trimester when fetuses are most sensitive to pro-inflammatory cytokines [34]. Researchers have also studied the impact of IBD medications on congenital malformations. For instance, Asacol HD, an aminosalicylate, has been associated with urologic defects in animal studies and should be avoided during pregnancy [4]. The use of methotrexate during pregnancy has been linked with congenital fetal malformations, such as congenital heart defects, cleft palates, hypospadias, congenital diaphragmatic hernias, and craniosynostosis [35]. Otherwise, studies have demonstrated that other medications used to manage Crohn’s disease such as anti-TNF agents, aminosalicylates (except for Asacol HD), thiopurines and corticosteroids are not associated with increased risk of congenital malformations, and are safe to take in pregnancy and while breastfeeding [4], 5]. These medications should be continued in order to prevent disease flares during this period [5].

A higher risk of IUGR was observed in births associated with maternal Crohn’s disease, which has been demonstrated in other studies [2], 4], 6]. Poor gestational weight gain, nutritional deficiencies and active disease appear to contribute to IUGR in pregnancies complicated by Crohn’s disease [2], 36]. As many patients with Crohn’s disease have some level of malnutrition, it is imperative that they be screened for nutritional deficiencies including iron, vitamin D, vitamin B12 and folate, and that replacements be administered if deficiencies are found [2].

Like all studies, this one had some limitations that should be considered. The main limitation is related to the retrospective study design using an administrative database. Like with any study, misclassification of information was possible. However, any data misclassification is most likely non-differential in nature between the Crohn’s and non-Crohn’s groups, which would tend to bias the results towards the null. Of note, the HCUP organization uses rigorous quality control procedures to ensure that data within each discharge report is valid and consistent. We can therefore be confident that the data used in our study were unbiased and of high quality. Another limitation pertinent to the HCUP-NIS database is the lack of certain data variables that would have allowed us to further interpret our study findings. For instance, it was unknown as to whether Crohn’s cases were in remission vs. in an active disease state prior to and/or during pregnancy. The severity of Crohn’s disease and patient parity were also not available within the HCUP-NIS, which are other variables that may impact the findings. Also, we were unable to identify cases treated with medical vs. surgical management, and no information was available regarding the medications used to treat Crohn’s disease.

On the other hand, there were several strengths to this study. The major strength was the vastness of the HCUP-NIS database. The study population consisted of over 4.3 million pregnancies, of which 5,671 of them were to patients with Crohn’s disease. With such large “exposed” and “comparison” groups, we were able to detect associations between Crohn’s disease and various adverse outcomes that may have been otherwise missed if our study sample was smaller. The precision of our estimates was also a reflection of the large study population. Further, the population-wide nature of the NIS data renders the results to be more generalizable to all pregnant women with Crohn’s disease in North America. In addition, although certain variables were not available, as previously discussed, the HCUP-NIS had a plethora of variables available related to patient demographics, lifestyle issues, hospital characteristics, and co-morbidities; hence, we were able to adjust regression models for potential confounders.

In conclusion, our population-based study demonstrates that Crohn’s disease is associated with many adverse maternal and neonatal outcomes in pregnancy. Therefore, it is crucial that these patients receive appropriate follow-up throughout their pregnancy in order to minimize the risk of these complications. A multidisciplinary approach involving the obstetrician and gastroenterologist is ideal when caring for pregnant patients with Crohn’s disease.