Clinical trial NCT02813850: Oxygen Therapy and Pregnancy in Sickle Cell Disease
Official title: Impact of Home-based Oxygen Therapy on Maternal and Fetal Complications, in Pregnant Women With Sickle Cell Disease. A Randomized Multi-center Trial.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Sickle Cell Disease
Keywords: sickle cell disease
oxygen therapy
pregnancy
pregnancy in sickle cell disease
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2016-06-27
Enrollment: 178
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: The purpose of this study is to assess the efficiency of the preventive oxygen therapy on the occurrence of vaso-occlusive complications, which last more than 24 hours and require hospitalisation, in women with sickle cell disease.

Detailed description: Sickle cell disease (SCD) corresponds to a group of inherited disorders with clinical manifestations resulting from the biochemical consequences of a single-base substitution of valine by glutamic acid at position 6 of the ß-hemoglobin (Hb) subunit (HbA \[ß6val\] to HbS \[ß6glu\]). When the oxygen tension is low, the solubility of HbS falls and the molecules polymerize. In turn, the intracellular formation of HbS polymers results in red blood cell (RBC) sickling. The aggregation of sickle cells is responsible for the vaso-occlusive crises (VOCs) that characterize SCD.

Thanks to improvements in the management of SCD patients, over 95% of affected infants survive to adulthood. Pregnancy is a high-risk situation for women with sickle cell disease, especially in the third trimester, during delivery and in the post-partum period. Conversely sickle cell disease can lead to pregnancy complications for both mother and fetus since maternal-fetal mortality remains elevated.

RBC transfusions and careful prevention of infections represent the only available treatments in this situation.

The complexity of this setting and the associated therapeutic strategy is further accentuated by the high frequency of post-transfusion side effects during SCD pregnancies, can indirectly affect the newborn by inducing hypoxia, and may ultimately prevent the woman from receiving further transfusions (RCOG, 2015) (Tuck et al, 1983). Post-transfusion complications constitute negative prognostic factors that affect both the mother's health and fetal development and thus increase the risk of premature death.

Another factor complicating the outcome of the pregnancy is the increase in oxygen demand in order to satisfy the increased metabolic requirements of the placenta and fetus. As the maternal oxygen reserve can be compromised during pregnancy for several reasons (such as the increased oxygen consumption, the SCD related anemia accentuated by the plasmatic increase), patients are particularly susceptible to hypoxemia - leading to the exacerbation of sickling events and SCD-related complications. (Hill \& Pickinpaugh, 2008)(Thame et al, 2007)(Rathod et al, 2007a)(Cines et al, 1998)(Hassell, 2005)(Pantanowitz et al, 2000)(Rathod et al, 2007b) Moving from this observation, the first innovative approach introduced was the widespread use of prophylactic oxygen treatment at home. The rationale behind this change came from experiments on a murine model of SCD mice, in which a high-oxygen environment during pregnancy was associated with a lower prenatal fetal/maternal mortality rate (Ye et al, 2008). The absence of severe complications was also noticed in some women who could not be transfused (because of severe alloimmunization) and who were already receiving oxygen therapy at home before pregnancy.

Then a preliminary retrospective study was performed to evaluate the clinical benefit of the widespread use of prophylactic oxygen treatment at home. It indicates that this innovative treatment is safe and seems to be associated with a significant decrease in the transfusion rate in SCD patients during pregnancy.

These findings are encouraging, but they are preliminary and bias have to be taken into account. These results have to be confirmed by a randomized trial.

The project aim is to assess preventive oxygen therapy impact on women with sickle cell disease, their fetal and their newborn. Firstly, investigators want to assess preventive home-based oxygen therapy efficacy for preventing vaso-occlusive complications which last 24 hours and require a hospitalization. Secondly, they want to assess oxygen therapy impact on prevention and characteristics of obstetrical complications, prevention of neonatal complications, fetal and newborn's characteristics, type of medical care, transfusion balance sheet, way of transfusion and maternal, fetal and newborn tolerability of home-based oxygen therapy during pregnancy.

