Inflammatory Bowel Disease and Adverse Pregnancy Outcomes

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1		Antonio M Caballero-Mateos	--	2987	2024-01-04 11:39:21	\|
2	Reference format revised.	Lindsay Dong	Meta information modification	2987	2024-01-05 06:35:32	\|

This entry is adapted from the peer-reviewed paper 10.3390/jcm12196192

Inflammatory Bowel Disease (IBD) presents distinct challenges during pregnancy due to its influence on maternal health and pregnancy outcomes. IBD can affect women of reproductive age aspiring for a safe pregnancy. Effective disease control before conception is vital to improve fertility and ensure a healthy pregnancy, thus reducing potential flare-ups. Continuation of IBD treatments during pregnancy and breastfeeding is generally viewed as safe, emphasizing the importance of thorough disease management for both mother and child.

:inflammatory bowel disease pregnancy newborn

1. Background

Inflammatory Bowel Disease (IBD) is a long-term condition causing inflammation in the digestive tract. This primarily includes ulcerative colitis (UC) and Crohn’s disease (CD) ^[1]. The etiology of IBD is multifactorial, encompassing genetic predispositions, aberrant immune responses, alterations in the intestinal microbiota, and environmental influences. Although genetic factors are significant, currently identified genes provide only a partial understanding of disease pathogenesis ^[2]. Additionally, disruptions in immune regulation and changes in the gut microbiome are also pivotal in the progression of IBD ^[3]^[4].

For IBD patients desiring children, fertility is a significant concern. Most studies show that infertility rates in patients with quiescent IBD are similar to those of the general population ^[5]^[6]^[7]. However, active disease has been observed to decrease fertility in both genders ^[8]. During flare-ups, male IBD patients may experience significantly affected sexual function due to depression, which may interfere with testosterone secretion and spermatogenesis, as well as erectile dysfunction and reduced libido ^[9]^[10]^[11]^[12]. Regarding fertility in female IBD patients, pregnancy rates have been found to be slightly lower compared to the general population, especially in patients with CD and those who have undergone abdominal surgeries ^[12]^[13]. However, women with UC who have not undergone surgery have fertility rates similar to the general population ^[5]^[14]. During disease flare-ups, fertility may decrease further, with a live birth rate of 35.6 per 1000 person-years, regardless of the type of IBD, whereas other population studies place it at 49.3 per 1000 person-years ^[5]^[15].

Previous surgeries, such as ileo-rectal anastomosis, have been observed to be associated with a significant reduction in fertility rates in UC patients due to the formation of adhesions that could block the fallopian tubes ^[7]^[16]. In CD patients, previous abdominal surgeries can also affect fertility ^[17], although evidence is limited ^[18].

Family planning is a key aspect for IBD patients. Although fertility itself is not usually affected in these patients, there is a noted decrease in birth rates, which could be due to voluntary decisions by these individuals ^[5]^[11]. A reduced interest in having children has been observed, reaching up to 17–37% of patients ^[19]^[20]. This decision appears to be associated with various factors, such as fear of a disease relapse, concerns about their medication or the progression of the disease, fear of pregnancy complications, concerns about disease transmission, being over 35, unemployment, being single, or lack of medical counseling ^[20]^[21]^[22].

In summary, fertility in IBD patients can be affected by disease activity, abdominal surgeries, and other factors. During flare-ups, both men and women may experience a decrease in sexual function and fertility. A lower willingness to have children has been observed in IBD patients, and previous abdominal surgeries may affect fertility in some cases. Proper disease management and counseling before conception are important for improving reproductive outcomes in these patients. Therefore, it’s crucial to provide them with accurate information and medical advice about fertility and pregnancy. This information could help patients make informed decisions about childbearing and understand how IBD might affect these aspects of their lives.

2. Effect of IBD on Pregnancy

The placenta is pivotal in fetal development, managing metabolism, waste disposal, and nutrient exchange through diverse cell types. Placental formation impacts cytokine changes relevant to IBD, with placental macrophages expressing TNF and IL-17—key IBD therapeutic targets ^[23]^[24]. Elevated TNF levels in the placenta during pregnancy affect hormone synthesis, placental structure, and embryonic development ^[25]. Additionally, the placenta’s role in mediating maternal-fetal interactions may have implications for the course of IBD, highlighting its significance in understanding this complex disease context.

The disease’s activity at the time of conception is the primary factor associated with complications such as premature birth, low birth weight, and being small for gestational age ^[26]^[27]. Recent research indicates that the degree of disease activity might play a crucial role in identifying those at risk for adverse outcomes or complications ^[28]^[29]. Specifically, only patients who experienced active disease or flare-ups during pregnancy showed higher complication rates ^[30]^[31]. Additionally, it’s well-understood that managing IBD activity directly impacts patients’ nutritional status. This impact is evident in pregnancy, where higher complication rates are observed in both the mother and the newborn. In this regard, one study found that weight gain during pregnancy in women with IBD was an indicator of complications during the pregnancy itself ^[32].

