Ulcerative Colitis and Pregnancy

Abstract

Ulcerative colitis (UC) is characterized by relapsing and remitting episodes of inflammation limited to the mucosal layer of the colon. It commonly involves the rectum and may extend to involve other parts of the colon. The age of onset for females is during the reproductive years, and many are likely to get pregnant after the diagnosis of the disease. Women have comparable fertility to the general population when the disease is in remission. Fertility is likely to get affected in women with active disease and in women who had undergone ileal pouch-anal anastomosis (IPAA). Assisted reproduction has improved the chances of successful pregnancy in these women whose fertility is impaired following surgery. Affected females delay pregnancy due to active disease, fear of medications affecting the fetus, and fear of transmitting the disease to the newborn. Most drugs used in the management are safe in pregnancy except for drugs such as methotrexate and tofacitinib. Congenital abnormalities are not increased in pregnancies complicated with ulcerative colitis. Preconception counseling with the objective of planning the pregnancy during remission, reviewing drug therapy, and educating on the importance of continuing medication and its safety are important for better outcomes for the mother and the baby.

1. Introduction

Ulcerative colitis (UC) is an inflammatory bowel disease, sometimes diagnosed during the reproductive years. The incidence and prevalence of ulcerative colitis vary not only according to geographical region but also to race and ethnicity. In an Australian study, the estimated crude prevalence of IBD was 653 per 100,000 patients, Crohn’s disease was 306 per 100,000, and ulcerative colitis was 334 per 100,000. In this study, males had a lower risk of Crohn’s disease and a higher risk of UC compared to females [1].

In a systematic review and meta-analysis of studies done in the Arab world, quantitative analysis revealed a pooled incidence of 2.33 (95% confidence interval [CI] 1.2–3.4) per 100,000 persons per year for UC and 1.46 (95% CI 1.03–1.89) per 100,000 persons per year for CD [2].

The incidence and prevalence of UC in Latin America were different between regions and studies, ranging from 0.04 to 8.00/100,000 and 0.23 to 76.1/100,000, respectively. An increasing trend was seen over the period from 1986 to 2015. Most patients with UC were females (53.6–72.6%) [3]. In the Asian region, the mean annual incidence of IBD was 1.5 per 100,000. India had the highest incidence of IBD and ulcerative colitis [4].

Approximately 25% of women are likely to get pregnant after the diagnosis of the disease [5]. Prepregnancy counseling and controlling the disease activity before pregnancy are important because active disease at the time of conception and during the pregnancy has shown to result in poor maternal and fetal outcomes [6, 7, 8, 9]. Review of drug therapy is also important since some of the drugs such as Methotrexate and Tofacitinib used in the management could affect the fetus.

Active disease during pregnancy is associated with an increased risk of maternal and fetal complications; therefore, it is important to continue therapy and have the disease under control at the time of conception and during pregnancy [6, 7, 9, 10].

Almost 50% of women with IBD have been identified to have a poor knowledge of pregnancy-related issues [11]. Poor knowledge of specific issues related to reproductive health leads to patient concerns and noncompliance. Different educational activities, including eLearning, have shown to improve the patient’s knowledge of pregnancy-related issues and reduce patient concerns, which in turn will improve compliance [12, 13]. Current knowledge of prepregnancy assessment of patients with UC, the management of pregnancy, safety and the effects of medication, management of delivery, and the postpartum period will be discussed in this chapter.

2. Prepregnancy planning

Women with UC have a higher risk of adverse pregnancy outcomes than women without the disease. The magnitude of this risk is related to the disease activity at the time of pregnancy. As such, a woman with inflammatory bowel disease needs interventions to manage the disease before pregnancy to minimize adverse outcomes [6, 7, 9, 10]. This is particularly important if the patients have undergone surgical management.

Ulcerative colitis (UC) can affect women during their childbearing years. Pregnancy presents a unique challenge, in the management of UC, where the physician needs to make sure the mother’s health is optimally managed, while not compromising the health of the fetus. At most instances, pregnancy in a UC patient would have an uncomplicated course. A multi-disciplinary treatment approach is required when a UC patient becomes pregnant.

2.1 Preconception counseling and education

It is important that patients are advised to conceive during a period of remission of their disease. Prepregnancy planning and proper communication with the treating physician are paramount in this context. Fertility wishes must be discussed with any female with UC in their reproductive age during the consultation and appropriate advice should be given. There are several concerns regarding UC during pregnancy, its impact on pregnancy outcomes, and its effect on the disease. These should be discussed with the patients before pregnancy.

It has been shown that 30–35% of pregnancies are complicated by flares [14]. A meta-analysis of 14 studies found a significantly higher risk ratio of active disease during pregnancy in mothers with UC who commenced pregnancy with active disease (55%) as opposed to the mothers in remission at conception (36%) (risk ratio, 2.0; 95% confidence interval, 1.5–3; P < .001). Similar results were seen in a recent European multicenter cohort: where only 14% of patients in remission at conception relapsed during pregnancy. In contrast, 26% of those with active disease at conception remained in active disease during pregnancy [8].

Having active disease at conception is found to be associated with adverse pregnancy outcomes. In a Danish study of inflammatory bowel disease, 55% of mothers had an inactive disease and 45% had mild to moderate active disease during pregnancy. There was a twofold higher risk of preterm delivery in the active disease group when compared to the disease inactive group [15]. Several such studies have reiterated the importance of the woman being in remission or at least only having mild disease at the time of conception.

When the woman is in remission or has only mild disease activity at the time of conception, it is very likely that the pregnancy will be uncomplicated [16]. A meta-analysis by Miller et al. in more than 1300 female UC patients demonstrated that normal pregnancies are observed in 85% of women with UC (76–97% in individual studies) [17].

In a study by Mountfield et al. on fear and fertility in patients with IBD, 25.8% of patients reported fear of fertility due to ulcerative colitis. This fear was equally seen in males and females suffering from the disease. Only 15.3% have consulted for medical advice before pregnancy in this study. Fear of congenital abnormalities, fear of teratogenicity of drugs, fear of genetic transmission, and inappropriate advice negatively influenced the reproductive decisions. The impact of fertility is variable in different couples as such, it is important to use an individualized approach for prepregnancy advice [18].

Familial occurrence of inflammatory bowel disease (IBD) is well documented. In a study with over 2000 UC patients, a positive family history of IBD was confirmed in 31 patients (1.5%), and 24 (77.4%) had only first-degree relatives affected. All the affected relatives had UC [19]. Different studies have reported varying familial risks of developing ulcerative colitis depending on the study population [20].

The initial prenatal visit is very important to plan out the future pregnancy and communicate and alleviate any concerns of the couple. Discussion should focus on nutritional aspects, weight gain, disease activity, monitoring of mother and fetus, and managing a potential flareup in the future. This discussion that begins at the preconception visit should continue in a dynamic process throughout the pregnancy, further reiterating the importance of management steps.

The principle underlying the treatment of UC during pregnancy is balancing the risks associated with active disease versus any probable or actual risk associated with specific UC medications. Most mothers would feel any medication during pregnancy will be harmful to the baby and would opt not to continue with their medications. It is important this fear is acknowledged and discussed and set into context. Proper counseling of the potential adverse effects of the medications and untreated disease needs to be discussed with the mother and other relevant persons. It is important to communicate with the mother and highlight the importance of continuing the medications and being in remission throughout the pregnancy. Most drugs are considered safe in pregnancy and active disease is likely more harmful than the medication that maintains remission. Medication used by the woman should be reviewed. Medicines which are considered unsafe in pregnancy should be changed to more pregnancy friendly medication when a couple plans a pregnancy. Ideally this should be done at least 3 months prior to the pregnancy, so that there is adequate time for the new medication to take its action and the woman to be in remission at the time of conception.

