Download Prevention of handicap in children by reducing the preterm birth rate

Prevention of handicap in children by reducing the preterm
birth rate in twin pregnancy: a randomised clinical trial
comparing profylactic progesterone administration with
placebo.
Projectleiding
Dr. B.W. Mol, gynaecologist, AMC Amsterdam
Dr. H.W. Bruinse, gynaecologist, UMC Utrecht
Deelnemende centra
UMC Utrecht
AMC Amsterdam
TweeSteden ziekenhuis
MMC Veldhoven
OLVG Amsterdam
Elisabeth Tilburg
UMC Groningen
Deventer ziekenhuizen
AZM Maastricht
Health Technology Assessment
E. Birnie
AMC Amsterdam
Correspondentie
Dr. B.W. Mol
Afdeling Verloskunde/ gynaecologie
Academisch Medisch Centrum
Postbus 22700
1105 AZ
Amsterdam
Nederland
020-5663857
[email protected]
Versie 20 october 2005
Study protocol ProTwin study – final draft 20 october 2005
SUMMARY
OBJECTIVE: To investigate the hypothesis that prophylactic administration of 17 alpha
hydroxyprogesterone (17OHPC) will reduce the incidence of the composite neonatal
morbidity of neonates by reducing the early preterm birth rate in twin pregnancies. The
composite morbidity rate after early preterm delivery between 24-27, 28-32 and 32-34 weeks
of gestation is respectively 77%, 35% and 12%. After 34 weeks it sharply declines to less than
2%. The incidence of preterm birth in twins in these gestational periods is 1.8, 5.2 and 7.4%,
respectively. As a result of this early delivery finally about 8% of the children will die, 6%
will remain severely disabled and 20% will be moderately disabled.
At present, no general accepted strategy for prevention of preterm birth in multiple
pregnancies exits. Prophylactic administration of 17OHPC that proved to be effective in
singleton pregnancies at high risk for preterm delivery is as yet not advised.
STUDY DESIGN: Prospective randomised placebo controlled trial.
STUDY POPULATION: Women with a twin pregnancy (bichorionic or monochorionic)at a
gestational age between 15 and 20 weeks of gestation.
INTERVENTION: Weekly 250 mg 17 OHPC i/m injections from 16-20 weeks up to 36
weeks of gestation versus placebo.
OUTCOME MEASURES: Primary outcome is composite bad neonatal condition (death or
severe morbidity). Secondary outcome measures are time to delivery, preterm birth rate
before 32 and 37 weeks, days of admission in neonatal intensive care unit, maternal
morbidity, maternal admission days for preterm labour and costs.
POWER/ DATA ANALYSIS: Analysis will be by intention to treat. The effectiveness of
progesterone versus placebo will be assessed by calculating relative risks and 95% confidence
intervals. Assuming a decrease of the incidence of bad neonatal outcome from 14.9% without
to 7.9% with progesterone, using a two sided test with an alpha 0.05 and a beta of 0.8, 700
women (350 per arm) are needed in the study.
TIME SCHEDULE: Three months for logistics of the study set up, 30 months for recruitment
and seven months for the final data collection and evaluation.
2
Study protocol ProTwin study – final draft 20 october 2005
INTRODUCTION
Preterm birth is the major cause of handicaps in genetically normal children despite the enormous
advanced neonatal care during the last decades. So, prevention of preterm birth is the major goal of
obstetrical care. However, strategies to prevent preterm birth have been largely unsuccessful.
Recently, it has been shown that prophylactic progesterone administration to women with a singleton
pregnancy at high risk for a preterm birth significantly reduced the incidence of preterm birth (1,2).
Factors that play a role in the onset of delivery are activity of the uterus, consistency of the cervix and
bacterial infection in the vagina. These factors are likely to play a role in preterm delivery, both in
singleton as well as in multiple pregnancies. In singleton pregnancies, only 1% of the women delivers
prior to 32 weeks. However after previous delivery this risk increases to 15-20%.
Twin pregnancies are at high risk for preterm birth. In The Netherlands about 15% of the women with
a multiple pregnancy deliver before 34 weeks of gestation (3,4,5). At present, about 1 in 60
pregnancies is a twin pregnancy, and about 30% of the preterm born children admitted in a neonatal
care (NICU) are from twin pregnancies (Source: LVR (Dutch Obstetrical Database), LNR (Dutch
Neonatal Database))(4,5). Due to an increase in age of pregnant women and an increase in assisted
reproductive technologies the incidence of twin pregnancies is still rising. The financial burden of
preterm born babies is enormous: about € 1000,- per day when admitted in a NICU with the
concomitant costs in case the child appears to be handicapped, for both parents as the society in
general.
The composite poor neonatal outcome contains severe RDS, broncho pulmonal dysplasia (BPD),
intraventricular haemorrhage II B or worse (IVH), periventricular leucomalacia (PVL), necrotizing
entercolitis (NEC), sepsis and death before discharge (Guinn (4)). The prevalence of this composite
neonatal outcome is 77%, 35% and 12% in children born after early preterm delivery between 24-27,
28-32 and 32-34 weeks, respectively (5). After 34 weeks this incidence sharply declines to less than
2% at term. The probability that a woman delivers at these gestational ages is 1.8%, 5.4% and 7.2%,
respectively (4). In total, this means that about 8% of the multiple pregnancies will result in the death
of at least one child, whereas in 7% of the pregnancies at least one of the children will remain severely
disabled. Moreover, another 20% of the pregnancies results in a moderate handicap of at least one of
the children.
Women with a twin pregnancy are seen by a gynaecologist for their antenatal care. Although preterm
birth is known to be the most important complication of a twin pregnancy no general accepted strategy
is available to prevent this condition. Progesterone administration [with a recently proven effect on the
occurrence of preterm birth in high risk singleton pregnancies (1,2,7)] is not as yet used. In conclusion
no generally established strategy is at present available to prevent the most common and important
complication of twin pregnancies.
We propose an intervention with weekly progesterone injections (250 mg 17 alpha
hydroxyprogesterone caproate (17OHPC)) from 16-20 weeks up to 36 weeks of gestation.
This intervention had been chosen since
a) it has been proven that this prophylactic administration of 17OHPC injections is effective in
reducing the preterm birth rate in singleton pregnancies at high risk for a spontaneous preterm delivery
and
b) a twin pregnancy is considered to be a pregnancy at high risk for a spontaneous early preterm
delivery with a high composite neonatal morbidity rate, as demonstrated by the data from the LVR and
LNR shown above.
In view of the previous disaster with diethylstilbestrol, it is understandable that many patients, doctors,
and others (among which the committee judging this proposal) are concerned about negative long term
side effects on women or their offspring. The 17-alpha-hydroxyprogesterone caproate is a natural
metabolite of progesterone that is produced by the placenta itself. Apart from a painful spot at the
3
Study protocol ProTwin study – final draft 20 october 2005
injection side no side effects have been described regarding the mother or the child. Although
masculinisation of the genital tract in female foetuses was feared in the past no such side effect has
been found after thorough follow-up even when 17OHPC was administered in early pregnancy. The
same applies for the incidence of hypospadics in male infants. In the last 40 years progestin has been
administered to pregnant women for several reasons: threatening miscarriage, repeated miscarriage,
threatening abortion labour and prevention of preterm labour. Especially for progestins with an
androgenic effect, there was a fear for masculinisation of the female fetus. Research among 2500
exposed women and controls showed no difference with respect to central nerve system, limbs and
joints, tractus urogenitalis and tractus circulatorius.
4
Study protocol ProTwin study – final draft 20 october 2005
METHODS
DESIGN: Double blinded placebo-controlled randomised study.
STUDY POPULATION: All women presenting with a twin pregnancy between 15 and 20 weeks of
gestation are eligible for the study. Since in December 2004 it was decided that the DUNAMO twin
study on monochorionic twin pregnancies would not be funded, we propose to include women with a
monochorionic twin also in the study (in contrast with the earlier application). Women with twin
pregnancies in which at least one of the fetus(es) has major congenital anomalies known at study entry
will not be included. Gestational age has to be confirmed at a first trimester fetal scan.
Women who are eligible for the study but who do not give informed consent, are registered and treated
according to the local protocol in the participating clinic. Data on outcome of these cases will be
collected. Progesterone injections will not be prescribed to these women.
RANDOMISATION: The boxes of 17OHPC or placebo for each center will be packaged according to
the randomisation sequence prepared by the AMC in Amsterdam.
INTERVENTIONS: Eligible women will be randomly allocated to receive either weekly 17 alpha
hydroxy progesterone caproate (17OHPC) injections (250 mg) or placebo. The intervention is
prophylactic i/m administration of 250 mg 17OHPC injections at weekly intervals from the time of
inclusion (16-20 weeks) up to 36 weeks or up to delivery. Next to this research intervention cases are
treated according to the local protocol in the participating clinics and other interventions i.e. tocolysis
in case of a threatened preterm birth, antibiotics in case of rupture of membranes will be applied
according to the local protocol.
The choice of 250 mg 17OHPC per week is chosen analogous to the study of Meis et al (1), that
studies the effect of 17-OHPC in singleton with preterm labour. This choice is made in view of the
similar mechanism for preterm labour in singleton and multiple pregnancy. Moreover, the
pathofysiological background of 17-OHCP is not clear. Placebo will be manufactured by the apotheek
Haagse Ziekenhuizen (dr. S. Samavati).
BLINDING: The injections are labelled, and the label codes indicating 17OHPC or placebo are only
known in the local pharmacy. These data will disclosed to the central office only after the study. For
purpose of the interim analysis the label codes will become available to the epidimiologist involved in
the study as A and B.
The study will be stratified for parity (previous vaginal delivery or not), chorionicity (bichorial versus
monochorial) and centre. To do so, each centre will have intramuscular injections with either 17OHPC
or placebo, that are available for one of the four possible combinations (nulliparous bichorial,
multiparous bichorial, nulliparous monochorial, multiparous monochorial).
OUTCOME MEASURES: The main outcome parameter is the composite morbidity rate of children in
the two groups. This composite morbidity rate contains the following variables: severe Respiratory
Distress Syndrome (RDS), Broncho Pulmonal Dysplasia (BPD), Intraventricular Haemorrhage II B or
worse, Necrotizing Enterocolitis (NEC), proven sepsis and death before discharge from the nursery
(6). They will be measured until 10 weeks after the expected term date.
Secondary outcome measures are time to delivery, preterm birth rate before 32 and 37 weeks, days of
admission in neonatal intensive care unit, maternal morbidity, maternal admission days for preterm
labour and costs. At present, a longer folluw-up is not planned.
DATA COLLECTION: Data will be collected using a website dedicated to studies in the Dutch
consortium for obstetric studies. A similar website oriented database is already developed for the
ZonMW funded DIGITAT study, that will start to recruit patients from April 2005 onwards. Data
monitoring will be done by research nurses in each of the participating centres. A substantial part of
these research nurses is already working for the above mentioned DIGITAT study.
SAMPLE SIZE CALCULATION: The sample size is calculated based on the primary outcome 'bad
5
Study protocol ProTwin study – final draft 20 october 2005
neonatal outcome'. We assume a decrease in the preterm birth rate below 34 weeks from 14.4%
without intervention to 7.2% after the intervention.
In the control group, 'bad neonatal outcome' is expected in (1.8%*77% + 5.2%*35% + 7.4%*12% +
35.6%*8% + 50%*.5% = 7.2%). In this calculation, the first rate represents the probability that a
patient delivers at that gestational age, whereas the second probability represents the probability of
'bad neonatal outcome' at that particular gestational age. In case of treatment, 'bad neonatal outcome' is
then expected in (.9%*77% + 2.6%*35% + 3.7%*12% + 18.3%*8% + 75%*.5% = 3.9%) of the
children.
taking into account the fact that each women will deliver two children, the probability of at least one
child with a poor neonatal outcome per pregnancy is 14.9% with placebo and 7.9% with progesterone.
Using a two-sided test with an alpha of 0.05 and a beta of 0.80 we need 345 women in the control
group and 345 in the intervention group.
FEASIBILITY OF RECRUITMENT: Each of the participating centres has at least 80 eligible cases
per year. An intake of about 40 cases per year per centre is anticipated and therefore recruitment of the
required number is feasible within 30 month.
The study will be performed in a collaborative effort of large perinatal centres, who are already
collaborating in the Zon-MW funded study DIGITAT. Large periferal centers, already participating in
DIGITAT as well as in the implemenation study on progesterone in women with a previous preterm
birth, will be invited to participate at the start of the study.
DATA-ANALYSIS: Data will initially be analysed according the intention to treat method. The main
outcome variable, 'bad neonatal outcome', will be assessed by calculating rates in the two groups,
relative risks and 95% confidence intervals as well as numbers needed to treat. To evaluate the
potential of each of the strategies, we will also perform a par protocol analysis, taking into account
only those cases that were treated according to protocol.
Time to delivery will be evaluated by Kaplan-Meier estimates, with account for differing durations of
gestation at entry, and will be tested with the logrank test. The other secondary outcome measures will
be approached similar as the primary outcome measure. The analysis will be stratified for parity,
chorionincity and centre.
An interim analysis will be performed after the inclusion of 300 women. This analysis will be done by
an independent data and safety monitoring committee, that will not be aware of the allocation of
treatment or placebo when they judge data on effectiveness. In case of severe side-effects, the safety
monitoring committee can order to disclose the label of patients with such side effects.
