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Inflammatory bowel disease
Original article
Tailored anti-TNF therapy during pregnancy in patients with IBD: maternal and fetal safety
  1. A de Lima1,
  2. Z Zelinkova1,2,
  3. C van der Ent1,
  4. E A P Steegers3,
  5. C J van der Woude1
  1. 1Department of Gastroenterology and Hepatology, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands
  2. 2IBD Center, Thalion, Bratislava, Slovakia
  3. 3Department of Obstetrics and Gynecology, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands
  1. Correspondence to A de Lima, Department of Gastroenterology and Hepatology, Erasmus University Medical Center Rotterdam, ‘s Gravendijkwal 230, Rotterdam 3015 CE, The Netherlands; a.delima{at}erasmusmc.nl

Abstract

Objective Antitumour necrosis factor (TNF) during pregnancy in patients with IBD is related to high fetal anti-TNF levels. We evaluated maternal and child safety on discontinuing anti-TNF in the second trimester of pregnancy.

Design Two groups of women with IBD were prospectively followed-up during pregnancy: women in sustained remission stopped anti-TNF before week 25 (stop group) and the remaining group continued anti-TNF beyond week 30 (continue group). Maternal, birth and 1-year child outcomes were compared with children of non-IBD women.

Results Overall, 106 patients with 83 completed pregnancies were included. Relapse rate after week 22 did not differ between the stop (n=51) and continue (n=32) groups (5 (9.8%) versus 5 (15.6%), p=0.14). There was no difference in allergic reactions (p=1.00) or loss of response (p=1.00) postpartum between the two groups. Birth outcomes were comparable. Infants from both groups had lower birth weight (p=0.001), shorter gestational term (p=0.0001), were more often delivered via caesarean section (p=0.0001) and were less often breastfed (p=0.0001) compared with infants from non-IBD controls. Growth, infection rate, allergies, eczema and adverse reactions to vaccines were comparable across the stop and the continue groups as well as the children of anti-TNF-exposed and non-IBD women at 1 year.

Conclusions To limit anti-TNF exposure in utero, anti-TNF can be stopped safely in the second trimester in women with IBD in sustained remission. In patients not in sustained remission, anti-TNF may be continued without clear additional risks to the fetus. We observed excellent 1-year child outcomes compared with children from non-IBD controls.

  • IBD

https://doi.org/10.1136/gutjnl-2015-309321

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    Significance of this study

    What is already known on this subject?

    • Antitumour necrosis factor (TNF) agents such as infliximab and adalimumab are Food and Drug Administration category B and considered to be of relatively low risk during pregnancy in terms of teratogenicity.

    • Continuation of anti-TNF during pregnancy is associated with higher anti-TNF levels in the newborn.

    • Limited data is available on the immunological and developmental consequences in the infant exposed to anti-TNF in utero.

    What are the new findings?

    • Stopping anti-TNF in pregnant women with IBD, especially in pregnant women with Crohn's disease (CD), in sustained remission in the second trimester does not lead to an increased relapse risk during pregnancy, allergic reactions or loss of response after resumption of anti-TNF postpartum.

    • Birth outcomes of women with IBD stopping anti-TNF in the second trimester compared with those treated with anti-TNF throughout the entire pregnancy are comparable.

    • At birth, the anti-TNF exposed infants had lower birth weights, shorter gestational term and were more often delivered by caesarean section compared with the infants from non-IBD mothers.

    • At 1 year of age, growth, infection rate, allergies, eczema and adverse reactions to vaccines were comparable between the anti-TNF stop and continue groups.

    • At 1 year of age, growth, infection rate, allergies, eczema and adverse reactions to vaccines were comparable between the anti-TNF exposed infants and the infants born to non-IBD mothers.

    How might it impact on clinical practice in the foreseeable future?

    • To limit fetal anti-TNF exposure, women with IBD in sustained remission can safely stop anti-TNF in the second trimester. When indicated, however, continuation of anti-TNF during the entire pregnancy also seems of low risk.

    • Development in the first year of the anti-TNF-exposed infant seems comparable with that in controls.

