Preconceptional Counselling in Active Rheumatoid Arthritis (PreCARA)

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2016 by Erasmus Medical Center
Sponsor:
Collaborators:
Erasmus Medical Center
Dutch Arthritis Association
Information provided by (Responsible Party):
J.M.W. Hazes, Erasmus Medical Center
ClinicalTrials.gov Identifier:
NCT01345071
First received: April 13, 2011
Last updated: April 26, 2016
Last verified: April 2016

April 13, 2011
April 26, 2016
September 2011
June 2021   (final data collection date for primary outcome measure)
DAS28(3)CRP at all study points [ Time Frame: Every 3 months from baseline till 6 months after delivery ] [ Designated as safety issue: No ]
number of pregnancies [ Time Frame: 2 years ] [ Designated as safety issue: No ]
Percentage of women that become pregnant during 2 year period of time, with accurate controlled disease activity of RA.
Complete list of historical versions of study NCT01345071 on ClinicalTrials.gov Archive Site
  • Time to pregnancy [ Time Frame: At baseline and every 3 months till pregnant ] [ Designated as safety issue: Yes ]
    Patient is asked whether is she is pregnant. Pregnancy is defined as positive pregnancy test or ultrasound.
  • Number of miscarriages [ Time Frame: After conception, every 3 months ] [ Designated as safety issue: Yes ]
    Patients normally report miscarriages spontaneously at the next visit after miscarriage or contact the research nurse themselves to report this. If not, and patient is not pregnant anymore, reason for ending of pregnancy will be asked.
  • Complications during pregnancy [ Time Frame: Every 3 months during pregnancy and first visit after delivery ] [ Designated as safety issue: Yes ]
    Complications are: hypertensive disorders, pre-eclampsia, diabetes, mode of delivery, hospitalization
  • Gestational age of child [ Time Frame: First visit after delivery ] [ Designated as safety issue: Yes ]
  • Birth weight of child [ Time Frame: First visit after delivery ] [ Designated as safety issue: Yes ]
  • Congenital malformations [ Time Frame: First visit after delivery ] [ Designated as safety issue: Yes ]
  • Growth of child and tempo of growth during first year [ Time Frame: One year after birth ] [ Designated as safety issue: Yes ]
  • Maternal serum levels of anti-TNF [ Time Frame: Every three months during pregnancy ] [ Designated as safety issue: Yes ]
  • Levels of anti-TNF in cord blood [ Time Frame: Collected at birth ] [ Designated as safety issue: Yes ]
  • Levels of anti-TNF in child [ Time Frame: Every six weeks after birth ] [ Designated as safety issue: Yes ]
    Only if anti-TNF in cord blood was above reference value, blood will be drawn from the newborn every six weeks, till anti-TNF-levels are below reference value
health of newborn exposed to TNFalfa inhibitors [ Time Frame: 3 years ] [ Designated as safety issue: No ]
Development (growth and health) of newborns exposed to TNFalfa in utero / early in pregnancy.
Not Provided
Not Provided
 
Preconceptional Counselling in Active Rheumatoid Arthritis
PreConceptional Counselling in Active Rheumatoid Arthritis
The first objective of the study is to evaluate a treat to target treatment strategy in women with moderate to high disease activity of RA and a pregnancy wish, from pre-pregnancy. The treatment strategy is based on deliberate treatment decisions to lower disease activity, including the continuation or start of biological treatment (in particular anti-Tumor Necrosis Factor [anti-TNF]), based on a standard care protocol in the Erasmus MC. The second objective is to evaluate the safety of the use of anti-TNF during pregnancy among women with a rheumatic disease that require the use of anti-TNF before or during pregnancy.

Rheumatoid Arthritis (RA) is an auto-inflammatory disease that particularly involves chronic inflammation of the joints.The disease is in essence a systemically active one that can affect almost any organ. Pregnancy can spontaneously reduce the activity of RA. This phenomenon has been investigated in the PARA-study (Pregnancy-induced Amelioration of Rheumatoid Arthritis study), a nationwide prospective cohort study initiated and coordinated by the department of Rheumatology, Erasmus University Medical Center, Rotterdam the Netherlands.

The PARA-study reconfirmed previous data that RA improved during pregnancy. However, it also showed that this improvement was less pronounced than previously thought since > 50% of RA-patients still had active disease during third trimester of pregnancy. It also demonstrated that active RA was associated with lower birth weight and that children of mothers with active RA demonstrated rapid catch up growth in weight. Lower birth weight as well as rapid catch up growth in weight have been shown to be associated with a less favorable cardiovascular profile in early adulthood. Finally, it showed that time to pregnancy is prolonged in RA-patients with active disease. Also the use of prednisone > 7,5 mg daily or the use of NSAIDs (Non-Steroidal Anti-Inflammatory Drugs) were associated with a prolonged time to pregnancy. These latter associations were independent of disease activity.

