Inflammatory Bowel Disease and Reproductive Health

Inflammatory Bowel Disease and Reproductive Health: Comparison

Please note this is a comparison between Version 1 by Camilla Ronchetti and Version 2 by Rita Xu.

Despite the fact that knowledge on obstetrical management of Inflammatory Bowel Diseases (IBDs) has greatly improved over the years, many patients still actively avoid pregnancy for fear of adverse maternal or neonatal outcomes, of adverse effects of pregnancy on the disease activity, of eventual IBD inheritance, or of an increased risk of congenital malformations. Indeed, though data prove that fertility is hardly affected by the disease, a reduced birth rate is nevertheless observed in patients with IBD. Misconceptions on the safety of drugs during gestation and breastfeeding may influence patient choice and negatively affect their serenity during pregnancy or lactation.

inflammatory bowel diseases
Crohn’s disease
ulcerative colitis
malabsorption
gut microbiota

1. Introduction

The definition of Inflammatory Bowel Diseases (IBDs) includes two main multifactorial diseases: Crohn’s Disease (CD) and Ulcerative Colitis (UC). Both imply a chronic intermittent intestinal inflammation that can worsen due to an ineffective epithelial barrier function, triggers from the environment, genetic susceptibility, or an impaired immune reaction to the gut microbiota. Based on a recent epidemiological study, the incidence of IBD is increasing worldwide, due to the global evolution of newly industrialized countries developing in a modern, western-like manner [1]. As prevalence exceeds 0.3%, the increasing social burden highlights the need for research into prevention and improvement in health-care systems to manage these complex and costly diseases [2]. Since IBDs have their peak incidence at reproductive age (i.e., from 15 to 40 years of age [3]), and in half of patients, their diagnosis occurs before the age of 35 [4], their relationship with fertility and reproduction is crucial. IBD patients seem to have fewer children than the general population [5] despite similar fertility rates: the reasons for this voluntary childlessness could be anxiety about fertility, potentially adverse pregnancy outcomes, and the fear of vertical transmission of the disease to the offspring. Sexual dysfunction related to psychological comorbidities, like anxiety and depression, and body image misperception may also play an additional role [6].

2. IBD and Fertility

According to the latest European Crohn’s and Colitis Organization (ECCO) guidelines on reproduction, ulcerative colitis without previous pelvic surgery and inactive CD do not impair fertility ^[7]. Conversely, active CD may impair fertility via multiple factors such as fallopian tube inflammation and ovarian reserve lowering ^[6]. Different considerations should be made in UC patients who underwent ileal pouch anal anastomosis (IPAA), which seems to increase the risk of infertility by approximately threefold ^[8][9], mainly due to tubal dysfunction caused by adhesions. On the other hand men with IBD may suffer from infertility due to two iatrogenic pathways: either the use of sulphasalazine producing reversible oligospermia or possible complications of IPAA (e.g., retrograde ejaculation or erectile dysfunction ^[7]). Considering all the above possible factors lead to infertility, patients with IBD may be referred to Assisted Reproductive Technologies (ART) earlier than the general population, even after only six months of attempts ^[6]. It is still not clear if the ART success rate in IBD patients differs from the general population.

2.1. Active CD and Infertility

Although the mechanism of tubal damage by a chronic pelvic inflammatory status can be easily understood, evidence concerning the pathophysiological pathway that may diminish the ovarian reserve is still a matter of debate. The assessment of the ovarian reserve includes both biochemical analysis (i.e., basal Follicle Stimulating Hormone (FSH), estradiol and Anti-Mullerian Hormone (AMH) concentrations) and ultrasound imaging of the ovary for antral follicular count ^[10]. AMH can be measured at any point of the menstrual cycle and it is not an operator-dependent variable, which is the reason why it is commonly recognized as the best tool for an assessment of the ovarian reserve ^[11]. It was hypothesized that pelvic inflammation in CD patients could be related to a reduction of AMH levels; however, this correlation is still not clear. Senates et al. conducted a cross-sectional case–control study including 35 CD patients which revealed that AMH levels of affected women were significantly lower compared to healthy controls (1.02 ± 0.72 ng/mL vs. 1.89 ± 1.80 ng/mL, p = 0.009). Furthermore, among CD patients, those with active disease had lower levels compared to patients in remission. It is questionable whether this finding is applicable to the general affected population, or to a selected sub population, and different cohort studies tried to identify an age-related threshold. Notably, Frèour et al. found a significant reduction of AMH, but only in CD patients over 30 years of age, and showed an association between colonic localization of the disease and a lower ovarian reserve. On the other hand, according to a more recent study, the threshold age could be identified at 25 years ^[12]. Despite the evidence reported so far, a case control study conducted on 50 CD patients and published in 2021 shows that a decrease in AMH levels is detectable only in patients older than 30 years and with a disease duration equal or superior to 5 years ^[13]. In conclusion, it appears that an impact on ovarian reserve is evident, but only in some specific circumstances, such as long lasting and active disease; thus in order to reassure young women affected by CD, further studies or a meta-analysis is needed.

2.2. IPAA: Surgical Approaches and Effects

Almost 20 to 30% of patients with UC will necessitate colectomy despite medical therapy ^[14]. IPAA is the most used surgical treatment for these patients and it may also be required in the case of indeterminate colitis (IC) or CD ^[15][16]. IPAA can be successfully performed using a traditional laparotomic approach or by minimal invasive laparoscopy: ECCO guidelines on reproduction suggest the use of a laparoscopic approach. Indeed Beyer-Berjot et al. found a lower infertility rate in 63 patients who underwent laparoscopic IPAA compared with the infertility rate reported in previous studies, which were conducted on patients who underwent laparotomy (27% vs. 63%). Another study carried out on 160 women, through a questionnaire addressing medical and fertility history, observed a higher pregnancy rate after laparoscopic IPAA; however, a recent Cochrane review criticizes the latter study because of the high overall risk of bias and imprecise estimates ^[17].

2.3. IBD and ART Efficacy

From a nationwide Danish cohort study, it emerged that patients with UC and CD have a lower chance of live birth per cycle compared to infertile women without IBD. Notably, CD patients who had previous surgery had the worst prognosis, whereas IPAA appears not to have a negative impact ^[18]. According to the same group, prescribing corticosteroids in IBD patients before embryo transfer would improve their chances of a live born child ^[19]. Other studies found a comparable live birth rate between IBD patients and infertility controls ^[20][21]. It should be noted that these studies included a limited number of patients compared to the nationwide Danish cohort, and for this reason, in researchers opinion, in the absence of other large-scale studies, a worse ART prognosis should be suspected for IBD patients. Another debated matter is whether ART pregnancy outcomes differ in IBD patients. Norgard et al. reported a higher risk of preterm birth in UC patients, but the risk vanished when only singleton pregnancies were included ^[18]. Conversely, a recent study found a comparable pregnancy outcome between IBD patients, other infertile women undergoing ART, and patients with IBD with spontaneous conception ^[22].

3. IBD and Pregnancy

During pregnancy, many physiological changes occur in order to allow implantation and fetal growth. This is the reason why pregnancy represents a period of intense endocrine fluctuation and immune modulation ^[23]. In previous years, it was thought that during pregnancy there was a rise in maternal immune tolerance; however, it is now emerging that immunological states fluctuate during these months to meet various needs. For example, during the first stage of pregnancy (i.e., implantation), a proinflammatory Th1 state is predominant. Later, a tolerogenic Th2 response prevails until shortly before delivery when a new Th1 polarization occurs ^[24]. It is unclear if these placental immunological shifts are also associated with peripheral changes in the immune system response, which may, for example, affect disease activity in the intestinal tract. Studies published so far reported conflicting results ^[25][26][27]. It is well known that some autoimmune diseases improve during pregnancy (known as “the honeymoon period”), suggesting a potential different immune response that is also in peripheral sites ^[24][25][28]. More specifically, there would be an improvement of Th1-driven diseases ^[29]. CD is known to be a Th1/Th17 disease, whereas UC is more Th2/Th17 driven, and this would explain why the two diseases behave differently during pregnancy ^[30]. A recent study comparing IBD and non-IBD pregnant women ^[31] showed an improvement in the modulation of cytokine patterns during pregnancy in the first group. Indeed, IL-6, IL-8, IL-12, IL-17, and TNF-a proinflammatory cytokines significantly decreased after conception. During pregnancy itself, serum cytokine levels in patients with IBD subsequently remained relatively stable over the 40 weeks of gestation. On the other hand, Kim et al. ^[32] showed that a surrogate marker of bowel inflammation (i.e., Fecal Calprotectin (FC)), had higher levels in pregnant patients affected by IBD compared with controls, but it gradually decreased in the case-group. The opposite trend was observed in the control-group, demonstrating a slight gradual increase in their FC inflammation marker levels during gestation. As for babies born to mothers with IBD, the same study showed significantly higher FC levels compared with control babies from 2 to 36 months of age, after adjusting for sex, breastfeeding or not, antibiotic use, and delivery mode. The authors speculated that those babies may have been less able to achieve a balanced mucosal immunity or to establish an optimal intestinal barrier function. This fact is probably explained by a lower immune tolerance to commensal bacteria in babies born to IBD mothers, potentially leading to chronic mild intestinal inflammation due to a modification in the intestinal microbiota.