    Introduction

    IBD typically affects young people with reproductive potential.1 In most patients, the chronic and relapsing character of the disease calls for intensive, lifelong medical treatment to maintain disease remission. Inevitably, a proportion of female patients with IBD will require medical treatment for IBD during pregnancy. Although most IBD medications are considered of low risk, a full safety profile of especially the more recent IBD medications during pregnancy has not yet been established. Until now, IBD activity during pregnancy has proved more harmful to the pregnancy than most IBD medications.2–4 Women with IBD with a pregnancy wish therefore face the dual challenge of maintaining disease remission during pregnancy and at the same time avoiding possible harmful effects of medication on the fetus. One of the most recent medical treatments for IBD is the antitumour necrosis factor α (anti-TNF) agents such as infliximab (IFX) and adalimumab (ADA). Over the past decade, an increasing amount of evidence suggests a low risk of anti-TNF use during pregnancy.2–7 Both ADA and IFX, however, are capable of crossing the placenta in the second and third trimester of pregnancy. Anti-TNF levels in the newborn are dependent on the timing of anti-TNF cessation during pregnancy, and these levels tend to exceed maternal anti-TNF levels.6 ,8 The long-term effects of these clinically significant anti-TNF levels in children are relatively unexplored. Although a few small follow-up studies4 ,9 suggest no serious adverse events in these children, one case report described a fatal case of disseminated bacille Calmette-Guérin infection in an infant exposed to IFX in utero, which showed that live attenuated vaccinations in children exposed to anti-TNF in utero may be associated with adverse outcome. In addition, a recent case series reported four infants exposed to IFX in utero with severe neutropenia at birth.10 Adverse outcomes in the newborn may be avoided by lowering perinatal anti-TNF serum levels in the infants by stopping anti-TNF treatment in the second trimester of pregnancy in women with IBD in remission.6 At our institution, it has been standard clinical care to stop anti-TNF in women with IBD in sustained remission in the 22nd gestational week. The aim of this study was to assess the effect of anti-TNF cessation in the second trimester on the mother in terms of (1) risk of disease relapse after anti-TNF cessation, (2) loss of response and (3) allergic reactions after re-initiation of anti-TNF postpartum. As a secondary aim, the neonatal outcomes of and health status at 1 year of life of children exposed to anti-TNF in utero were compared with a control group of children born to non-IBD mothers matched by maternal age and ethnicity. In addition, cord blood and maternal peripheral blood anti-TNF levels at delivery were measured and compared between the stop and continue groups.

    Methods

    Study design and setting

    A single centre ongoing prospective clinical cohort study was conducted at the Erasmus University Medical Center Rotterdam. From December 2008 until June 2014, all women with a confirmed diagnosis of IBD treated with any anti-TNF agent who visited the IBD preconception outpatient clinic were enrolled in the study. In part this cohort consists of patients from a previously published cohort;6 however, this study has collected additional follow-up data on these patients. At this specialised outpatient clinic, an experienced gastroenterologist counsels and treats patients with IBD before pregnancy and bimonthly during pregnancy. All consultations were performed in a standardised manner adhering to European Crohn´s and Colitis Organisation guidelines.11 ,12 At every visit, data on disease activity, medication use and pregnancy complications was recorded. In case of disease activity, patients were seen every 2 weeks at our outpatient clinic. Further, these patients were followed up at the department of obstetrics.

    Participants

    Anti-TNF treatment in women with IBD in sustained remission around gestational week 20 was discontinued before week 25 (stop group). Women with IBD not in sustained remission continued anti-TNF during the entire pregnancy and their last dose was administered at gestational week 30 or later (continue group) according to their regular treatment schedule. Sustained remission was defined as remission from 3 months prior to pregnancy and throughout pregnancy until gestational week 20. Women not in sustained remission had disease activity with or without achieved remission at any time 3 months prior to pregnancy and/or within the first 20 weeks of pregnancy or a history of a very difficult to achieve remission in the year preceding pregnancy. Pregnant women in whom the anti-TNF was stopped in the first trimester or at the decision of another physician were not eligible for enrolment in this study.

    Control group

    Birth and child outcomes of anti-TNF exposed children were compared with children born to non-IBD mothers not treated with anti-TNF as recruited from the Generation R cohort.13 Generation R is a large prospective birth cohort (n=9778) from the same geographical region as where the patients with IBD in our cohort originate from. In the Generation R cohort mothers are prospectively followed up during pregnancy and their children will be prospectively followed up until the age of 18. Children born in this cohort were born between 2002 and 2006. A random sample of approximately 800 children from live, singleton births participating after birth was drawn. This sample was age and ethnicity matched and the selection was made blinded for the follow-up outcomes.