3. Effect of Pregnancy on IBD

Pregnancy generally has a positive influence on the course of IBD. One study found a 30% risk of disease reactivation during pregnancy, numbers that align with those of non-pregnant women ^[31]. Yet, more optimistic studies reported a decreased risk of re-lapse compared to the years preceding pregnancy ^[33]. In this context, a critical determining factor was the state of the disease at the time of conception. Patients who become pregnant during an active disease phase, or shortly after overcoming it, face a higher risk of a flare-up during pregnancy and the postpartum period, compared to those in remission ^[13]^[34]. A 2013 meta-analysis reinforced the notion that active UC (RR 2.0, 95% CI 1.5–3) or active CD (RR 2.0, 95% CI 1.2–3.4) at conception is associated with a two-fold in-crease in flare-ups compared to the disease in remission ^[35]. Because of this, the European Crohn’s and Colitis Organization (ECCO) advises patients to maintain a remission period of more than 6 months before trying to conceive ^[14].

Finally, it’s essential to underscore that if IBD first manifests during pregnancy in a previously healthy patient, this onset is not linked to a worse prognosis for IBD or for the pregnancy, compared to patients diagnosed before conception ^[36].

4. Monitoring and Management of IBD during Pregnancy

IBD Activity Assessment and Biomarkers: During pregnancy, physiological adaptations can alter the serum biomarkers typically used to evaluate IBD activity. For in-stance, hemoglobin and albumin levels tend to decrease, while C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) tend to increase ^[37]^[38]. Hence, these biomarkers are not viewed as reliable indicators of disease activity during pregnancy. However, fecal calprotectin (FCP), a protein released in response to intestinal inflammation, appears to be a dependable biomarker during pregnancy. Its levels have shown a strong correlation with disease activity, and it can even be suggested as a predictor of symptom onset ^[39]^[40]^[41].
Imaging Techniques and Endoscopy: Intestinal ultrasound has proven useful in determining the activity, extent, and complications of IBD without the need for prior bowel preparation or invasive procedures. Various studies have assessed its feasibility and accuracy in pregnant women with IBD, concluding that it’s an appropriate, non-invasive tool for patient monitoring ^[42]^[43]. Magnetic resonance imaging (MRI) can be used without gadolinium, but its utility might be limited in the last trimester due to the interference of fetal structures ^[44]. Endoscopy during pregnancy poses certain risks, such as an increased chance of premature birth and low birth weight for gestational age ^[45]. When possible, endoscopy should be avoided, especially during the first trimester. If necessary, rectosigmoidoscopy is preferred over full colonoscopy, and it should be performed without sedation and without bowel preparation ^[44].
Thromboembolic Risk: Both pregnancy and IBD, especially in its active phase, raise the risk of thromboembolic events (TEV). Thus, it’s essential to assess thromboembolic risk factors before conception and during pregnancy. Starting thromboprophylaxis with low-molecular-weight heparin is recommended for patients admitted due to an IBD flare-up or those undergoing cesarean delivery ^[46]. Additionally, for patients with a history of TEV or other risk factors, prophylactic anticoagulation should be extended for 3–6 weeks postpartum ^[47].
Surgery in Pregnant Women with IBD: Indications for surgery in pregnant women with IBD are evaluated similarly as in non-pregnant patients: refractory ulcerative colitis, fulminant colitis, toxic megacolon, or persistent bleeding in UC, and perforation, obstruction, perianal abscess, refractory bleeding, and fulminant colitis in CD ^[48]. It’s advised to timely perform surgery for appropriate indications instead of waiting for emergent reasons ^[49].

5. Treatments and Pregnancy

5.1. Steroids

Steroids, often used to treat IBD flare-ups, have been the subject of numerous studies regarding their effects during pregnancy, yielding varied results. Steroids can cross the placenta but are rapidly metabolized into less active metabolites, reducing fetal exposure ^[48]^[50]^[51]^[52]^[53]. However, they have been linked to potential adverse effects for both the mother and the fetus, including premature birth, low birth weight, gestational diabetes, and intrauterine infections ^[54]^[55]^[56]. The PIANO (Pregnancy in IBD and Neonatal Outcomes) registry found an increased risk of premature birth, low birth weight, and admission to the neonatal intensive care unit ^[48].

