Elevated cord levels of ustekinumab following its use in the treatment of Crohn's disease in pregnancy

Abstract

Ustekinumab (USK) was used in the treatment of two pregnant patients with Crohn's disease. It was given in the third trimester and restarted postnatally for both women. One woman remained on USK and in remission throughout pregnancy. The second woman, took a treatment break, flared, and then had remission induced with reintroduction of USK. Both women delivered healthy term infants. The interval from last dose to birth was 11 and 8 weeks respectively. Interestingly, USK levels in cord blood was observed in higher concentrations than in the maternal serum taken in third trimester. While no adverse effect in infants has been observed, clinicians should remain aware of fetal transfer when using USK in pregnancy. An evaluation of risk and benefit may favour continuing USK in pregnancy in patients with refractory disease.

Introduction

Inflammatory bowel disease (IBD) (Crohn's disease and ulcerative colitis) is commonly diagnosed in women of reproductive age. Active disease is associated with increased rates of preterm delivery, caesarean section, and low birth weight. ¹ Patients with Crohn's disease have higher rates of voluntary childlessness. ² This may be explained by misinformation, and subsequent fear of the effect their disease and medications will have on pregnancy.^3,4 Poorly controlled disease is associated with subfertility. ⁵ Effective treatment enables the majority of women with IBD to have healthy pregnancies.

Ustekinumab (USK) is a monoclonal antibody against IL-12 and IL-23. Studies have shown USK to be an effective treatment for patients with moderate to severely active Crohn's disease who have had a suboptimal response to anti TNF agents. ⁶ Although it has been in use for a number of years there is limited data on its use in pregnancy.

Case 1

A 32-year-old woman in her first pregnancy, with a history of stricturing Crohn's disease treated with USK, booked at 12 weeks’ gestation. Her last flare was three years prior to pregnancy. She had an ileocaecal stricture and a history of poor response to adalimumab and infliximab. She had a past history of a rectal abscess and fistula 12 years prior from which she made a good recovery with no active perianal disease in pregnancy. Her disease was well maintained on USK prior to pregnancy and the decision was made to continue this during pregnancy. Baseline C-reactive protein was 2.6mg/L prior to pregnancy. She attended a obstetric medicine clinical regularly and her antenatal course was uncomplicated with no abnormality detected on fetal ultrasound at 20 weeks’ gestation. She continued on maintenance USK at a dose of 90mg subcutaneously every eight weeks and remained in clinic remission throughout her pregnancy. The last dose of USK was given at 28 weeks’ gestation. She had a spontaneous vaginal delivery of a liveborn male infant at 39 weeks’ gestation who weighed 3.4kg and had APGAR scores of 9 and 9 at 1 min and 5 min respectively. Maternal serum and infant cord bloods were sent at delivery for serum USK levels, 11 weeks from the last dose of USK. This showed a serum USK level of less than 1.1mg/L on the maternal delivery sample and 2.5mg/L on the cord sample (suggested therapeutic range 1.1–1.4mg/L). Levels were measured by an automated enzyme linked immunosorbent assay (ELISA) (Immundiagnostik). Serum levels in the neonate were not checked as it was not felt to be clinically indicated. The infant was admitted to the neonatal unit with mild transient tachypnoea of the newborn. Prophylactic antibiotics were commenced and blood and urine cultures were subsequently negative. The infant was breastfed and discharged home well with the mother on the third day of life. USK was recommenced at two weeks postpartum. At three months postpartum mother and infant were both well. No severe infections in the infant were reported. As it is a live vaccine, rotavirus vaccination was withheld in the first six months of life.

Case 2

A 34-year-old woman in her first pregnancy, booked at 13 weeks’ gestation. She had been diagnosed with ileocolonic Crohn's disease eight years prior and previously had an allergic reaction to azathioprine and adalimumab, and a secondary loss of response to infliximab. Her disease had been well controlled on USK 90mg eight weekly since 2018. Her baseline c-reactive protein was less than 1mg/L and her faecal calprotectin was 31µg/g.