2.2 Ulcerative colitis and fertility

A systematic review of 11 studies to evaluate nonsurgically treated inflammatory bowel disease found that there is no reduction in fertility in women and men with UC in remission [21]. Lower fertility rates have been reported in women with active disease [22, 23]. However, in UC patients with ileal-pouch anal anastomosis (IPAA), there is an observed reduction in fertility. In a recent meta-analysis, the relative risk of infertility is reported as 4.17 (95% CI 1.99, 8.74) compared with patients before surgery in women who had UC [24]. This is likely due to reproductive organ damage during deep pelvic dissection, formation of scar tissue and adhesions, and the increased prevalence of dyspareunia following surgery.

However, a recent Cochrane review of 16 studies concluded that the effect of surgery on female fertility is uncertain. Any differences in infertility among those undergoing open versus laparoscopic procedures were also uncertain [25].

Assisted reproduction is safe and effective in patients with ulcerative colitis. In medically managed patients, the live birth rates are like that of the general population. However, the live births are reduced after IPAA failure [26].

2.3 Contraception

Since it is advisable to get pregnant during disease remission, contraception plays a significant role in prepregnancy management. Women with UC often present during the reproductive years [5, 7], and thus, women with this disorder need effective contraceptives to prevent unintended pregnancies or to optimally time desired pregnancies.

With regard to oral contraceptives, concerns are expressed about their absorption, increasing the risk of relapses, and increasing the risk of venous thrombosis during their use. In a systematic review on contraceptive use among patients with inflammatory bowel disease, the studies have shown that absorption of the hormones is not affected by the presence of ulcerative colitis, including the patients who had undergone surgery. The frequency or severity of relapses is also not affected compared to nonusers of oral contraceptives. There is no adequate data on the risk of venous thrombosis [27].

Long-term use of depot medroxyprogesterone acetate (DMPA) is associated with small but reversible changes in bone mineral density [28], but it is not known whether the use of DMPA modifies the risk of osteoporosis or osteopenia in women with UC.

Long-acting reversible contraceptives, such as copper or levonorgestrel intrauterine devices or levonorgestrel implants, are highly effective contraceptive methods. Center for Disease Control and Prevention (CDC) recommends the use of these methods for patients with ulcerative colitis [29].

3. Effect of pregnancy on ulcerative colitis activity

Patients with disease remission at the time of conception have 26–35% chance of flare during pregnancy, and this is comparable to the risk of flare in nonpregnant women [7, 8]. There is a significantly higher risk of disease relapse in patients with UC during pregnancy, particularly in the first and second trimesters and the postpartum period compared with nonpregnant women with UC [8, 17]. Similar results were seen in a recent European multicenter cohort: where only 26.4% of patients in remission at conception relapsed during pregnancy. In contrast, 33% of those with active disease at conception remained in active disease until delivery [8]. Most of patients with active disease went into remission during pregnancy [8, 30].

A meta-analysis of 227 women with active UC at conception identified that 24% of women continued to have active disease, 45% experienced worsening disease activity, and 27% improved during pregnancy [17, 30].

In a study with 206 women with IBD, postpartum flares occurred in 31.6% of women, out of which 60% were in patients with UC [31]. The development of postpartum flares was predicted by disease activity during the third trimester, therapy de-escalation during pregnancy, and therapy de-escalation after pregnancy [31].

4. Effect of ulcerative colitis on the pregnancy and child

Many studies have shown that women with UC have an increased risk of preterm delivery, low birth weight (LBW), small-for-gestational-age (SGA), and cesarean section (CS) delivery [30, 32, 33, 34, 35, 36, 37]. It has also been shown that these complications are higher in patients with active disease requiring drug therapy [10, 32].

Having active disease at conception is found to be associated with negative pregnancy outcomes as well. In a Danish study of inflammatory bowel disease, 55% of mothers had inactive disease and 45% had mild to moderate active disease during pregnancy. There was a twofold higher risk of preterm delivery in the active disease group when compared to the inactive group [15]. Several such studies have reiterated the importance of the woman being in remission or at least only having mild disease at conception.

If the woman is in remission or has only mild disease activity at conception, it is very likely that the pregnancy will be uncomplicated [16].

Some studies have shown an increased rate of miscarriage in patients with UC compared to the normal population. However, this difference was not statistically significant [38].

Most studies have shown that there is no increased risk of congenital abnormalities in patients with UC compared to patients without the disease [32, 35, 37].

5. Management of a patient with UC during pregnancy

5.1 Obstetrics care

Once pregnant, it is recommended to refer patients with UC for consultant-led care early. An ultrasound scan to exclude an ectopic pregnancy is important, especially in patients who have undergone bowel surgery. After confirming the viability of pregnancy, arranging specialized care in a joint clinic with an experienced obstetrician and IBD physician is recommended for optimal care during pregnancy [39, 40].

Dating the pregnancy with an ultrasound scan between 12 and 14 weeks should be done as there is an increased risk of preterm delivery in a patient with UC. Aneuploidy screening should be performed in line with local guidelines. An anomaly scan to screen for congenital anomalies should be offered to all patients with UC.

Serial growth scans in the third trimester are recommended as there is an increased risk of small for gestational age and fetal growth restriction [30, 32, 33, 34, 35, 36, 37].

Vaccinations during pregnancy should be offered as routine, including vaccination against COVID-19, although very limited data is available regarding its safety. Preliminary studies have shown no significant increased risk with COVID-19 mRNA vaccines during pregnancy [41].

5.2 Nutrition

During pregnancy, the fetus derives all its nutrition from the mother via the placenta. Therefore, the mother’s nutrition should be optimal to ensure a healthy baby. IBD patients are at increased risk of macro and micronutrient deficiencies due to mucosal loss and impaired absorption [42]. Zinc, Vitamin D and B12, Calcium, folic acid, iron, and protein deficiencies are known to occur in IBD patients and should be actively suspected and treated as indicated [40, 43, 44].

There are studies that have shown that a diet rich in vegetable oils, fruits, grains, and fish has protective effects on adverse pregnancy outcomes [44].

5.3 Drug therapy and safety during pregnancy

Most medications used in UC are considered safe during pregnancy (Table 1). But an honest discussion with the mother is important to ensure compliance.

Medication	Risk during pregnancy	FDA category
Mesalazine	Low risk	B
Sulphasalazine	Low risk	B
Corticosteroids	Low risk	C
Thiopurines	Low risk (Limited data for 6 TG)	D
Anti TNF Agents	Low risk, consider stopping in 3rd trimester if in remission	B
Methotrexate	Do not take during pregnancy	X
Metronidazole	Avoid in the first trimester	B
Ciprofloxacin	Avoid in the first trimester	C
Tofacitinib	No reliable human studies are available	C

Table 1.

Summary of medications used in ulcerative colitis.

5.3.1 5 Aminosalicylates (5 ASA)

Aminosalicylates are used in the treatment of mild to moderate UC. Aminosalicylates are generally considered safe for use in pregnancy as per the European Crohn’s and colitis guidelines (ECCO) [45]. Several case series, population-based cohort studies, and two meta-analyses did not demonstrate an increased risk for early pregnancy adverse outcomes such as miscarriage and ectopic pregnancy in mothers continuing with 5 ASA during pregnancy [46]. Few trials have demonstrated premature birth and low birth weight with 5 ASA use, but whether active disease during pregnancy was considered a confounding factor cannot be ascertained [46]. Reassuringly, animal and human data, including recent meta-analysis, did not demonstrate any teratogenic effects with 5 ASA and therefore is recommended to be continued during pregnancy [47]. Sulfasalazine can potentially interfere with folate absorption, which is essential for neural tube development. Folic acid supplementation is therefore always required if not already given.

5.3.2 Corticosteroids

Steroids are needed in the management of most acute flares of UC and are recommended for use in the ECCO guidelines [45]. Corticosteroid may increase the risk of pregnancy-related adverse outcomes and gestational diabetes. Although most studies have not shown an increased risk of congenital malformations associated with the use of steroids, there seems to be an increased risk of orofacial malformations if steroids are used in the first trimester [48]. However, a large population-based study, including 51,973 pregnancies, did not show any adverse events from using steroids during pregnancy [49].

5.3.3 Ciclosporin and tacrolimus

Both ciclosporin and tacrolimus are widely used for the treatment of solid organ transplantation, and most data on pregnancy outcomes are derived from such patients. In a meta-analysis of 15 studies with 410 pregnant patients, ciclosporin did not cause an increased rate of congenital malformations [50]. Data on pregnant women with IBD are minimal.

5.3.4 Thiopurine

Thiopurines, both azathioprine and 6-mercaptopurine, are used in the maintenance of remission of UC and are considered low risk and well tolerated during pregnancy [45].

Thiopurine use in pregnancy has been evaluated in several studies. Initial studies showed an increased risk of preterm delivery, small for gestational age and low birth weight, [51, 52] but these studies overall failed to consider disease activity, which is commonly associated with these pregnancy outcomes. On the contrary, several recent studies revealed thiopurines did not cause any negative pregnancy outcomes [53, 54]. With respect to congenital anomalies, studies have revealed an association with thiopurine use in pregnancy, but again several long-term studies have refuted these findings, adding up to the debate on the safety of thiopurines in pregnancy [55, 56, 57]. In a Spanish study, interestingly, patients on thiopurines had better pregnancy-related outcomes than those not exposed to thiopurines, further emphasizing the importance of controlling the disease throughout pregnancy [53, 58].

5.3.5 Biologics

Although there is substantial evidence of its safety in pregnancy, some mothers may insist on stopping biologics during pregnancy. Discontinuation of biological therapy early during pregnancy poses several problems. There is a potential risk of flares during pregnancy and postpartum period, increased risk of developing antibodies against the biologics, and possible loss of response if restarting is needed. Therefore, discontinuation of biologics during pregnancy should only be considered under certain circumstances in patients who are at a very low risk of relapse. Studies have shown patients may be considered low risk if objective sustained endoscopic remission is seen for 6 months before conception, appropriate therapeutic levels before conception, no hospitalization in the last 3 years, no prior bowel resection, no previous loss of response to anti-TNFs, or need for dose optimization [59].

5.3.5.1 Anti-TNF agents

Anti-TNF agents used for IBD include infliximab (IFX), adalimumab, golimumab, and in some countries certolizumab (CZP). Anti-TNF agents do not cross the placenta passively as they are large molecules. However, as their structure resembles maternal immunoglobulins that are transported actively from the end of the second trimester, they too can be actively transported across the placenta. Therefore, not only is the fetus potentially exposed to these agents, but they can have blood levels exceeding maternal levels [60]. In contrast to the other anti-TNF agents, certolizumab has a pegylated molecular structure and is not transferred across or has very low or no detectable fetal drug levels at birth [61]. As organogenesis occurs before this transplacental anti-TNF drug transfer, there are no reported congenital malformations with the use of biological agents. In the PIANO (Pregnancy Inflammatory bowel disease And Neonatal Outcomes) registry, more than 500 women were exposed to the anti-TNF medications during pregnancy, and no increased risk of adverse pregnancy outcomes was reported [62]. Several studies have shown anti-TNF agents do not increase pregnancy-related outcomes [53, 63] and are therefore considered low risk and recommended for being used in pregnancy in the ECCO guidelines [45]. It is important to delay the scheduled dose of anti-TNF agents as late as possible during the second trimester (around 24–26 weeks of gestation), to maintain remission during the third trimester and to limit its transport to the fetus [64].

Infliximab has been detected at 6 months after birth in the child; therefore, there have been concerns about its implications on neonatal vaccinations. No adverse outcomes have been reported for non-live vaccines [65]. It s recommended to only institute live vaccines after 6 months of age when no detectable anti-TNF medication is seen in the child’s blood. Levels of other immune suppressants used in pregnancy are probably not elevated in neonates, and routine vaccination schedules can be followed, although reliable data are lacking.

5.3.5.2 Anti-integrin agents – Vedolizumab

Vedolizumab (VDZ) is unique as it is a gut-selective IgG-1 monoclonal antibody against the integrin α4β7. There is limited data on the effects of VDZ in pregnancy. A small case series consisting of 24 and 73 pregnancies exposed to VDZ had no safety concerns reported [66, 67].

