Study information

 

HYPITAT-II: Hypertension and Pre-eclampsia Intervention Trial At near Term


Objective
Pregnancy-induced hypertension (PIH) and preeclampsia (PE) occur often in pregnancy, and can result in severe complications such as eclampsia, placental abruption, preterm delivery, HELLP syndrome or even intra-uterine death and maternal death. Hypertensive disorders in pregnancy are the largest cause of maternal mortality in the Netherlands. Recently, our group evaluated in the HYPITAT trial whether a policy of induction of labour in women with mild preeclampsia or pregnancy induced hypertension at term was superior to a policy of expectant management. In this trial, we found that induction of labour reduced the number of complications, such as severe hypertension, whereas there was no increase in caesarean section. In view of the outcome of the HYPITAT study, one can raise the question how women with preeclampsia or severe hypertension between 34 and 37 weeks of gestation should be managed. International there is a tendency for induction while in the Netherlands mostly an expectant policy is preferred. Induction of labour might prevent maternal complications and progression to a severe preeclampsia. However, late preterm births are common and associated with increased neonatal morbidity compared with births at 39 weeks. At present, there is no evidence on the effectiveness and efficiency of induction of labour in women with pregnancy induced hypertension or mild preeclampsia with a gestational age of 34 - 37 weeks of pregnancy, as compared to expectant management under regular monitoring.

Study design
Multicentre randomized controlled clinical trial

Study population

 

Inclusion criteria

·         Maternal age ≥ 18 years

·         Pregnancy induced hypertension

o    100 mmHg ≤ diastolic blood pressure ≤ 110 mmHg, without medication

at two occasions at least six hours apart

o    Patients who after stabilization of the high blood pressure (diastolic blood pressure > 110 mmHg) with oral or i.v. medication reach a stable diastolic blood pressure RR ≤ 110 mmHg.

·         Preeclampsia

o    diastolic blood pressure  ≥ 90 mmHg

at two occasions at least six hours apart

o     0,3 g ≤ proteinuria 24 hours urine < 5 g or

o     Eiwit Kreatinine Ratio (EKR) > 30

·         Chronic hypertension

o    with superimposed preeclampsia (with proteinuria as defined above) or

o    the need for additional anti-hypertensive medication started after 34 weeks (i.e. another drug than that was used before)

·         Gestational age between 34+0 and 37+0 weeks

·         Informed consent

 

Exclusion criteria

Diastolic blood pressure ≥ 110 mmHg despite medication

Systolic blood pressure ≥ 170 mmHg despite medication

Renal disease

Heart disease 

Seropositive for HIV

Haemolysis Elevated Liver enzymes Low Platelets (HELLP) syndrome

Pulmonary edema or cyanosis

Proteinuria ≥ 5 g/L

Oliguria < 500 mL in 24 hours

Non-reassuring foetal heart rate, O-flow or reverse flow

Severe foetal abnormalities including abnormal karyotype.

Severe preeclamptic complaints, such as frontal headache

 

 

No reason for exclusion are:

Women with multiple pregnancy

Women with a child in breech presentation. (Patients can be counselled for a vaginal breech delivery or a caesarean section).

Women with a caesarean section in previous pregnancy. (Patients can be counselled for an induction of the delivery or a caesarean section. The use of prostaglandins are contraindicated. Induction should be performed by rupture of membranes or a Foley-catheter.)

Diabetes

Fetal Growth Restriction, though good fetal condition.


Intervention
Induction of labour, if necessary preceded by artificial ripening versus expectant monitoring. If there exists a contraindication for vaginal delivery, for example a breech presentation, a Caesarean section will be performed if this is agreed in by the patient and her physician.

 

Outcome measures


Primary outcome measure

The maternal primary outcome measure will be a composite endpoint of maternal mortality, maternal

complications (eclampsia, HELLP syndrome, pulmonary edema) and progression to severe pre-eclampsia. The neonatal primary outcome measure will be respiratory distress syndrome (RDS), which can be complicated by fetal mortality in rare cases.

 

Secondary outcome measures

Secondary maternal outcomes will be caesarean section rate, instrumental vaginal delivery rate, maternal quality of life and quality of recovery and costs. Secondary neonatal outcome will be neonatal morbidity defined as neonatal infection or sepsis, intravenous therapy needed hypoglycaemia, wet lung syndrome, meconium aspiration syndrome, pneumothorax and/or pneumomediastinum, periventricular leucomalacia, convulsions and other neurological abnormalities necrotising enterocolitis (NEC), intraventricular haemorrhage (IVH) or asphyxia. Adverse neonatal outcome will be defined as a 5-minute Apgar score below 7, an umbilical artery pH below 7.05 or admission to the neonatal intensive care.


Power/data analysis
The analysis will be by intention to treat. We hypothesize that induction of labour can reduce maternal complications from 20% to 10%. Using a two sided test (alpha error 5%, beta error 20%) we need two groups of 100 patients to demonstrate such a difference. This sample size is also large enough to assess whether there will be relevant differences in the primary neonatal outcome (incidence of RDS 15% at 34 weeks versus <1% at 37 weeks).

 

Economic evaluation

We plan an economic analysis alongside the clinical trial. This analysis will be performed form the societal perspective. We will measure direct medical costs as well as non medical costs. We will use utilities that have been measured in a previous HTA-methodology report (¡®When outcome is a

balance. Methods to measure combined utility in obstetrics.)¡¯ that will be available in 2009. Utilities for

maternal and neonatal conditions will be integrated in the economic analysis, thus allowing comparison effects and costs through one outcome measure. Long term economic consequences from maternal and neonatal morbidity will be assessed through modeling.

Time schedule
Total study time 33 months. Preparation three months, recruitment 24 months, analysis and report six months.

 

Project leaders
Dr. B.W. Mol, gynecologist, AMC Amsterdam

Dr. M.T.M. Franssen, gynecologist, UMCG Groningen.

Health Technology Assessment
Dr. B.C. Opmeer, AMC Amsterdam

Methodology
Dr. J.Langenveld, Atrium MC Heerlen and Drs. K. Broekhuijsen, University Medical Center Groningen
           
Subsidy:

Zon-Mw funded (80-82310-97-11075)

 

Contact

Drs. K. Broekhuijsen, PhD candidate, University Medical Center Groningen.

Tel: +31(0)6-16972879 Email: hypitat2@studies-obsgyn.nl

Drs. J. Langenveld, gynecologist, Atrium MC Heerlen. Tel: +31(0)6-17530662

hypitat2@studies-obsgyn.nl