5.2. Aminosalicylates (5-ASA)

Aminosalicylates (5-ASA), including mesalamine and sulfasalazine, are generally considered low-risk for use during pregnancy ^[51]. A meta-analysis demonstrated that the use of 5-ASA compounds during pregnancy is not associated with an increased risk of miscarriage, premature birth, mortality, or congenital anomalies ^[57]. Mesalamine has limited transplacental transfer and achieves low levels in fetal circulation ^[58]. Sulfasalazine can affect the absorption of folic acid, so during pregnancy, it should be associated with folic acid supplementation to be safe (>2 mg/day) ^[59]. On the other hand, in men, sulfasalazine can reduce sperm motility and count and increase abnormal sperm forms ^[60]^[61]. Much less frequently, and through unknown mechanisms, the same effect has been observed with mesalamine ^[62], so it is recommended for men to stop taking sulfasalazine or switch to mesalamine three months before conception ^[61]. Finally, it’s important to note that the use of mesalamine products is safe during pregnancy despite their presence in umbilical cord blood.

5.3. Immunomodulators

Thiopurine drugs, such as 6-mercaptopurine and its prodrug azathioprine, are detected in fetal blood, reaching levels of up to 5% of the maternal medication ^[63]. Older studies suggested that the use of thiopurines during pregnancy led to congenital anomalies, perinatal mortality, low birth weight, infants small for their gestational age, and premature births ^[64]^[65]. However, more recent studies and those conducted on transplant patients indicate that the use of thiopurines does not pose an increased risk to fetuses and is safe for continued use in pregnant patients ^[66]^[67]. An interim analysis of the PIANO registry confirmed that thiopurine use does not lead to worse fetal outcomes ^[68].

Methotrexate is an inhibitor of the enzyme dihydrofolate reductase (DHFR), which plays a crucial role in the metabolism of folic acid, which in turn regulates the synthesis of purines and pyrimidines essential for DNA and RNA synthesis ^[69]. It is currently a drug categorized in pregnancy category X and must be discontinued ^[70]. This drug has a significant teratogenic effect and has been associated with a high risk of multiple congenital anomalies and severe fetal development complications, including neural tube defects, developmental delay, ileal perforation, abnormal facial features, skeletal deformities, and miscarriages ^[70]^[71].

5.4. Anti-TNFa

Anti-TNF drugs, including infliximab, adalimumab, and golimumab, are classified as low-risk in relation to their use during pregnancy for the treatment of IBD ^[29]^[72]. These drugs have the ability to cross the placental barrier during the second and third trimesters of pregnancy due to their monoclonal antibody IgG1 structure, without interfering in the organogenesis that occurs during the first trimester ^[73]^[74].

The safety of these medications during pregnancy has been studied in-depth. Nu-merous meta-analyses, large-scale retrospective and prospective studies have not shown adverse effects in pregnant women or their offspring with continuous use of anti-TNF medications.

The PIANO study, which included 1490 full-term pregnancies, provided solid data on the safety of anti-TNF therapies in pregnant women with IBD ^[29]. The study’s results showed that the use of anti-TNF medications did not increase the risk of pregnancy com-plications compared to thiopurines and with the absence of treatment for IBD. Additionally, this study found that the use of thiopurines or anti-TNF was associated with fewer neonatal complications. This finding underscores the importance of maintaining IBD remission during pregnancy.

5.5. Anti-Integrins: Vedolizumab

Vedolizumab is a humanized monoclonal IgG-type antibody that inhibits the binding of α4β7 integrin to the vascular cell adhesion molecule in the mucosa ^[75]. Like other monoclonal antibodies, it can cross the placental barrier through Fc receptors. Although the information on vedolizumab during pregnancy is more limited compared to anti-TNF drugs. Several studies and retrospective analyses have shown encouraging results. Vedolizumab use has been classified as low risk for use during pregnancy in the treatment of IBD. Retrospective analyses in Europe, including the CONCEIVE study (73 patients) and a French study (44 patients), showed no increase in adverse events in patients who received vedolizumab compared to controls on anti-TNF therapy or no therapy ^[76]^[77].

5.6. Anti Il 12/23 and Anti Il 23: Ustekinumab and Risankizumab

Ustekinumab is a human monoclonal antibody that inhibits the activity of the cytokines IL-12 and IL-23, binding to the p40 subunit common to both. Although it has not been extensively studied in pregnant women with IBD, existing data suggest it may be safe. The placental transfer pattern of ustekinumab seems similar to that of anti-TNF drugs, with levels in the umbilical cord blood exceeding those in the maternal blood, but without correlation with the interval between the last dose and childbirth ^[78].

Regarding risankizumab, another monoclonal antibody that inhibits the p19 subunit of IL-23, data are even more limited. Although its safety profile is expected to be similar to other biologicals due to its monoclonal antibody structure, a firm recommendation on its safety during pregnancy cannot yet be made ^[79].