She attended an obstetric medicine clinic regularly and her antenatal course was uncomplicated with no abnormality detected on fetal ultrasound at 20 weeks. She self discontinued her medication in the first trimester. This was restarted at 16 weeks following a flare of her Crohn's disease and a peak calprotectin of 5792 µg/g. Within a week of restarting USK her symptoms had improved, and within three weeks her calprotectin dropped to 2222 µg/g. Her last dose of USK was given at 32 weeks’ gestation.

She had a spontaneous vaginal delivery of a female infant at 38 weeks, who weighed 3.4kg with APGAR scores of 9 and 9 at 1 min and 5 min respectively. The infant was breastfed. Maternal serum and infant cord USK levels were measured as described for Case 1, eight weeks from the last administered dose.

Serum USK level from delivery was 1.6mg/L in the maternal delivery sample and 2.6mg/L (ref 1.1–1.4mg/L) in the cord sample. Serum levels in the neonate were not checked as it was not felt to be clinically indicated. USK was recommenced on day five postpartum and on day 9 the patient was readmitted with mastitis which responded to intravenous antibiotics. At three months postpartum mother and infant were both well. No severe infections occurred in the infant. Rotavirus vaccine was also withheld.

Discussion

IBD pregnancies can be complex and require multidisciplinary team input. Well controlled disease in women of reproductive age allows them to consider and plan for pregnancy. Optimal disease control before and during pregnancy is imperative. A meta-analysis of disease activity in pregnancy, found women with active disease at conception had twice the risk of ongoing active disease during pregnancy, compared to those in remission at conception. ⁷ Active disease may impair fertility ⁴ and in pregnancy, it is associated with an increased risk of low birthweight and preterm labour. ⁵

Ustekinumab is an IgG1 class monoclonal antibody. Trans-placental transport of IgG1 is facilitated by the fetal Fc receptors, first detected at 14 weeks. Therefore, the lowest period of fetal exposure is during the period of organogenesis in the first trimester. ⁸ Transplacental passage peaks in the third trimester. ⁸

As a relatively new treatment for IBD there is limited data on its use in pregnancy. Its use in pregnancy for psoriasis, which is usually treated with lower doses of USK, is not currently recommended due to insufficient fetal safety data. ⁹ To date, reports have demonstrated no increased risk of miscarriage or congenital malformation with use of USK in pregnancy, although controlled studies are not available. ¹⁰

Previous case reports have noted high cord USK levels with its use beyond 28 weeks’ gestation^11,12 consistent with the findings in this report. This finding has also been seen in animal studies with no adverse effects noted at supra-therapeutic doses. ¹³ Increased cord blood levels have also been found with anti-TNF monoclonal antibodies (infliximab and adalimumab). ¹⁴ Large studies have not shown adverse pregnancy outcomes with either of these agents.^15,16

The suggested therapeutic range for USK as a maintenance therapy is 1.1 to 1.4 mg/L . ¹⁷ Of note, this is based on slightly different methodology to the assay used in our cases. ¹⁸ The cord USK levels in both cases presented were above the level noted in the maternal serum. USK may be present in breastmilk ¹¹ but the risk of exposure of the infant is thought to be low due to the large size of the molecule and the degradation that occurs in the gastrointestinal tract. ¹⁹ It is recommended that live vaccines be avoided in infants potentially exposed to biologic agents in utero for the first six months of life. ¹⁰

These cases highlight the potential for USK to remain in the fetal circulation following exposure in the early third trimester. No apparent adverse effects were noted in these cases or in the small number of cases reported in the literature. These findings may impact practice as clinicians can inform their patients of this effect and could consider avoiding USK in the third trimester if the clinical situation allows. An evaluation of risk and benefit may favour continuing USK in pregnancy in patients with refractory disease due to the absence of reported adverse effects in pregnancy compared with the well documented pregnancy-related morbidity of poorly controlled IBD.