The findings of the PARA-study implicate that one should strive for low disease activity in women with RA and a pregnancy wish, but that in the meantime NSAIDs and doses of prednisone exceeding 7.5 mg daily should be avoided. Since common drugs to treat RA, like methotrexate, are incompatible with pregnancy, lowering disease activity in pregnant RA-patients or with a pregnancy wish becomes a real challenge for the patient and the treating physician. This all underscores the importance of new treatment modalities for RA-patients with a pregnancy wish.

In the last decade new treatment options for RA, the so-called biologicals, became available. During pregnancy the most experience has been gained with biologicals belonging to the class of anti-TNF therapy. In the USA, anti-TNF has been approved for use during pregnancy as a FDA (Food and Drug Administration) class B (i.e. Animal reproduction studies fail to demonstrate a risk to the fetus, and adequate, but well-controlled, studies of pregnant women have not been conducted). Registry studies show that anti-TNF use seems to be safe during pregnancy in humans also. Furthermore, anti-TNF therapy has been used intentionally preconceptionally to improve the chance of pregnancies in women with recurrent spontaneous abortions. Since no randomized controlled trials can be done during pregnancy, circumstantial evidence has led to decision making in daily practice. In case of high disease activity use of anti-TNF to control disease activity outweighs the risk of potential harm to the foetus.

Most anti-TNF medications are monoclonal antibodies of the IgG class. For that reason these antibodies are, from around week 14 of gestation, actively transported across the placenta. When used into third trimester of pregnancy, higher levels of these TNF-alpha antibodies are reached in the fetal circulation compared to the maternal circulation, making the newborn more prone for infections. Vaccination of newborns with live inactivated vaccines are therefore contraindicated till anti-TNF alpha antibody levels are not detectable anymore. It is often advised to stop anti-TNF in the first trimester of pregnancy. The rationale behind this approach is that RA improves during pregnancy anyway and that it is safe to taper off medication. In addition it is thought that with discontinuation of anti-TNFearly during pregnancy no placental transfer of anti-TNF antibodies will take place. However, currently no scientific evidence is available to support both assumptions.

An alternative approach is to prescribe Certolizumab during pregnancy or in women with a pregnancy wish. Certolizumab is a pegylated antibody against TNF-alpha. Since it lacks an Fc-tail it is not transported across the placenta and only trace amounts can be detected in the newborn. In the Erasmus MC a protocol was recently developed to standardize care for patients (already pregnant or with a pregnancy wish) that in theory might benefit from treatment with anti-TNF therapy. This protocol is being evaluated in the Pre-CARA study.

The Pre-CARA study is a continuation of the previous PARA study, but focuses on RA patients with high disease activity and a pregnancy wish. The first objective is to evaluate a treat to target treatment strategy in women with moderate to high disease activity of RA and a pregnancy wish, from pre-pregnancy till six months after delivery. The treatment strategy is based on deliberate treatment decisions to lower disease activity, including the continuation or start of biological treatment (anti-TNF), based on a standard care protocol in the Erasmus MC. The second objective is to evaluate the safety of the use of anti-TNF during in women with any chronic arthritide who require the use of this medication preconceptionally and/or during pregnancy.

Observational
Observational Model: Cohort
Time Perspective: Prospective
Not Provided
Retention:   Samples With DNA
Description:
Blood of mother before, during and after pregnancy; cordblood of newborn; blood of newborn if anti-TNF in cord blood was above reference level.
Non-Probability Sample

For first objective: Women with high disease activity of RA and a pregnancy wish.

For second objective: Women with a rheumatic disease that requires the use of anti-TNF before or during pregnancy

  • Rheumatoid Arthritis
  • Pregnancy
Not Provided
RA patients
RA patients with active disease or current use of anti-TNF. Treatment is according to treat to target principles.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
150
May 2025
June 2021   (final data collection date for primary outcome measure)

Inclusion criteria for first objective (150 subjects)

  • Rheumatoid Arthritis according to 2010 ACR/EULAR criteria
  • active pregnancy wish
  • either DAS28(3)CRP > 3.2 or the current use of anti-TNF

Inclusion criteria for second objective (no limit on number of subjects needed, recruitment will end when 150 RA patients have been included)

  • rheumatic disease that requires the use of anti-TNF before or during pregnancy
  • active pregnancy wish

Exclusion criteria:

- none

Female
18 Years to 45 Years
No
Contact: Marieke van Wier, PhD +31 10 7032181 m.vanwier@erasmusmc.nl
Contact: Radboud Dolhain, PhD MD r.dolhain@erasmusmc.nl
Netherlands
 
NCT01345071
ErasmusMC-MEC-2011-032
No
Undecided
This will be discussed in the research group
J.M.W. Hazes, Erasmus Medical Center
J.M.W. Hazes
  • Erasmus Medical Center
  • Dutch Arthritis Association
Principal Investigator: Radboud Dolhain, PhD MD Staff Rheumatologist
Erasmus Medical Center
April 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP