Inflammatory bowel disease is a risk factor for giving birth preterm even when in apparent disease remission, a University of Gothenburg study shows. If corroborated, the results may eventually affect recommendations for women with ulcerative colitis who tries to conceive.
Inflammatory bowel disease (IBD) is chronic inflammatory disease with a prevalence of approximately 0.5 percent. IBD, which includes ulcerative colitis and Crohn’s disease, and—unlike irritable bowel syndrome (IBS)—causes visible damage to the mucous membrane (mucosa) lining the intestines. Characteristic of IBD is its recurrent tendency for symptoms to flare up (relapse), followed periods of low or no disease activity (remission).
Also, women without obvious IBD activity often have microscopic inflammation in the intestinal mucosa. Until now, however, it has been unknown whether even microscopic inflammation may be associated with risks in pregnancy.
Higher risk of preterm birth
The present study, published in the journal eClinicalMedicine, shows that microscopic inflammation in IBD, especially ulcerative colitis, is linked to an elevated risk of giving birth prematurely.
The results are based on register data on women in Sweden, diagnosed with IBD in 1990–2016, in whom information was available on the microscopic appearance of the intestine shortly before pregnancy. The study included 1,223 children of women with microscopic IBD inflammation of the intestine and 630 children of women with IBD but with microscopically healed intestinal mucosa.
Through register linkages, data were also retrieved from several national health registers, such as the Swedish Medical Birth Register and the Swedish Quality Register for Inflammatory Bowel Desiease (SWIBREG).
Prospect of new treatment targets
The study’s first author and corresponding author is Karl Mårild, associate professor of pediatrics at Sahlgrenska Academy, University of Gothenburg, and senior consultant pediatrician at the Department of Pediatrics, Queen Silvia Children’s Hospital, Gothenburg.
“Even a modestly increased relative risk of preterm birth is important, given that preterm birth can greatly affect the child’s health in both the short and the long term. Preterm birth is still one of the most common causes of death for children under the age of five in Sweden,” Karl Mårild concludes.
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. B
ased 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].
It is therefore indisputably worthwhile to provide a practice-based review on the impact of IBD on fertility, pregnancy, and possible therapeutic strategies, in order to set useful practical guidelines both for physicians and patients. Once pharmaceutical and surgical options are well established, we will then focus our attention on diet and microbiomes, which are still new matters of debate.
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.
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.
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.
reference link :https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9026369/
More information: Karl Mårild et al, Histological remission in inflammatory bowel disease and risk of adverse pregnancy outcomes: A nationwide study, eClinicalMedicine (2022). DOI: 10.1016/j.eclinm.2022.101722
