Inflammatory bowel disease (IBD) affects mainly women at childbearing age, resulting in a challenge for obtaining a pregnancy. This issue is being discussed with interest by international organizations. The European Crohn’s and Colitis Organization (ECCO) developed the European Consensus on reproduction in inflammatory bowel disease, first in a meeting held in Prague in February 2010(1), and updated the statements in the second European evidence-based consensus on reproduction and pregnancy in inflammatory bowel disease, in 2015(2). The ECCO statements are based on an international consensus on guidelines in fertility, pregnancy and delivery, maternal-fetal outcome and lactation in patients with IBD(2). The existing data of the IBD impact on the reproduction function are still inconsistent, and the potential correlation between IBD, its treatment during pregnancy and maternal-fetal complications – such as miscarriage, preterm delivery, insufficient fetal growth, preeclampsia, low Apgar score and fetal malformations – are still topics of medical interest.
Fertility and IBD
Crohn’s disease (CD) and ulcerative colitis (UC) have an increasing incidence and prevalence among young fertile patients(3). Getting a pregnancy in this category of patients is often a sensitive issue, due to concerns about the impact that IBD has on fertility and pregnancy, with influence on the maternal-fetal outcome, on the timing and mode of delivery and in the postpartum and lactation period. Regarding the subject of fertility, a new category of infertility – dubbed “voluntary infertility” – has appeared. This so-called “voluntary childlessness” refers to the fear of procreation, the fear of transmitting the disease, the fear of fetal malformation due to the IBD treatment(4). However, it is important to note that all studies published so far on this topic concluded that the fertility rate in IBD patients is the same as in general population(5,6). So, the fact that patients with IBD have less children than general population is related to voluntary childlessness(4,7). An active disease can reduce the fertility directly by inducing inflammation in the fallopian tubes and ovaries and by perianal disease associated with dyspareunia, or indirectly by adhesion formation post-surgical approach(8). Şenateş and Fréour have studied the relation between ovarian function and IBD, and concluded that there is a reduction in the level of AMH at women over the age of 30 and with active disease(9,10). ECCO concluded that there is no evidence that controlled IBD reduces fertility, but active disease and the fear of childbearing being ill impacts negativly the fertility rate(2). When the active disease needs pelvic surgery, the rate of fertility may be decresead due to the appereance of pelvic adhesions, altering the tubes motility and ovarian ovulation process. Moreover, pelvic surgery may affect the sexual function due to perianal disease, dispareunia and lowering self-esteem(11,12). Severe cases complicated with the need for an ileoanal pouch or an ileorectal anastomosis may be associated with subfertility(13,14). Searching the literature, we found some studies that indicate that infertility rates after laparoscopic ileal pouch-anal anastomosis surgery are lower than those seen after open ileal pouch-anal anastomosis surgery, which may be due to the lower adhesion formation after laparoscopic approach(15). Taking into account the abovementioned, it is indicated that young women who have not conceived avoid pelvic surgery until having a baby.
IBD and maternal-fetal outcome
The maternal-fetal outcome in patients with IBD is a provocative topic. There are both concerns about the impact that a pregnancy can have on the IBD evolution, and about the IBD itself on the fetal development and outcome and maternal health. So, the impact of IBD on pregnancy depends on disease activity at conception(16). When a pregnancy is obtained in a moment of quiescent disease, the patient has similar risks to those of the general population regarding miscarriage, pregnancy-related complications and adverse fetal and neonatal outcomes, and the risk of relapse is the same as in non-pregnant women(2,17). Regarding the impact that pregnancy has on the disease course, studies have showed that when pregnancy occurs during a period of disease remision, the rate of relapse of Crohn’s disease is similar to that of non-pregnant women (i.e., a third of patients)(18), and in ulcerative colitis this risk is higher(19). ECCO states that conception occurring at a time of active disease increases the risk of persistent activity during pregnancy, and pregnancy may influence the course of inflammatory bowel disease(2). Pregnancy itself has an impact on the immune system. Studies showed that pregnancy may be favorable to Crohn’s disease, but can worsen the evolution of ulcerative colitis(20). The disease activity at conception has been associated with adverse perinatal outcomes such as preterm births, low birth weight (LBW), eclampsia, preeclampsia, placenta praevia, abruptio placentae, or prolonged premature rupture of membranes, miscarriage and an increased C-section rate. When having a comparison between CD and UC, the data from literature conclude that pregnant women with CD have more risk than those with UC(18). Although data regarding the effect of disease activity on pregnancy outcomes remain inconsistent, the medical advise is to conceive while the disease is in remission and to continue the medication throughout the pregnancy, in order to maintain the remission and avoid worse pregnancy outcomes(21). Regarding the risk of giving birth to a child with severe malformations, the studies are inconcludent. As a conclusion, it is of the utmost importance to conceive while IBD is in remision.
Delivery and postpartum in IBD
The delivery mode in IBD pregnant women is the obstetrician choice in the majority of cases, but C-section must be indicated when perianal disease is active or there is active rectal involvement(2). Multidisciplinary aproach regarding these cases (gastroenterology, general surgery, neonatology, obstetrics) should create a balanced view of the best choice of treatment, taking into account the posible consequences of a postpartum sphincter/pelvic floor impairment. Vaginal delivery can be tempted when there is no active perianal disease, but with the precaution of avoiding episiotomy(22). Hatch et al. published a large retrospective review about the delivery mode on patients with IBD and concluded that active perianal disease corelates with severe perineum laceration(23). Ileal pouch-anal anastomosis is considered a relative indication for C-section, but it is important to know that it is deemed borderline incontinence, so the risk of an impairment on pelvic floor with fecal incontinence may alter the quality of life in these patients(24).
The postpartum period is like a hormonal storm and may influence the disease flares. Studies showed that there is no risk for increased flares when maintaing the therapy during postpartum in CD, but UC can be complicated with a flare even being under treatment in postpartum(19).
A child from a family with IBD has a higher risk to develop IBD when compared to general population. The risk is higher in CD if both parents are affected(2). The overall risk to develop IBD for a child with one parent affected is about 2-13 times higher than in the general population(25).
Management of IBD during pregnancy
An adequate therapeutic control of the disease during pregnancy and puerperium will reduce both maternal-fetal and neonatal complication rates. It is important to maintain the remission during pregnancy and postpartum by having a strict adherence to the treatment. IBD medication can be used safely in pregnancy, except for thalidomide and methotrexate, which are teratogenetic. The aminosalicylates (sulfasalazine, mesalamines) are of category B in the FDA classification. Although mesalamine can be identified in the cord blood, there were reported no abnormalities in fetuses resulted from mothers with intake of these drugs during pregnancy(26). Delayed-release mesalamine is considered of category C. The studies published did not demonstrate an increased risk for misscariage, but have demonstrated a higher rate of premature birth, stillbirth and low birthweight; however, the confounding factor of active disease is difficult to delineate(26-28). Sulfasalazine is currently included in category B and, because it interferes with folate absorption, the supplementation is recommended, in order to avoid defects of the fetal neural tube(29). Rahimi et al. elaborated a meta-analysis and concluded that mesalamine and sulfasalazine are not associated with an increased risk for fetal malformations, premature birth, miscarriage or low birth weight(26).
Thiopurines (6-mercaptopurine, azathioprine) are classified as category D drugs in pregnancy, and are purine analogues which interfere with the synthesis of DNA, crosses the placenta and can be identified in fetal blood(30). The prospective PIANO (Pregnancy in IBD Neonatal Outcomes) Registry shows that the use of thiopurines does not lead to worse fetal outcomes(31). Due to its passing through the placenta and the insufficient safety data, it shouldn’t be used during pregnancy.
All corticosteroids cross the placenta and are converted by the placental 11-hydroxygenase in less active metabolites, so the fetal risks are decreased. The reports existing about corticosteroids in the first trimester are inconclusive: some studies reported an increased risk on orofacial malformations (cleft lip/palate), other studies disprove these findings, and other reports sugest that there is a risk for developing neonatal adrenal suppression when corticosteroids are used late in pregnancy(18,32,33). In addition to fetal risks, it must be taken into consideration the possible maternal complications that may occur due to corticosteroids intake, such as such as hypertension, diabetes and preeclampsia(34).
The biological therapy include anti-tumor necrosis factor α (anti-TNF) derivates, such as infliximab, adalilumab and certolizumab. These molecules are IgG-like immunoglobuline molecules that differ in their biochemical structure, half-life and transplacental passage(35). Unfortunately, there are few studies on the effects of biological therapy on pregnancy and fetus due to ethical causes. Searching the data from literature and from registries, we can conclude that the biological therapy is relatively safe when the medication is chosen according to the half-life, depending on the placental passage, and the possible adverse effects on the fetus and the newborn are known(37). Searching the persistence of TNFα inhibitors in the serum of the infants, studies have shown a persistence of 3-6 months for infliximab and for at least 11 weeks postpartum for adalimumab(36,37). Because TNF plays an important role in immunity against bacterial and viral infections, and pregnancy itself is a state of immunosuppression, this association represents a high risk for opportunistic infection in neonatal life(36). When compared with adalilumab and certolizumab, infliximab has the higher placental passage, and it must be stopped before 28 weeks of gestation.
The PIANO study showed no increased risk for maternal-fetal outcome when using adalilumab during pregnancy(31). Although intrauterine exposure to anti-TNF agents seems to have no risk on fetal development, the effects on the fetal imune system remain uncertain. Certolizumab pegol is a different IgG molecule, with different placental passage mechanism, having a low rate of transfer during the third trimester. It is a molecule that seems safer to use during late pregnancy(38). Unfortunately, data regarding the safety on using certolizumab during pregnancy are still limited.
Despite the lack of data, we should always keep in mind that the maternal-fetal risks related to an active maternal disease are higher compared to the risk of using therapy to control the disease. The biological therapy is a promising therapy, but it must be used properly in cases of steroid-refractory diseaseas, or multi-drug resistance disease. Adalilumab and infliximab should be interrupted before the third trimester, while certolizumab pegol seems to be safer to use even in the third trimester. Counseling during pregnancy is a must, because a interruption of therapy can induce a severe flare, with negative impact on the maternal-fetal outcome. The most frequent reason for non-compliance during pregnancy is the fear of adverse effects of medication on the fetus(39). Adequate treatment should be offered to those patients who wish to conceive, with the aim of reducing the risk of flares during pregnancy. Active disease and acute flares can compromise the maternal-fetal outcome in patients with IBD.
Conflict of interests: The authors declare no conflict of interests.