Clinical characteristics and risk factors of ovarian reserve decreases in women with Crohn’s disease: a case-control study

CD often sets on in a child-bearing age [1]. It remains a controversy whether CD impairs fertility of women. Studies have shown a lower fertility rate in CD women than in the healthy [15]. In our study, the number of children in the CD group were lower than the control group, and the miscarriage rate was higher, but no significant difference was found. It may be related to several factors. For example, some of the women with Crohn’s disease have had children before diagnosis, some may have a delayed fertilization plan, or some may be unwilling to be fertilized. Besides, the disease activity, medication history and surgery may also influence the fertility rate. Meanwhile, as the fertilization delays, the ovarian reserve declines. In addition, CD may also involve the ovarian ducts and the ovaries, the inflammation of which also damages female fertility [16, 17]. However, changes in fertility rate of patients could not fully represent the true ovarian reserve function. Therefore, it is a clinical urgency to define the association of CD with female fertility, as well as the risk factors of fertile failure [18, 19]. This information can help CD women to design an optimal strategy for pregnancy.

A lower AMH level predicts a poorer ovarian reserve or a weaker response to ovarian stimulation. A study has verified the accuracy of AMH in predicting the ovarian reserve in females with lupus erythematosus, indicating that AMH can be used to evaluate the toxicity in sexual glands. Therefore, AMH was introduced into the present study to judge the ovarian reserve and potential fertility of females with CD.

In this study, the AMH level in CD women was significantly lower than that in the healthy (2.17 ± 2.23μg/L vs 3.95 ± 2.01μg/L; 95%CI [1.34 to 2.21], P < 0.001), so was the incidence of decreased ovarian reserve (AMH ≤ 1.1 μg/L) (42.15% vs 0%, P < 0.001). These findings verify that the ovarian reserve declines in CD women, thus explaining why CD women show a lower fertility rate than the healthy [17, 20].

Ovarian reserve falls as age increases, which is also proven in the present study. In both groups, the AMH levels decreased with age, but their decreasing rate showed no significant between-group difference. Subgroup analysis further demonstrated that age > 30 years (OR, 2.905; 95%CI [1.053-8.531], P = 0.017) was an independent risk factor of decreased ovarian reserve in CD women, a finding that supports the profile of AMH in these patients. Freour [21] et al. reported that AMH levels were significantly lower in CD women under 30 years old, but remained comparable in those over 30 years old. This difference may be attributed to the fact that their study only chose the patients with quiescent disease, and an IVF population with a normal ovarian reserve status as the control group, who can be considered different from the general population. For CD patients who delay their ferritization plan or those who are unwilling to be fertilized, they may worry about the impacts of disease activity, medication history, and surgery on their fertility. Therefore, for CD women aged over 30 years and refusing fertilization, health education should be carried out to alleviate their anxiety about disease heritability and adverse pregnancy outcomes.

During the development of CD, pro-inflammatory factors are released into the blood, then penetrate the bowel wall, and trigger peritoneal inflammation that may further involve the ovaries. This pathology, though having not led to reproductive organic damage, may still decline fertility. Winger has found that the use of TNF-alpha inhibitors and intravenous immunoglobulin (IVIG) significantly improves in vitro fertilization (IVF) outcome in young infertile women withTh1/Th2 cytokine elevation [22]. In a study including 35 CD women, the AMH level is inversely associated with the score of Crohn’s Disease Activity Index (CDAI) [23]. In the present study, we found a consistent result that disease activity (OR, 4.314; 95%CI[1.561-12.910], P = 0.002) is an independent risk factor of decreased ovarian reserve. It has also proven that the risk of adverse pregnancy is higher in the active phase than in the remitting phase [20, 24]. Therefore, accelerating the disease into the remitting phase can reduce the damage to ovarian reserve and increase the odds of successful fertilization.

Some drugs have been suspected to have negative effects on ovarian reserve. In the present study, we reviewed the history of medication in CD women. Multivariate analysis discovered use of thalidomide (OR,12.628; 95%CI[4.351-42.380]; P < 0.001) as an independent risk factor for decreased ovarian reserve, which is consistent with our previous finding that thalidomide exerts negative effects on ovarian reserve [5]. Thalidomide, as a palliative and antiemetic, has been marketized to treat during-pregnancy vomiting, but later withdrawn for its teratogenic effect [25]. In 1960, its immunomodulatory effect was exploited to deal with Behcet’s disease and erythema nodosum [26]. Currently, this drug is selected for refractory CD that fails first-line and second-line treatments [27, 28].

We speculate that thalidomide can repress TGF to inhibit follicular growth and decrease ovarian reserve. TGF-α acts to promote the proliferation and differentiation of germ cells. In vitro studies have exhibited that TGF-α is expressed in ovarian follicles and theca-interstitial cells and regulates follicular growth, degeneration and atresia [29]. In the primordial phase, TGF-α is highly expressed in the oocytes, and as the primordial follicles develop, its expression decreases, indicating that it mainly modulates the development of primordial follicles and oocytes [30].

Thalidomide can suppress the expression of TNF-α, IL-6, IL-8, as well as TGF-α and TGF-β [31]. TGF downregulation further inhibits follicular growth, thus decreasing ovarian reserve. Therefore, CD women, if willing to be fertilized or pregnant, should avoid use of thalidomide. If unavoidable, their ovarian reserve should be closely monitored during medication.

We next assessed the effect of CD duration, extent, behavior and surgery on ovarian reserve. The results showed that they decreased ovarian reserve, but this decrease was not statistically significant. Previous studies have presented that surgery may decline the fertility of patients with inflammatory bowel disease, which can be explained by the fact that pelvic surgery, especially ileum pouch-anal anastomosis (IPPA), may injure reproductive organs, mainly the ovaries and oviducts [32]. But we did not find out the association between surgery and decreased ovarian reserve. We suppose that CD-related abdominal surgery brings less injury to pelvic organs in CD patients. In addition, the low fertility in CD women is not just associated with decreased ovarian reserve, but also post-surgical adhesions [33]. In the present study, we just evaluated the effect of ovarian reserve on fertility.

This study focused on the ovarian reserve function of patients with CD during their reproductive years, to explore the difference in AMH level between them and healthy women at matched age, and to analyze possible risk factors. Despite above-mentioned inspiring results, the present study, as a retrospective study, had certain limitations. First of all, although we recorded the patient’s fertility status, we lacked the data of adverse pregnancy outcome, and did not analyze the fertility status base on disease and drugs. Secondly, the methodology of serum AMH assays is still evolving and not globally standardized. The blood samples from both groups were not frozen during the study period and analyzed together at the end of recruiting for standardized AMH assay and methodology, which may cause some data bias. Finally, we did not compare AMH levels before and after medication. Long-term prospective studies may provide data on CD effect on ovarian reserve function in future. But we believe that our findings in the present study can be used to improve the management of CD women.

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