    Study size

    The aim was to include at least 100 pregnant women with IBD on anti-TNF. This study enrolled 106 pregnant women with IBD on anti-TNF with 83 live births. For each participating pregnant woman with IBD with a live, singleton birth, approximately 10 non-IBD mother–child pairs were selected.

    Variables and data measurement

    The primary aim of this study was to assess maternal safety of stopping anti-TNF treatment in the second trimester of pregnancy. Disease relapse after treatment cessation and allergic reactions and secondary loss of response to anti-TNF after delivery after re-initiation of anti-TNF were measured. Only newly acquired disease activity after the median time of treatment cessation in the stop group was compared. Persistent disease activity in the continue group was excluded from the analysis. Disease activity was assessed at every 2 months during pregnancy and relapse was defined as a Harvey Bradshaw Index for CD >5 and Simplified Clinical Colitis Activity Index for UC >2 and/or either C-reactive protein >9.0 mg/L (n≤9.0 mg/L) or faecal calprotectin >200 µg/g (n≤200 µg/g). If necessary, endoscopy was performed to assess mucosal inflammation. Allergic reaction upon anti-TNF re-initiation was defined as anaphylactic/allergic reaction at the first three infusions or injections postpartum requiring treatment. Secondary loss of response to anti-TNF after delivery was defined as disease activity while on anti-TNF treatment 6 months after delivery requiring dose escalation or switch to another treatment strategy.

    Secondary outcomes included anti-TNF levels, birth outcomes and 1-year child outcomes. Pregnancy and birth outcomes were noted. At delivery, umbilical cord and maternal peripheral blood samples were obtained. Cord blood anti-TNF levels were reported to the parents and precautionary advice was given based on the results. Cord blood anti-TNF levels below the cut-off of 3 µg/mL were not repeated at 3 months. We used this arbitrary cut-off because in adults it is associated with response to anti-TNF treatment.14 ,15 In infants with anti-TNF levels in their cord blood exceeding 3 µg/mL, the levels were again measured at 3 months. Patients were advised to reinitiate their anti-TNF treatment 2 weeks postpartum. Further, we advised parents to refrain from daycare admittance of their child, to be extra cautious of infectious sources and delay any possible live attenuated vaccine until anti-TNF levels in the infant were below 3 µg/mL. One-year follow-up of the child was obtained through telephonic questionnaires with the mothers and by obtaining the medical information of the children from the general practitioner. Anti-TNF levels in cord blood, maternal peripheral blood and if necessary in the infant at 3 months were assessed by ELISA according to a previously described protocol.8 Birth outcomes included birth weight, gestational age at birth, APGAR (Appearance, Pulse, Grimace, Activity, Respiration) scores and congenital abnormalities.

    Definitions

    Low birth weight (LBW) was defined as birth weight lower than 2500 g and preterm birth as delivery prior to gestational week 37. Small for gestational age (SGA) referred to a weight below the 10th percentile for gestational age.16 One-year child outcomes included growth of the child, number of infections requiring antibiotics or hospitalisation, allergies, eczema and adverse reactions to vaccinations. Abnormal growth was defined as weight or height for age and sex deviating more than ±2SD from the mean Dutch growth chart at any measurement point in the first year.

    Bias

    Inherently, the continue group will have an increased risk of relapse after gestational week 22 compared with the stop group. We therefore only compared newly acquired disease activity after week 22 for our primary outcome, and did not count persistent disease activity. Other confounding variables for both the primary outcome and the secondary outcomes such as smoking, alcohol use and folic acid intake were also collected.

    Statistical methods

    All analyses were performed using IBM SPSS statistics (V.20.0 Chicago III, USA). Descriptive statistics of continuous variables are depicted as means with SEM and medians with IQR. These were compared across the study and the control group using student t tests and Mann Whitney U tests, respectively. Categorical variables are depicted in absolute numbers and percentages and compared across groups using χ2 or Fisher's exact tests. All tests were performed using 2-tailed tests and tested at a significance level of 0.05.

    Ethical considerations

    The local ethics committee approved data collection and analyses. Informed consent of the legal guardians of the children was obtained to collect 1-year follow-up data of the child participants. The use of data from the ‘Generation R’ cohort was also approved by the local ethics committee.

    Results

    IBD group

    We followed up 106 pregnancies in 106 women treated with anti-TNF. These 106 pregnancies resulted in 87 live singleton births (82%), 18 spontaneous abortions (17%) and 1 termination of pregnancy (1%). In four women the anti TNF was stopped in the first trimester. This was indicated by a physician other than the IBD consultant. These pregnancies were excluded from further analysis. The baseline characteristics are shown in table 1.

    View this table:
    Table 1

    Baseline characteristics

    Non-IBD control group

    The random age-matched and ethnicity-matched sample drawn from the Generation R cohort resulted in a control group of 804 non-exposed, non-IBD women with 804 live singleton births.

    Maternal outcomes

    Maternal outcomes are shown in table 2. The stop group had a median time off anti-TNF drugs of 21 weeks (IFX) and 20.5 weeks (ADA), whereas the continue group had a median time off anti-TNF drugs of 11.5 weeks (IFX) and 2.3 weeks (ADA) (p=0.0001 and p=0.0001). The median gestational time of anti-TNF cessation in the stop group was 22 weeks (21–23). Overall, we observed no differences in relapse rate after gestational week 22. Five women relapsed after gestational week 22 in the stop group, whereas five women relapsed after gestational week 22 in the continue group (p=0.14). There was no difference in concomitant treatment in both groups. Furthermore, only two patients developed allergic reactions to anti-TNF postpartum and only one woman experienced loss of response to anti-TNF after resumption postpartum. There were no statistically significant differences in allergic reactions and loss of response postpartum (p=1.00 and p=1.00, respectively).

    View this table:
    Table 2

    Maternal outcomes

    Birth outcomes

    Stop versus continue group

    The birth outcomes are shown in table 3. No differences in birth weight, gestational age at birth, congenital abnormalities and mode of delivery were observed between the stop and the continue groups. Gestational age at birth was significantly lower in children born to women with IBD with disease activity during pregnancy compared with women without disease activity (38.0 vs 39.3 weeks, p=0.005). There was no significant difference in birth weight between mothers with IBD with disease activity during pregnancy and mothers with IBD without disease activity during pregnancy (3252 vs 3363 g, p=0.44). Women who stopped anti-TNF in the second trimester more often breastfed their child compared with the anti-TNF continuation group (20 vs 5, p=0.04).

    View this table:
    Table 3

    Birth outcomes

    Anti-TNF exposed versus non-IBD controls

    Birth outcomes of anti-TNF exposed pregnant women (n=83) were compared with birth outcomes of non-IBD maternal controls (n=804). Children born to mothers with IBD treated with anti-TNF during pregnancy had statistically significant lower birth weights (3320 vs 3512 g, p=0.0001) and a shorter gestational age at birth (39.0 vs 40.1 weeks, p=0.0001). Birth weight and gestational age at birth were significantly correlated (r=0.52, p=0.0001). There were no differences in the prevalence of SGA babies between the exposed and the non-IBD controls (4.9% vs 9.7%, p=0.17). Gestational age at birth was significantly lower in children delivered by caesarean section (38.6 vs 40.0 weeks, p=0.0001). The anti-TNF-exposed group also had a higher proportion of LBW (<2500 g) babies compared with the non-IBD maternal controls (9.8% vs 3.6%, p=0.02). There were no significant differences in the proportion of preterm (<37 weeks) babies across the groups (8.5% vs 3.7%, p=0.08). No difference in congenital abnormalities was observed between the anti-TNF exposed and the non-IBD controls (3.7% vs 3.5%, p=0.79). Mothers with IBD more often delivered by caesarean section compared with the non-IBD controls (43.9% vs 11.3%, p=0.0001). Secondary caesarean sections were performed in 10 (27.1%) women with IBD compared with 47 (51.6%) non-IBD controls (p=0.01). Labour was induced in 5 (11.1%) women with IBD versus 87 (12.2%) non-IBD women (p=1.00). Breastfeeding was more common among the non-IBD controls than the women with IBD (86.3% vs 30.5%, p=0.0001).

    Anti-TNF levels

    Median IFX cord blood levels were significantly lower in the stop group compared with the continue group (1.9 vs 13.1 µg/mL, p=0.0001) and median IFX cord blood levels were significantly higher than the median IFX levels in the maternal peripheral blood (p=0.001 and p=0.003, respectively). All repeated IFX measurements in the children at 3 months were below 3 µg/mL. Similar results were seen in the ADA-treated patients, but the groups were too small to achieve statistical significance (n=18 vs n=7, 0.9 vs 3.3 µg/mL, p=0.16).

    One-year follow-up data

    Complete 1-year follow-up data of the children was available in 53 women with IBD (70.6%) and in 459 non-IBD maternal controls (57.1%). Another 345 non-IBD control women (42.9%) had partially complete 1-year follow-up data of the child. The 1-year follow-up data of the children are shown in table 4.

    View this table:
    Table 4

    Child outcomes in the first year of life

    Between the stop group and the continue group, no differences in growth, number of infections, allergies and eczema were observed. The most common infections requiring antibiotic treatment in the children were acute otitis media (n=19, 46.2%) and upper respiratory tract infection (n=13, 26.9%). Other less common infections included conjunctivitis (n=3, 12%), tonsillitis (n=1, 4%), paronychia (n=2, 8%) and rotavirus (n=1, 4%). Three infants in the stop, as well as three infants in the continue group, were admitted to the hospital for serious infections. These infections included serious respiratory tract infections (n=4), multiple skin abscesses requiring intravenous antibiotics (n=1) and respiratory syncytial virus infection (n=1). All infections resolved without sequelae. There were no adverse reactions to vaccinations in the anti-TNF exposed group.

    No statistically significant differences in growth, infections requiring hospitalisation, allergies and eczema were observed between the anti-TNF exposed children and the children of non-IBD controls. Overall, there was no difference in median number of infections requiring antibiotics between the anti-TNF-exposed children and the controls. However, children from the non-IBD controls more often had infections requiring antibiotics (24.5% vs 39.9%, p=0.02). There was no difference in infection rate requiring antibiotics or hospitalisation between the children from mothers on anti-TNF monotherapy and from mothers that were treated concomitantly with immunomodulators (IS) (n=16 (38.1%) vs 2 (20%), p=0.29). Data on adverse reactions to vaccinations was not available in the children born to non-IBD mothers.

    Discussion

    In this study, we assessed the safety of discontinuing anti-TNF for women with IBD in the second trimester of pregnancy.

    We show that in pregnant women in sustained remission anti-TNF can be stopped in the second trimester without increased risk of relapse during the time off drugs, compared with pregnant women who continue anti-TNF. The continue group as a control group may be biased in terms of relapse risk; however, we exclusively compared newly developed disease relapse after gestational week 22, and with this approach excluded persistent disease activity from the analysis. In addition, stopping was not associated with a higher risk of allergic reactions or secondary loss of response after anti-TNF re-initiation postpartum. Studies in non-pregnant patients with IBD demonstrated that episodic treatment and increasing the interval between anti-TNF administration led to an increased risk of relapse and side effects.17 ,18 We did not measure antibodies which might be related to our contrasting results in pregnant patients with IBD.19

    Reasons for stopping anti-TNF in the second trimester are primarily the unknown effects of anti-TNF on the developing child. Preliminary results from a large prospective registry in the USA (PIANO registry) showed that combination therapy of anti-TNF and IS in women with IBD during pregnancy increases the risk of infection in their offspring.20 This was compared with women with IBD using other or no medication, instead of non-IBD controls. In our study we did not observe an increased infection risk in children born to mothers treated with anti-TNF monotherapy or combination therapy. Approximately 50% of the children were treated for an infection with antibiotics and this is in line with data from an uncontrolled study with follow-up data on anti-TNF exposed children from 25 mothers with IBD where 32% of children were treated with antibiotics in the first year of life.9 We show that the infection risk in the children exposed to anti-TNF in utero is comparable with the infection risk in children born to non-IBD controls and therefore anti-TNF during pregnancy seems not associated with a higher risk for infections in the offspring. However, we have to underline that parents of anti-TNF-exposed children, especially the ones with high anti-TNF cord blood levels, were advised to be extra careful of infectious sources such as daycare centre admittance. This advice likely confounds the infection data in this study.

    IFX and ADA are both complete IgG1 antibodies, and are transported across the placenta,21 ,22 depending on the neonatal FcR expression. We have previously reported that cord blood IFX and ADA levels significantly relate to timing of anti-TNF stoppage during pregnancy and we confirmed this with this larger study.6 ,8 Unfortunately, we were not able to obtain cord blood samples from all newborns (67.5%). The missing cord blood samples were missing at random because of logistic difficulties. Of interest, in the stop group ADA cord blood levels, but not the IFX cord blood levels, never exceeded the threshold of 3 µg/mL. IFX levels at 3 months were still detectable, but none of the measurements in both the stop and continue groups were above 3 µg/mL. However, although the cut-off value of 3 µg/mL may be an indicator for therapy response, it is unclear whether anti-TNF levels above 3 µg/mL might be related to immune-mediated complications in the child.

    This study did not demonstrate a difference in the rate of congenital abnormalities at birth. However, we cannot exclude differences in the number of pregnancy terminations earlier in pregnancy because of fetal malformations related to disease or medication. We have no information on this. Furthermore, pregnancies in women with IBD are characterised by a lower birth weight of the children as well as lower gestational age at birth. Further, there was an increased risk of caesarean sections in our patients with IBD, mainly in CD women. These findings are in line with several previous studies.23–28 In this study, earlier gestational age at birth, but not lower birth weight, was associated with active disease. The observed lower birth weight in the anti-TNF-exposed babies compared with non-IBD controls cannot be fully explained by shorter gestational terms. It is likely that the observed lower birth weight in this study is a result of the presence of maternal IBD alone (see online supplementary table S1) and less likely an effect of the anti-TNF exposure in utero. The latter is also in contrast to several studies which report higher TNF-α cord blood, and placental levels are associated with fetal growth restriction.29–31 We demonstrate in our study a catch-up growth comparable with the children born to non-IBD controls for the LBW and preterm infants born to mothers with IBD at 1 year of age.

    Although we found no deleterious effects of continuing anti-TNF during pregnancy we still feel that we have to be cautious with continuing anti-TNF in women with IBD in sustained remission. First of all, this study could be underpowered to detect a significant difference in child outcome data across the anti-TNF stop and continue groups. Second, our patients were part of a carefully monitored and counselled group. As a precaution, mothers of children with anti-TNF blood levels above 3 µg/mL were strongly advised to refrain from daycare centre admittance, to be extra cautious of infections and to keep the children away from infectious sources. The cord blood anti-TNF levels reported in this study show that this advice has predominantly been given to the mothers who continued anti-TNF throughout pregnancy. These precautions are likely to have influenced the number of infections in the children born in this group. In an unregulated setting, however, a difference in infection rate could have been detected. Further, the long-term immunomodulatory effects of exposure to high levels of anti-TNF in utero are still uncertain. Finally, responses to vaccinations and the development of the immune system of these children still need to be elucidated. We did not observe any adverse reactions to vaccinations; however, in the Netherlands the first live attenuated vaccine is given at 14 months. Because other countries administer live attenuated vaccines at an earlier age, we feel that limiting anti-TNF exposure in utero remains important.

    Based on the results of this study, stopping anti-TNF in the second trimester of pregnancy in women with IBD in sustained remission appears to be feasible and safe for the mother. When indicated, the continuation of medication seems safe for the child at least in the first year.

    Acknowledgments

    Special thanks to Generation R data manager Claudia Kruijthof for assistance in generating the age-matched and ethnicity-matched sample of non-IBD controls, and also special thanks to M van Amelsfort and SL Kanis for their assistance in collecting the 1-year follow-up data.

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    Supplementary materials

    • Supplementary Data

      This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

    Footnotes

    • Contributors AdL: data collection, performed analyses, written manuscript. ZZ: data collection, critically revised manuscript. CvdE: cord blood sample collection, critically revised manuscript. EAPS: provided non-IBD control group, critically revised manuscript. CJvdW: project initiator, data collection, critically revised manuscript.

    • Funding This study was funded by a grant from Janssen Biologicals BV.

    • Competing interests ZZ: consultancy and lecture fees from MSD, consultancy for Abbott. CJvdW: consultancy and lecture fees from MSD, Abbott, consultancy for Shire, Ferring.

    • Patient consent Obtained.

    • Ethics approval Local Ethics Committee Erasmus University Medical Center Rotterdam.

    • Provenance and peer review Not commissioned; externally peer reviewed.