For this they propose to analyze 200 pregnant SCD women. 100 women in the first arm with standard medical care. 100 women in the second arm who will have home-based oxygen therapy early at night.

This study will be performed in 9 French hospitals. Blood samples of SCD women and blood cord will be drawn to monitor red cell adherence protein expression and function and their mechanic and adhesive properties.

Eligibility criteria: Inclusion Criteria:

* Pregnant women from 18 to 50 years old
* Maximal term: 20SA
* Patient with sickle cell disease
* Consent form signed by the patient
* Affiliated or beneficiary of a health insurance regimen and State Medical Aid.

Exclusion Criteria:

* Patients with transfusion restrictions
* Patients whose house can not receive the device
* Patients who have a weekly use of prophylactic oxygen therapy at home
* Patients who don't understand the operating instructions \*Include patients with a doctor's prescription only. The portable oxygen concentrator will be removed from patients' home at the initiation visit prior to the overnight home oximetry test.

Primary outcomes:
measure: Occurrence of at least one vaso-occlusive complication which last more than 24h
timeFrame: 30 days postpartum
Secondary outcomes:
measure: Occurrence of at least one vaso-occlusive complication which last more than 24h
timeFrame: 30 days postpartum
measure: Occurrence of pregnancy-induced hypertension, pre-eclampsia, eclampsia
timeFrame: 20 months
measure: Occurence of hospitalisation because of premature delivery risk
timeFrame: 20 months
measure: Occurence of late miscarriage
timeFrame: 20 months
measure: Occurence of Preterm (<35SA) and very preterm ( from 26 to 32SA)
timeFrame: 20 months
measure: Type of delivery (vaginal, active, caesarean)
timeFrame: 20 months
measure: Number of days hospitalisation postpartum
timeFrame: 20 months
measure: Occurence of Neonatal complications ( respiratory distress, analgesics withdrawal symptom)
timeFrame: 20 months
measure: Number of days of hospitalisation for the newborn
timeFrame: 20 months
measure: Number of days of hospitalisation in resuscitation unit for the newborn
timeFrame: 20 months
measure: Newborn weight
timeFrame: 20 months
measure: Newborn size
timeFrame: 20 months
measure: Newborn head circumference
timeFrame: 20 months
measure: Apgar score assess 1 min after birth
timeFrame: 20 months
measure: Apgar score assess 5 min after birth
timeFrame: 20 months
measure: Apgar score assess 10 min after birth
timeFrame: 20 months
measure: Perinatal and neonatal death
timeFrame: 20 months
measure: pH of of the newborn
timeFrame: 20 months
measure: Lactate of of the newborn
timeFrame: 20 months
measure: Number of days using painkiller (level II and III) during pregnancy
timeFrame: 20 months
measure: Number of urgent consultation
timeFrame: 20 months
measure: Number of days of hospitalisation and hospitalisation in intensive care during pregnancy
timeFrame: 20 months
measure: Stage of pregnancy at the first transfusion
timeFrame: 20 months
measure: Total volume of transfusion during pregnancy
timeFrame: 20 months
measure: Way of transfusion: simple, bleeding-transfusion, erythrocytapheresis
timeFrame: 20 months
measure: Maternal, fetal and newborn tolerability of home-based oxygen therapy during pregnancy
timeFrame: 20 months
Other outcomes:
Locations:
city: Paris
country: France
facility: Hôpital Necker Enfants-Malades (Public Hospitals of Paris)
Study officials:
affiliation: Assistance Publique - Hôpitaux de Paris
name: Alexandra BENACHI, MD, PhD
role: STUDY_DIRECTOR
affiliation: Assistance Publique - Hôpitaux de Paris
name: Laure JOSEPH, MD,PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Assistance Publique - Hôpitaux de Paris
name: Marina CAVAZZANA, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: