Inheritance

Family history is the strongest predictor for developing IBD. A Danish study looking at a population of 5.2 million found that the risk for UC and CD among offspring of patients with IBD was 2 to 13 times higher than the risk within the general population. Another study looking at the lifetime risks for IBD estimated that there was a 5.2% risk for CD and 1.6% risk for UC in first-degree relatives of probands. If both parents have IBD, this risk of their child having IBD has been shown as high as 36%. Although these statistics can be intimidating to patients, it is important to emphasize that IBD is an uncommon condition and not inherited in a true mendelian fashion.

Fertility

Fecundability is the ability to conceive after 1 menstrual cycle whereas infertility is the inability to conceive after 12 months of unprotected intercourse in women less than 35 years of age or after 6 months in women 35 or older. The current infertility rate for the general population has been shown to be approximately 10%, with 11.8% of women ages 15 to 44 with impaired fecundity. Although older studies have estimated infertility rates as between 32% and 42% in women with CD, more recent population-based and community-based studies indicate infertility rates as closer to 5% to 14%, which is similar to the general population. Although one case-control study documented the increased need for infertility treatments in IBD women, this was not significant after controlling for maternal age. Before surgery, age is the only independent risk factor affecting IBD fertility. Voluntary childlessness in IBD women is most likely greater than in the general population, as one case-control study of 216 patients revealed that a decrease in mean number of children born to IBD women was the result of choice and not inability.

Women with UC or CD seem to have fertility rates similar to the general population although this changes after surgical intervention. In 2002, Ording Olsen and colleagues found that women before and after the diagnosis of UC had fecundability ratios equal to that of the general population (fecundability ratio = 1.01) but after ileal pouch–anal anastomosis (IPAA) the fecundability ratio decreased to 0.20 ( P <.001). A meta-analysis demonstrated a 3-fold increased risk for infertility in patients who had an IPAA, with infertility increasing from 15% to 48% in women post-IPAA. Among a study of 945 patients in 7 studies, the infertility rate before restorative proctocolectomy was 12% and rose to 26% after IPAA. A decrease in fertility also occurs in women with familial adenomatous polyposis who undergo IPAA and those with a proctocolectomy with ileostomy. In CD, surgery may decrease fertility more than medical therapy alone. Fertility in CD is most likely consistent with the general population but may be impaired in those with active disease. Infertility risks should be discussed with patients along with the consideration of delaying pouch formation until after childbearing or considering an ileorectal anastomosis to possibly preserve fertility.

The true rate of male IBD infertility is unknown and a difficult endpoint to measure. A survey of 106 CD men, 62 UC men, and 140 controls revealed a similar fecundability between IBD patients and controls, suggesting that the high rate of infertility in CD men was voluntary. There are no definitive studies, but the general consensus is that IBD does not affect male fertility. In those men who have undergone an IPAA, there has been a small incidence of retrograde ejaculation and erectile dysfunction but overall IPAA may preserve or improve sexual function outcome.

Although cervical dysplasia has been cited as a factor for reduced fertility, it is controversial whether this plays a role in women with IBD.

Men on sulfasalazine have reversible impairment of sperm motility and sperm counts in up to 60% of patients. This effect is reversible, however, within 2 full cycles of spermatogenesis or within 2 months of cessation of the drug. A small single-center study suggests that infliximab (INF) therapy decreases sperm motility and oval forms, but this has yet to be translated into a clinical decrease in male fertility rates on INF.

Reproductive issues are major concerns of IBD women; recent studies reported that many IBD patients refrain from having children due to concerns of adverse reproductive outcomes. Discussions on fertility and risk factors should be with a more positive outlook than in the past to overcome many misconceptions.

Fertility

Fecundability is the ability to conceive after 1 menstrual cycle whereas infertility is the inability to conceive after 12 months of unprotected intercourse in women less than 35 years of age or after 6 months in women 35 or older. The current infertility rate for the general population has been shown to be approximately 10%, with 11.8% of women ages 15 to 44 with impaired fecundity. Although older studies have estimated infertility rates as between 32% and 42% in women with CD, more recent population-based and community-based studies indicate infertility rates as closer to 5% to 14%, which is similar to the general population. Although one case-control study documented the increased need for infertility treatments in IBD women, this was not significant after controlling for maternal age. Before surgery, age is the only independent risk factor affecting IBD fertility. Voluntary childlessness in IBD women is most likely greater than in the general population, as one case-control study of 216 patients revealed that a decrease in mean number of children born to IBD women was the result of choice and not inability.

Women with UC or CD seem to have fertility rates similar to the general population although this changes after surgical intervention. In 2002, Ording Olsen and colleagues found that women before and after the diagnosis of UC had fecundability ratios equal to that of the general population (fecundability ratio = 1.01) but after ileal pouch–anal anastomosis (IPAA) the fecundability ratio decreased to 0.20 ( P <.001). A meta-analysis demonstrated a 3-fold increased risk for infertility in patients who had an IPAA, with infertility increasing from 15% to 48% in women post-IPAA. Among a study of 945 patients in 7 studies, the infertility rate before restorative proctocolectomy was 12% and rose to 26% after IPAA. A decrease in fertility also occurs in women with familial adenomatous polyposis who undergo IPAA and those with a proctocolectomy with ileostomy. In CD, surgery may decrease fertility more than medical therapy alone. Fertility in CD is most likely consistent with the general population but may be impaired in those with active disease. Infertility risks should be discussed with patients along with the consideration of delaying pouch formation until after childbearing or considering an ileorectal anastomosis to possibly preserve fertility.

The true rate of male IBD infertility is unknown and a difficult endpoint to measure. A survey of 106 CD men, 62 UC men, and 140 controls revealed a similar fecundability between IBD patients and controls, suggesting that the high rate of infertility in CD men was voluntary. There are no definitive studies, but the general consensus is that IBD does not affect male fertility. In those men who have undergone an IPAA, there has been a small incidence of retrograde ejaculation and erectile dysfunction but overall IPAA may preserve or improve sexual function outcome.

Although cervical dysplasia has been cited as a factor for reduced fertility, it is controversial whether this plays a role in women with IBD.

Men on sulfasalazine have reversible impairment of sperm motility and sperm counts in up to 60% of patients. This effect is reversible, however, within 2 full cycles of spermatogenesis or within 2 months of cessation of the drug. A small single-center study suggests that infliximab (INF) therapy decreases sperm motility and oval forms, but this has yet to be translated into a clinical decrease in male fertility rates on INF.

Reproductive issues are major concerns of IBD women; recent studies reported that many IBD patients refrain from having children due to concerns of adverse reproductive outcomes. Discussions on fertility and risk factors should be with a more positive outlook than in the past to overcome many misconceptions.

Effect of IBD on pregnancy

It is widely believed that the impact of IBD on pregnancy depends on disease activity at conception. Studies suggest that quiescent disease throughout pregnancy leads to risks similar to that of the general population regarding spontaneous abortion, pregnancy-related complications, and adverse perinatal outcomes. Disease activity at conception has been associated with preterm births, low birth weight (LBW), and fetal loss. In addition, active disease during pregnancy has been shown the greatest risk of adverse perinatal outcomes. This risk seems higher in women with CD than with UC. Severe disease relapses during pregnancy in UC, however, are associated with shorter gestation periods and lower birth weights. Reddy and colleagues found a higher risk of preterm births among their study group, with the mean gestational age 35 weeks versus 38.7 weeks in the control group (without disease relapse). Despite a consistent trend of preterm delivery, most of the deliveries occurred after 35 weeks with favorable outcomes.

In a cohort of 54 pregnant CD patients, patients with active disease at conception had rates of miscarriage up to 35% higher than those patients who were in remission. In 2007, Norgard and colleagues examined the impact of disease activity on birth outcomes in CD and reported that activity during pregnancy only increased the risk of preterm birth. It also has been shown that the presence of ileal disease in CD women was a strong predictor for LBW. In a study by Dominitz and colleagues, greater risk of congenital abnormalities was seen in UC women compared with controls (7.9% vs 1.7%, P <.001). This study failed to take into consideration, however, disease activity or medication use and has not been replicated by other investigators. Most studies have found no greater risk in malformations in UC or CD. Lamah and Scott determined that there was no increased risk of spontaneous abortions, perinatal mortality, or congenital malformations in their UC cohort.

The largest study to date on this topic is the meta-analysis by Cornish and colleagues, which evaluated 12 studies in regard to the impact of IBD on pregnancy. This study comprised 3907 patients with IBD and 320,531 controls. Based on this analysis, women with IBD were more likely to experience adverse pregnancy outcomes, such as premature birth and LBW. Premature delivery was almost twice as likely compared with the general population. Women with IBD were also 1.5 times more likely to undergo cesarean section. Unfortunately, neither medication use nor disease activity was analyzed as a confounder, which makes it difficult to put the results into perspective. The meta-analysis reported a 2.37-fold greater risk of congenital abnormalities (95% CI, 1.47, 3.82; P <.001) but most of the studies included failed to differentiate between minor and major malformations. In 2006, a Spanish study of 124 pregnant CD women looked at pregnancies before and after diagnosis. It concluded that the course of IBD did not adversely affect pregnancy or the postpartum time period. Furthermore, the study determined that diagnosis before pregnancy did not influence the number of cesarean sections performed or increase the presence of LBW infants.

In 2007, in the largest US study to date, Mahadevan and colleagues compared pregnancy outcomes between women affected with IBD and those unaffected. The study comprised 461 pregnant IBD patients and a randomly selected cohort of age-matched controls. They found that women with IBD were more likely to have an adverse pregnancy complication (stillbirth, preterm birth, or small for gestational age; odds ratio [OR] 1.54 (95% CI, 1.00, 2.38), spontaneous abortion (OR, 1.65; 95% CI, 1.09, 2.48), or complication of labor (OR 1.78; 95% CI, 1.13, 2.81) than those women without IBD. Irrespective of disease activity, there was no difference in adverse newborn outcomes or congenital abnormalities. Independent predictors of adverse outcomes included IBD diagnosis, history of IBD surgery, and nonwhite ethnicity. The use of IBD medications was not found predictive of adverse outcome in this large, nonreferral population. There also was no statistically significant difference in newborn outcomes between the IBD and control pregnancies. Furthermore, severity of disease and medical treatment were not associated with adverse outcomes.

In the general population, maternal smoking is a known risk factor for LBW infants and for disease activity in CD women. Pregnant CD patients who smoke are at a substantial increased risk for LBW and preterm delivery. Conversely, maternal smoking in UC women does not increase their risk of preterm delivery. Given the known risk of maternal smoking on the mother and baby, maternal smoking cessation should be discouraged in all scenarios.

Many studies continue to associate preterm birth and IBD; however, the majority of these “preterm” deliveries occurred after 35 weeks of gestation. It is possible that safety concerns for the mother and baby may prompt induction of early delivery, which would bias the end result of an LBW infant. These factors need to be more clearly defined. Despite many observational studies, it is difficult to determine the effect of drug and/or drug cessation versus the disease itself on pregnancy outcomes. Premature infants and LBW are consistently observed, although most studies have shown that the risk of congenital malformations shows no increase compared with the 1% to 4.8% risk seen in the general population. Despite mixed data, it seems that the disease activity can be an impetus for adverse pregnancy outcomes, because miscarriages are seen more frequently with active disease. In the Mahadevan study, however, disease activity was not found predictive of adverse outcome.

Effect of pregnancy on IBD

A consistent finding in recent literature has been that the rate of disease flare during pregnancy (26%–34%) is similar to nonpregnant flare rates. An exacerbation rate of 34% per year during pregnancy in UC women and 32% per year when not pregnant was observed by Nielson and colleagues in 1983. These rates of relapse were similar in the CD population. In addition, the Kaiser cohort, as discussed previously, included women with inactive disease throughout their pregnancy with no sudden increase in activity postpartum.

Delivery

The recommended mode of delivery in CD patients is still controversial. In comparison with the general population, CD patients undergo cesarean sections more frequently, with the rate of cesarean sections increasing after first delivery. Using the 2005 Nationwide Inpatient Sample, Nguyen and colleagues examined 2372 CD deliveries and 1368 UC deliveries. In this population-based study, the adjusted ORs of a cesarean section were higher in women with CD (adjusted OR 1.72) and UC (adjusted OR 1.29) compared with non-IBD controls. There are conflicting data concerning vaginal deliveries and perianal disease. The recommendation to avoid vaginal deliveries in the setting of active perianal disease was based on small, observational studies. In contrast, many IBD physicians feel that CD patients with uncomplicated disease should be treated like the general population when deciding on delivery, but episiotomy should be avoided. The concern with vaginal delivery is not pouch injury but potential anal sphincter damage. Although pouch function may deteriorate during pregnancy, after pregnancy it has been shown to revert back to the prepregnancy state. The presence of a colostomy or ileostomy also should not designate delivery choice. Despite limited data, choice of delivery should be a collaborative decision between patient, gastroenterologist, and obstetrician.

Breastfeeding

Any detriment to maternal health secondary to nursing after delivery is controversial. There have been many reported associations between nursing and increased disease activity, but it is unclear whether this is related to disease course or cessation of medication. Kane and Lemieux found the OR of disease flare for women who breastfeed to be 2.2 (95% CI, 1.2, 2.7) compared with those who did not breastfeed. Once medication discontinuation was factored in, however, the OR became nonsignificant. Moffatt and colleagues published a population-based study of breastfeeding and found no increased risk of flare in the postpartum period and a possible protective effect once the discontinuation of medications was taken into account.

Patient concerns surrounding breastfeeding are related to secretion of medication into breast milk leading to exposure to the baby. Medications known to be safe for breastfeeding include sulfasalazine, mesalamine, and steroids with only a minimal amount secreted into the milk. There is a rare association of diarrhea in the infant with aminosalicylates. Metronidazole is excreted in breast milk and suspension of breastfeeding for 12 to 24 hours after dosing is recommended. Data thus far on thiopurines suggest minimal secretion into breast milk. In the past, breastfeeding was discouraged with azathioprine (AZA)/6-mercaptopurine (6-MP) use, but current data are more positive. Four women on AZA and breastfeeding were reported by Moretti and colleagues. Two of the women did not have detectable levels of AZA and all four successfully breastfed without complications. Two other studies measured metabolite levels in breastfeeding infants and found zero to low levels of drug in breast milk. They also found no signs of hematologic or clinical immunosuppression in 10 infants. The most recent and elegant study by Christensen and colleagues in 2008 revealed that the most 6-MP in breast milk was excreted in the first 4 hours after drug intake in the 8 lactating women studied. The maximum concentration was measured and it was calculated that the infant ingested less than 0.008 mg/kg bodyweight per 24 hours. Waiting 4 hours after dosing to breastfeed is warranted and one strategy is nighttime dosing with pumping and dumping of breast milk 4 hours later. Although all of this is reassuring, the risks and benefits of breastfeeding must be discussed and there does not seem to be a contraindication to breastfeeding on 6-MP/AZA. Biologics have not been detected in breast milk and are usually continued postpartum.

Long-term effects of pregnancy on IBD

There have not been any data to suggest a detrimental long-term effect of pregnancy on the course of IBD and there is never a role for elective termination based on a history of IBD alone. In specific cases of presence of methotrexate (MTX) or thalidomide exposure, the decision for a therapeutic abortion may need to be addressed given that these have a known association with fetal abnormalities. Pregnancy has not been shown to definitively alter disease phenotype. Riis and colleagues along with Castiglione and colleagues demonstrated that parous IBD patients experienced a reduction in relapse rate in the 3 years after pregnancy when compared with the 3 preceding years. The rate of relapse decreased in the years after pregnancy in both UC and CD. Riis and colleagues looked at 580 IBD pregnancies in a European cohort. The pregnancy itself did not influence disease phenotype or surgery rates, but it was associated with a reduced number of flares in the succeeding years (UC 0.34 vs 0.18 flares/y, P = .008, and CD 0.76 vs 0.12 flares/y, P = .004). In addition, a negative correlation between increasing parity and number of resections has been demonstrated. Nwokolo and colleagues found that in parous women with CD, the need for surgical resection was inversely correlated with increasing parity. In parous IBD women, the incidence of relapses in the first 3 years after pregnancy was lower than before pregnancy. Hormonal changes during and after pregnancy may account for a change in fibrosis and stricture formation. Some studies suggest a down-regulation of the immune system with maternal fetal HLA disparity. Maternal immune response to paternal HLA antigens may result in immunosuppression that can in turn affect the maternal immune-mediated response. Kane and colleagues looked at 50 pregnancies in 38 women and found 42 disparate (84%) at the HLA-DRB1 locus, 34 (68%) at the HLA-DQ locus, and 31 (62%) at both loci. A significant difference was found in IBD activity between women mismatched at both loci versus only 1 or neither locus (OR 8.4, P = .01). Improvement of IBD symptoms during pregnancy was associated with disparity in HLA class II antigens between mother and fetus. When logistic regression was performed, prepartum disease activity and disparity at both HLA-DRB1 and HLA-DQ were significant predictors of overall disease activity during pregnancy. There has been no evidence to support a detrimental effect of pregnancy on IBD and, on the contrary, pregnancy has been shown to decrease disease activity and surgical need in certain patients. Given the cumulative data, pregnancy should never be discouraged or terminated on the basis of an IBD diagnosis alone but on a combination of other factors.