Medical Therapy

Safety data are available for most medications used in IBD so that their use is highly recommended to keep the disease in remission status. Aminosalicylates (mesalazine, sulfasalazine, balsalazide, olsalazide), showed no increased obstetrical risk ^[33]. Formulations without dibutylphthalate are preferable in order to avoid any eventual risk of teratogenicity, even if this effect has not been proved in humans. The recommendations are to maintain pre-pregnancy doses and, if using sulfasalazine, to supplement with folate (>2 mg/day). Corticosteroids, in view of their rapid conversion into less active metabolites, reach fetal blood in low and harmless concentrations ^[34]. Due to some concerns about teratogenic effects, such as cleft lip or palate, though it has not been confirmed ^[35], corticosteroids are recommended only in case of active flares. In accordance with ECCO guidelines ^[7], the antibiotics metronidazole and ciprofloxacin should be prescribed only after the first trimester, due to the same risk of eventual orofacial malformations as corticosteroids ^[36]. As for immunomodulators, thiopurines (azathioprine or 6- mercaptopurine) are low-risk therapies in pregnancy ^[37], even if they showed a slight increase in preterm deliveries ^[38]. They are usually recommended as monotherapy in pregnant patients. In contrast to the above, methotrexate is a high-risk medication due to its strong teratogenic and abortive effects, so it must be discontinued at least 3 months before conception ^[39]. Lastly, in the immunomodulators group, cyclosporine should be used only as a rescue therapy for acute severe steroid-refractory UC, since no data on pregnant IBD women treated with cyclosporine are available ^[40]. Some anti-TNFα agents, such as infliximab, adalimumab and golimumab, cross the placenta, while certolizumab pegol does not. Even if they are considered safe in pregnancy, ECCO guidelines suggest stopping anti-TNF therapy around the 24th week of gestation to minimize transplacental transfer ^[7] if the patient’s case permits, because it is known that an early discontinuation may lead to a relapse of the IBD. Nowadays, therapies with monoclonal antibodies have been routinely introduced to control IBD evolution. Unfortunately, during pregnancy, they should be avoided due to their transmission across the placenta and only a few may still be considered on a personalized decision basis. Among the latter, vedolizumab, the human IgG1 antibody against α4β7 integrin, and ustekinumab, the human IgG1 antibody that inhibits the p40 subunit of IL-12 and IL-23, are the only ones that can eventually be prescribed during gestation, but only as a last resort due to the lack of data from randomized controlled trials ^[40]. On the other hand, tofacitinib, the janus kinases 1 and 3 inhibitors, filgotinib and upadacitinib, both janus kinase 1 inhibitors, and ozanimod, the sphingosine 1-phosphate receptor modulator, are contraindicated due to the complete lack of data on pregnant women. Drug safety and recommendations in pregnancy are listed in

2. IBD and Fertility

On the other hand men with IBD may suffer from infertility due to two iatrogenic pathways: either the use of sulphasalazine producing reversible oligospermia or possible complications of IPAA (e.g., retrograde ejaculation or erectile dysfunction [7]).

Considering all the above possible factors lead to infertility, patients with IBD may be referred to Assisted Reproductive Technologies (ART) earlier than the general population, even after only six months of attempts [6]. It is still not clear if the ART success rate in IBD patients differs from the general population.

2.1. Active CD and Infertility

It was hypothesized that pelvic inflammation in CD patients could be related to a reduction of AMH levels; however, this correlation is still not clear. Senates et al. conducted a cross-sectional case–control study including 35 CD patients which revealed that AMH levels of affected women were significantly lower compared to healthy controls (1.02 ± 0.72 ng/mL vs. 1.89 ± 1.80 ng/mL, p = 0.009). Furthermore, among CD patients, those with active disease had lower levels compared to patients in remission. It is questionable whether this finding is applicable to the general affected population, or to a selected sub population, and different cohort studies tried to identify an age-related threshold. Notably, Frèour et al. found a significant reduction of AMH, but only in CD patients over 30 years of age, and showed an association between colonic localization of the disease and a lower ovarian reserve. On the other hand, according to a more recent study, the threshold age could be identified at 25 years [12]. Despite the evidence reported so far, a case control study conducted on 50 CD patients and published in 2021 shows that a decrease in AMH levels is detectable only in patients older than 30 years and with a disease duration equal or superior to 5 years [13].

In conclusion, it appears that an impact on ovarian reserve is evident, but only in some specific circumstances, such as long lasting and active disease; thus in order to reassure young women affected by CD, further studies or a meta-analysis is needed.

2.2. IPAA: Surgical Approaches and Effects

Almost 20 to 30% of patients with UC will necessitate colectomy despite medical therapy [14]. IPAA is the most used surgical treatment for these patients and it may also be required in the case of indeterminate colitis (IC) or CD [15,16].

IPAA can be successfully performed using a traditional laparotomic approach or by minimal invasive laparoscopy: ECCO guidelines on reproduction suggest the use of a laparoscopic approach. Indeed Beyer-Berjot et al. found a lower infertility rate in 63 patients who underwent laparoscopic IPAA compared with the infertility rate reported in previous studies, which were conducted on patients who underwent laparotomy (27% vs. 63%). Another study carried out on 160 women, through a questionnaire addressing medical and fertility history, observed a higher pregnancy rate after laparoscopic IPAA; however, a recent Cochrane review criticizes the latter study because of the high overall risk of bias and imprecise estimates [17].

2.3. IBD and ART Efficacy

From a nationwide Danish cohort study, it emerged that patients with UC and CD have a lower chance of live birth per cycle compared to infertile women without IBD. Notably, CD patients who had previous surgery had the worst prognosis, whereas IPAA appears not to have a negative impact [18]. According to the same group, prescribing corticosteroids in IBD patients before embryo transfer would improve their chances of a live born child [19]. Other studies found a comparable live birth rate between IBD patients and infertility controls [20,21]. It should be noted that these studies included a limited number of patients compared to the nationwide Danish cohort, and for this reason, in our opinion, in the absence of other large-scale studies, a worse ART prognosis should be suspected for IBD patients. Another debated matter is whether ART pregnancy outcomes differ in IBD patients. Norgard et al. reported a higher risk of preterm birth in UC patients, but the risk vanished when only singleton pregnancies were included [18]. Conversely, a recent study found a comparable pregnancy outcome between IBD patients, other infertile women undergoing ART, and patients with IBD with spontaneous conception [22].

3. IBD and Pregnancy

It is unclear if these placental immunological shifts are also associated with peripheral changes in the immune system response, which may, for example, affect disease activity in the intestinal tract. Studies published so far reported conflicting results [25,26,27]. It is well known that some autoimmune diseases improve during pregnancy (known as “the honeymoon period”), suggesting a potential different immune response that is also in peripheral sites [24,25,28]. More specifically, there would be an improvement of Th1-driven diseases [29]. CD is known to be a Th1/Th17 disease, whereas UC is more Th2/Th17 driven, and this would explain why the two diseases behave differently during pregnancy [30].

A recent study comparing IBD and non-IBD pregnant women [31] showed an improvement in the modulation of cytokine patterns during pregnancy in the first group. Indeed, IL-6, IL-8, IL-12, IL-17, and TNF-a proinflammatory cytokines significantly decreased after conception. During pregnancy itself, serum cytokine levels in patients with IBD subsequently remained relatively stable over the 40 weeks of gestation. On the other hand, Kim et al. [32] showed that a surrogate marker of bowel inflammation (i.e., Fecal Calprotectin (FC)), had higher levels in pregnant patients affected by IBD compared with controls, but it gradually decreased in the case-group. The opposite trend was observed in the control-group, demonstrating a slight gradual increase in their FC inflammation marker levels during gestation. As for babies born to mothers with IBD, the same study showed significantly higher FC levels compared with control babies from 2 to 36 months of age, after adjusting for sex, breastfeeding or not, antibiotic use, and delivery mode. The authors speculated that those babies may have been less able to achieve a balanced mucosal immunity or to establish an optimal intestinal barrier function. This fact is probably explained by a lower immune tolerance to commensal bacteria in babies born to IBD mothers, potentially leading to chronic mild intestinal inflammation due to a modification in the intestinal microbiota.

Medical Therapy

Safety data are available for most medications used in IBD so that their use is highly recommended to keep the disease in remission status.

Aminosalicylates (mesalazine, sulfasalazine, balsalazide, olsalazide), showed no increased obstetrical risk [33]. Formulations without dibutylphthalate are preferable in order to avoid any eventual risk of teratogenicity, even if this effect has not been proved in humans. The recommendations are to maintain pre-pregnancy doses and, if using sulfasalazine, to supplement with folate (>2 mg/day).

Corticosteroids, in view of their rapid conversion into less active metabolites, reach fetal blood in low and harmless concentrations [34]. Due to some concerns about teratogenic effects, such as cleft lip or palate, though it has not been confirmed [35], corticosteroids are recommended only in case of active flares.

In accordance with ECCO guidelines [7], the antibiotics metronidazole and ciprofloxacin should be prescribed only after the first trimester, due to the same risk of eventual orofacial malformations as corticosteroids [36].

As for immunomodulators, thiopurines (azathioprine or 6- mercaptopurine) are low-risk therapies in pregnancy [37], even if they showed a slight increase in preterm deliveries [38]. They are usually recommended as monotherapy in pregnant patients. In contrast to the above, methotrexate is a high-risk medication due to its strong teratogenic and abortive effects, so it must be discontinued at least 3 months before conception [39]. Lastly, in the immunomodulators group, cyclosporine should be used only as a rescue therapy for acute severe steroid-refractory UC, since no data on pregnant IBD women treated with cyclosporine are available [40].

Some anti-TNFα agents, such as infliximab, adalimumab and golimumab, cross the placenta, while certolizumab pegol does not. Even if they are considered safe in pregnancy, ECCO guidelines suggest stopping anti-TNF therapy around the 24th week of gestation to minimize transplacental transfer [7] if the patient’s case permits, because it is known that an early discontinuation may lead to a relapse of the IBD.

Nowadays, therapies with monoclonal antibodies have been routinely introduced to control IBD evolution. Unfortunately, during pregnancy, they should be avoided due to their transmission across the placenta and only a few may still be considered on a personalized decision basis. Among the latter, vedolizumab, the human IgG1 antibody against α4β7 integrin, and ustekinumab, the human IgG1 antibody that inhibits the p40 subunit of IL-12 and IL-23, are the only ones that can eventually be prescribed during gestation, but only as a last resort due to the lack of data from randomized controlled trials [40]. On the other hand, tofacitinib, the janus kinases 1 and 3 inhibitors, filgotinib and upadacitinib, both janus kinase 1 inhibitors, and ozanimod, the sphingosine 1-phosphate receptor modulator, are contraindicated due to the complete lack of data on pregnant women.

Drug safety and recommendations in pregnancy are listed in

Table 1

Table 1.

Drug safety and recommendations in pregnancy and breastfeeding.

Medical Treatment	Safety and Recommendations in Pregnancy	Safety and Recommendations in Breastfeeding
Aminosalicylates (mesalazine, sulfasalazine, balsalazide, olsalazide)	No increased obstetrical risk. Always recommended (formulation without dibutylphthalate are preferable and, if sulfasalazine is used, suggestion to supplement with folate).	Safe and must be discontinued only in case of neonatal severe bloody diarrhea.
Corticosteroids	Concerns about teratogenic effects, such as cleft lip or palate. Recommended only in case of active flares.	Recommended to breastfeed babies 4 h after taking corticosteroids.
Antibiotics (metronidazole and ciprofloxacin)	Concerns about teratogenic effects, such as cleft lip or palate. Recommended only after the first trimester of gestation.	Recommended to breastfeed babies 12–24 h after metronidazole and 48 h after ciprofloxacin intake. A short-term antibiotic regimen must be preferred.
Thiopurines (azathioprine or 6- mercaptopurine)	Slight increase in preterm deliveries. Recommended as monotherapy.	Advisable, no a higher risk of physical or developmental anomalies in newborns.
Methotrexate	Strong teratogenic and abortive effects. Never recommended in pregnancy.	Contraindicated.
Cyclosporine	No data on pregnant women available, only recommended as rescue therapy for acute severe steroid-refractory ulcerative colitis.	Contraindicated.
Anti-TNFα agents (infliximab, adalimumab, golimumab and certolizumab)	Evidence of crossing the placenta, except of certolizumab. Recommended stopping around the 24th week of gestation, if the case permits.	Safe due to their transmission in breast milk only in small amounts and deactivation by neonatal digestion enzymes.
Vedolizumab and ustekinumab	Should be avoided due to their transmission across the placenta and partial lack of data in pregnancy. Can eventually be prescribed only as an ultimate alternative.	Safety data are still missing, so their use is not recommended.
Tofacitinib, filgotinib and upadacitinib	Contraindicated due to the complete lack of data in pregnancy.	Safety data are still missing, so their use is not recommended.