Through various cases, it has been observed that children are born healthy after their mothers were treated with ustekinumab during pregnancy. However, the decision to continue or discontinue treatment during pregnancy must be taken after a careful evaluation of the benefits and risks to the mother and fetus.

5.7. Small Molecules: JAK and S1P Inhibitors

Tofacitinib, filgotinib, and upadacitinib are inhibitors of Janus kinase (JAK), a type of enzyme involved in various cellular processes. Tofacitinib acts on JAK1 and JAK3, while the latter two are more specific for JAK1. Owing to their small size, they can cross the placenta during the first trimester. Based on animal studies, these drugs aren’t currently recommended during pregnancy. Tofacitinib has been observed to cause teratogenicity in rabbits at levels much higher than the doses used for CU ^[80]. However, two retrospective reviews of tofacitinib exposure during pregnancy showed no significant adverse outcomes among 11 maternal exposures and 14 paternal exposures in populations with CU and rheumatic diseases ^[81], and among 47 women with rheumatoid arthritis and psoriasis, 25 healthy newborns, seven spontaneous abortions, eight medical terminations, and only one congenital malformation: pulmonary valve stenosis, were reported ^[82]. These results seem consistent with background risks in the general population.

In terms of men, it’s been shown that tofacitinib doesn’t affect male fertility, sperm quality, sperm motility, or sperm concentration in male rats ^[80]. Pregnancy outcomes identified from randomized controlled trials of tofacitinib, non-interventional post-approval studies, and spontaneous adverse event reporting did not report fetal deaths or congenital malformations in cases of paternal tofacitinib exposure ^[81]^[82]. In summary, while some animal studies raise concerns, human data on Tofacitinib’s impact during pregnancy remains limited, emphasizing the need for caution.

6. Childbirth

Decisions surrounding childbirth for patients with IBD should be steered by a thorough evaluation of each patient’s unique situation, with an emphasis on both mother and child’s safety. The type of IBD should not exclusively influence the choice of childbirth method. Current clinical guidelines recommend that IBD patients continue their treatments during childbirth unless there’s a complication, like an infection during the peripartum period, prompting a temporary cessation of biologic therapy ^[83].

It’s noteworthy that cesarean section rates are higher among IBD patients compared to the general population ^[13]^[84]. This trend is more pronounced in CD patients than in UC ^[85]. However, vaginal delivery isn’t linked with an increased incidence of perineal tears in IBD patients, nor does it predispose them to the onset of perianal disease if they were previously unaffected ^[86]. It’s crucial to highlight that cesarean sections come with their set of complications.

In some scenarios, a cesarean might be advisable, such as for women with active perianal disease or a previous rectovaginal fistula ^[83]. The presence of an ileo-pouch anal anastomosis (IPAA) can introduce added complexities to the childbirth method decision. Some studies have noted a deterioration in symptoms in CD patients with active perianal disease following vaginal delivery and a decline in the reservoir function in cases of complicated vaginal childbirth ^[86]. These findings, however, are disputed ^[83], and the childbirth method choice for IPAA patients should be made judiciously by a multidisciplinary team consisting of obstetricians, surgeons, and gastroenterologists ^[83].

7. Breastfeeding

Breastfeeding offers potential advantages over formula feeding. It provides a complete nutritional source and contains immunoglobulins that transfer from the mother to the child, aiding the development of the child’s immune system. Pediatric societies advocate for exclusive breastfeeding for at least the initial six months post-birth and suggest continuing it alongside other foods for at least another six months ^[87]. However, when choosing to breastfeed for its health benefits to the child, IBD patients also undertake the risk of exposing the infant to medications used for their disease management. In the post-partum period, between 45% and 95% of women initiate breastfeeding ^[88].

Most medications used for IBD are considered breastfeeding-compatible. Even though traces have been found in milk, it doesn’t indicate a biological effect on the new-born. As previously mentioned, methotrexate is contraindicated during breastfeeding ^[89]^[90]. Mesalamine and sulfasalamine are excreted in breast milk in minimal amounts, making them compatible with breastfeeding ^[91]. Prednisone and prednisolone are considered breastfeeding-friendly, but a gap of about 4 h is recommended between drug intake and breastfeeding to reduce drug concentration in the blood ^[92]. For budesonide, this window isn’t necessary since its levels in milk are nearly undetectable. Despite initial reservations about infant immunosuppression with mothers on thiopurine treatment, long-term prospective studies haven’t found evidence of such effects, leading to these drugs being considered safe with continued use ^[93]. Cyclosporine is likely compatible with breastfeeding, but its concentration in breast milk can vary. It’s known that the dose the infant receives through breast milk is below 2% of the weight-adjusted dose received by the mother. In this case, monitoring the infant’s blood drug levels is advised ^[94].

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