In a European retrospective study, no difference in miscarriages was seen with VDZ exposed and a control group on IFX (16 vs. 13%, p = 0.71) or a control group not exposed to any biologics (16 vs. 10%, p = 0.236). Similar number of miscarriages were seen once patients with active disease were excluded from the analysis [68]. It is recommended to use VDZ in pregnancy if indicated. But, if the childbearing age woman is naïve to biologics, as most data are available with anti-TNF agents, anti-TNFs, especially CZP, are most appropriate as a first-line treatment option for use of biologics in pregnancy.

5.3.5.3 Ustekinumab

Ustekinumab is increasingly used in pregnancy, and like the other anti-TNF agents, it is an actively transported IgG1 antibody across the placenta via neonatal Fc receptors. It appears to have stable drug levels during pregnancy, with a similar infant: maternal ratio of the older anti-TNFs. It is completely cleared from the infant’s blood by 20 weeks. But like with other biologics, live vaccination needs to be avoided at least till 12 months of age until further clearance data are obtained [69].

5.3.5.4 Tofacitinib

Animal studies clearly show congenital malformations with tofacitinib in supra therapeutic doses. Although no reliable human studies are available, it is recommended to avoid this drug, especially in the first trimester. As the half-life of the drug is short, a washout period of approximately 1 week is adequate before conception [67].

5.4 Disease assessment and monitoring of UC

As IBD may adversely affect pregnancy and vice versa, it is important that the activity of the disease is objectively monitored before pregnancy and during a flair within the duration of the pregnancy. Various modalities are used to assess disease activity in IBD.

Along with histology, direct visualization with endoscopy is the definitive method to assess disease activity in IBD. But procedure-related hazards to the mother and fetus, including fetal hypoxia and demise, maternal positioning for the endoscopy and maternal hypotension, and sedation during pregnancy, are a concern [70].

Due to physiological changes in pregnancy haeamoglobin, albumin are lower and erythrocyte sedimentation rate (ESR) is higher than normal, therefore these should not be used to monitor disease activity. Fecal calprotectin that measures gastrointestinal mucosal inflammation is detected before clinical symptoms and is a useful noninvasive indicator of disease activity, although its use specifically in pregnancy has not been studied. Fecal calprotectin of lower than 50 ug/g has been shown to be predictive of quiescent disease in UC [71].

5.5 Management of flare and acute severe ulcerative colitis in pregnancy

Management of flares in UC would be like a nonpregnant patient. Serum biomarkers used traditionally to assess severity of UC may be physiologically abnormal during pregnancy.

Steroid therapy: The steroid regime is IV methylprednisolone 40 mg BD or IV hydrocortisone 100 mg QDS and rectal Hydrocortisone 100 mg in 100 ml normal saline BD given through soft rectal cannula (Foley catheter) over 30 minutes, via IV giving set.

Dehydration: Administer IV fluids to correct dehydration, with at least 60 mmol potassium per day. Patients are highly prone to hypokalemia due to diarrhea and steroid therapy, and this requires close attention.

Anti-coagulation: Prophylactic doses of LMW heparin should be considered in all pregnant females with acute relapse, as pregnancy and acute severe UC greatly predisposes a patient to venous thrombosis.

Antibiotics: Metronidazole and ciprofloxacin can be considered for patients suspected of infection after recent hospital admission, visit to an endemic area for amoebiasis, the first attack of UC, or when surgery is considered. In the absence of these features and especially in pregnancy, antibiotics are not routinely indicated [72].

Rescue therapy: Both infliximab and cyclosporine are equally effective and can be considered as rescue therapy in patients who do not respond to first-line therapy.

5.6 Endoscopy during pregnancy

Endoscopy during pregnancy is considered safe if indicated, except in states of placental abruption, ruptured membranes, or eclampsia. It should be performed by an experienced endoscopist and, if possible, should be postponed until after the first trimester. While performing the lower gastrointestinal endoscopy, mothers need to be lying in a left lateral position or what is known as “left pelvic tilt” to avoid compression to the major vessels supplying the placenta. Unsedated flexible sigmoidoscopy is preferred following an enema and would give the necessary information in a patient with UC [73].

If strongly indicated, colonoscopy can be done with obstetric anesthesia monitoring, but colonoscopy is generally avoided due to the difficulties in bowel preparation, technical difficulties, and negative effects on pregnancy. Sedation needs to be discussed with anesthetists, and benzodiazepines are best avoided during pregnancy. It is recommended to document the fetal heartbeat before and after endoscopy and to always have obstetric support available.

5.7 Timing, planning, and management of the delivery of the fetus

In the majority of patients with UC, the mode and timing of delivery can be decided according to the obstetric indications. There is no contraindication for vaginal delivery in a patient with UC without fetal or maternal complications. Episiotomy should be given, if necessary. Vacuum or forceps deliveries should be done for usual obstetrics indications.

When deciding the mode of delivery, the AGA guideline would be a good reference (Figure 1) [40]. Patients without perineal disease should be encouraged for vaginal delivery. However, for patients with active disease or with perineal disease (anorectal fistula, anal abscess, rectovaginal fistula, anal fissures, and anal stenosis), cesarean delivery should be offered [74]. IPAA is a relative contraindication for vaginal delivery. One should consider the possible protection of anal sphincter by performing an elective cesarean delivery. An experienced obstetrician should perform the cesarean section to minimize the risk of intraoperative organ injury with the possible involvement of the surgical team if required.

Figure 1.

Guide to decide the mode of delivery in patients with UC. VTE, venous thromboembolism.

Nevertheless, women with UC have a higher risk of cesarean deliveries compared to women in the general population [75]. Most of the time, a cesarean section is suggested or requested because of unjustified fears on the part of patients or care providers.

6. Breast feeding, postpartum management, and follow up including family planning

6.1 Thromboprophylaxis

Patients with UC have an increased risk of developing venous thromboembolism (VTE), especially during the postpartum period [76]. The need for thromboprophylaxis should be assessed in each patient according to AGA guideline [40] (Figure 1). Thromboembolic deterrent stockings and low molecular weight heparin (LMWH) should be offered to all women who have undergone cesarean delivery. UC patients with other risk factors for VTE regardless of the mode of delivery should be offered with both mechanical and LMWH as thromboprophylaxis. Some may need anticoagulation for an extended period. LMWH and warfarin can be used in these circumstances. UC patients who have been successful in vaginal delivery with no other risk factors for VTE can be offered mechanical thromboprophylaxis only.

Figure 2.

Postpartum care for women with UC.

6.2 Postpartum

The risk of relapse is higher during the postpartum period. Discontinuation of drug therapy during pregnancy and fear of drug therapy during breastfeeding are the main reasons. In one study, 75% of cases experienced a relapse during the postpartum period in patients who discontinued the drug treatment before 30 weeks of gestation. In contrast, only 26% of cases had a relapse in patients who continued the drug therapy throughout pregnancy [77].

Biological treatment can be restarted 24 hours after vaginal delivery and 48 hours after cesarean delivery [78]. However, exclusion of possible infection is mandatory before recommencing treatment. Methotrexate can be restarted during the postpartum period if the mother is not breastfeeding [79]. Most of the other drug therapies can be safely continued in the postpartum period (Figure 2).

Patients with IPAA are at a higher risk of developing paralytic ileus during the postpartum period, especially the ones who undergo cesarean deliveries. Early feeding and mobilization, proper hydration, and other supportive measures can reduce this risk significantly [80].

The risk of stoma complications is higher during the postpartum period. Liaising with a stoma specialist nurse and colorectal surgeon will help to minimize complications with stoma [79]. Covering the ostomy with a gauze towel is recommended to protect the operative field during cesarean section [76].

6.3 Lactation

In most instances, a woman with UC can breastfeed the child without any major issues. Exclusive breastfeeding for 6 months, with the continuation of breastfeeding for 1 year or longer as mutually desired by mother and infant is recommended. However, a significant number of women with UC defer breastfeeding due to fear of drugs in breast milk or discontinuing medication during the postpartum period, equally harmful to both the mother and baby. In the PIANO registry, the breastfeeding rate was significantly lower in women on immunomodulators and biologic treatments [81].

Breastfeeding has a protective effect on the development of UC in offspring. A systematic review has shown that ever being breastfed was associated with a lower risk of UC (OR 0.78, 95% CI 0.67–0.91) [82].

When deciding the drug therapy during the postpartum period and lactation, the AGA guideline will be very helpful [40].

5-ASA agents (mesalamine, basaloid, and olsalazine) can be continued when breastfeeding. Although they are excreted in breastmilk, only a few isolated cases of diarrhea are reported in infants who are exposed. Compared to sulfasalazine, which is excreted into milk and known to have hemolytic and antimicrobial properties, mesalamine derivatives are safer during lactation [83].

Thiopurines and corticosteroids are secreted in minute amounts in breast milk. Some studies have shown when corticosteroid dose is higher than 20 mg per day, significant levels are detected in breast milk [84]. They can also reduce breast milk production. Some advice avoiding breastfeeding for 3 to 4 hours after taking thiopurines as the drug is not detected in breast milk after 4 hours of dosing. Most of the biological agents are found in minute amounts in breast milk and are degraded in the stomach of the infant, and no significant adverse effects are reported, thus can continue during breastfeeding [85].

Anti-interleukin 12–23 and anti-integrin are considered safe during lactation, as only minute amount is secreted in breastmilk. Nevertheless, limited safety data are available for these relatively new therapies [86].

Due to lack of data, lactation is contraindicated in women who are on tofacitinib.

6.4 Postpartum contraception

Effective, safe, and reliable contraception should be offered to all women with UC after delivery. Long-acting reversible contraceptives are the safest and most effective. These include hormonal or nonhormonal intrauterine devices or hormonal implants. Estrogen-containing contraceptive methods may increase the risk of venous thromboembolism, hence should be offered only if no personnel or family history of DVT or no other risk factors. Estrogen patches or low-dose estrogen contraceptive pills are safer.

7. Long-term effects of ulcerative colitis on the Fetus

7.1 Ulcerative colitis and genetics

Genetic studies have shown an increased risk of developing UC in the offspring, although the risk is somewhat less than Crohn’s disease. Family history with multiple members having the disease increases the risk further for the offspring. In monozygotic twins, there is a 6–19% concordance for UC [87]. The incidence rate ratio is 3.7 for UC in an offspring if the mother is having UC and the absolute risk of an offspring developing UC is 1.6% [88]. The risk of developing IBD rises to 30% if both parents have UC [89]. There are no genetic tests available currently to predict the probability of a child developing the disease.

7.2 Infection and vaccination

There is a significant risk of neonatal infection postdelivery due to immunosuppressive treatment during pregnancy. Neonates and infants should be monitored for possible infections, especially if they are exposed to a combination of thiopurines and biologics [79].

It is recommended to avoid live vaccinations until 6 months postdelivery in infants exposed to biological therapy during the third trimester [39]. This is because of possible immunosuppression in the infant due to clinically significant drug levels detected up to 6 months after birth.

7.3 Mental development

PIANO registry data and other studies indicate that there is no significant effect on the neurodevelopment of babies regardless of exposure to the antenatal medication. In fact, some studies have shown better achievement of neurodevelopment milestones in infants with higher drug levels compared to infants with lower drug levels at birth. Therefore, good disease control with proper medication should be encouraged when counseling women with UC [90].

8. Conclusion

Ulcerative colitis affects women during their reproductive years and many of them are likely to plan pregnancy after the diagnosis of the disease. Fertility is reduced in women with active disease and in patients who have undergone surgical management. Development of advanced fertility management has improved the chances of pregnancy in these women. Prepregnancy assessment of the disease activity, counseling regarding the fetal and maternal outcome, and safety and importance of continuation of medication are important aspects of management of patients affected by ulcerative colitis. Because the pregnancy outcome is adversely affected by disease activity, adequate attention should be given to the continuation of treatment during pregnancy. Most of the drugs used in the management of ulcerative colitis are safe in pregnancy with a few exceptions. Multidisciplinary team management, including gastroenterologist, obstetrician, and neonatologist will help to reduce complications and improve maternal and neonatal outcomes.

Conflict of interest

The authors declare no conflict of interest.