ECONOMIC EVALUATION:
General considerations
The aim of the economic evaluation is to compare the optimality, in terms of costs and health effects,
of weekly (prophylactic) administration of 17OHPC progesterone injections (16/18-36 weeks) to no
intervention. As the clinical study is based on a superiority design (it is hypothesized that progesterone
decreases preterm birth considerably), the primary economic evaluation is a cost-effectiveness analysis
(CEA): the optimal strategy is the one with the largest health gain at the smallest extra costs.
Costs and outcomes are analysed according to intention-to-treat and described with appropriate
statistical measures. The sensitivity of costs and health outcomes for various parameters is tested in
sensitivity analysis. Scenario analyses for relevant subgroups (e.g. gestational age at birth, parity,
monochorionic/dichorionic multiples) are added.
Initially, discounting is not applied since the time horizon of the analysis does not exceed 12 months.
Cost analysis
The process of care is distinguished into three cost stages (antenatal stage, delivery/childbirth,
postnatal stage) and three cost categories (direct medical costs [all costs in the health care sector],
direct non-medical costs [costs outside the health care sector that are affected by health status or health
care] and indirect costs [costs of sick leave). For each stage and each cost category, costs are measured
6
Study protocol ProTwin study – final draft 20 october 2005
as the volumes of resources used multiplied with appropriate valuations (cost-per-unit estimates, fees,
national reference prices).
Cost volumes in the antenatal stage consist of direct medical costs (e.g. hospital care, outpatient visits,
administration of 17OHPC progesterone injections). Direct non-medical and indirect costs in that
stage may occur if role patterns or household routines shift.
Costs during childbirth are dominated by the course of childbirth and type of delivery. Cost volumes
in the postnatal stage consist of hospital-based maternal care (hospitalisation etc.), neonatal care
(admission to NICU/medium care or maternity ward, related diagnostic care and treatment, outpatient
visits) and primary care. If neonatal health is suboptimal, further direct medical, direct non-medical
and indirect costs may occur. Hence, for these infants, resource use of infants and/or parents is
measured during 12 months after childbirth.
Volumes of health care resource use are measured prospectively alongside the clinical study in all
participating centers as part of the CRF. Health resource use outside the hospital will be recorded by
questionnaires.
Valuations of direct medical resources are estimated as cost per unit estimates comprising "true
economic" costs, i.e. including shares of fixed costs and hospital overheads. Cost per units are
estimated for at least teaching and one non-teaching hospital. An analysis based on reimbursement
fees is added. Direct medical volumes outside the hospital and direct non-medical volumes are valued
using national reference prices (11). Indirect costs are quantified but remain unvalued. Study-specific
costs are excluded from analysis.
TIME SCHEDULE: Duration of the study 40 months. We will need a run-in period of three months
for the study set up. Thirty months years for inclusion of the required number of cases. Seven months
for follow-up data collection and report of results.
7
Study protocol ProTwin study – final draft 20 october 2005
REFERENCES
1. Meis PJ, Klebanoff M. Thom E et al. Prevention of Recurrent Preterm Delivery by 17 AlphaHydroxyprogesterone Caproate NEJM 2003:348;2379-85.
2. Da Fonseca EB, Bittar RE, Carvalho MHB and Zugaib M. Prophylactic administration of
progesterone by vaginal suppository to reduce the incidence of spontaneous preterm birth in women at
increased risk: A randomised placebo-controlled double-blind study. Am J Obstet Gynaecol
2003:188;419-24.
3. Bruinse HW, Visser GHA. Meerlingen (Multiple Pregnancy). Uitgeverij Elsevier/de
Tijdstroom 1997.
4. Landelijke Verloskundige Registratie 2002. Dutch obstetrical Database 2002. Prismant 2002.
5. Landelijke Neonatale Registratie 2003. Dutch Neonatal Database 2002. Prismant 2002.
6. Guinn DA, Atkinson MW, Sullivan L et al. Single versus Weekly Courses of Antenatal
Corticosteroids for Women at Risk of Preterm Delivery. A randomised controlled trial: JAMA
2001;286:1581-7.
7. Keirse MJCN. Progesteron administration in pregnancy may prevent preterm delivery. Br J Obstet
Gynaecol 1990:97;149-154.
8. Ressequie LJ, Hick JF, Bruen JA et al. Congenital malformations among offspring exposed in utero
to progestins, Olmsted County, Minnesota, 1936-1974 Fert Steril 1985:43;514-9.
9. Yonich JL, Turner SR, Draper R. Medroxyprogesterone acetate in early pregnancy has no
apparent fetal effects. Teratology, 1988:38;135-44.
10. Katz Z, Lancet M, Skornik J. Teratogenicity of progestogens given during the first trimester of
pregnancy Obstet Gynecol 1985:65;775-80.
12. Oostenbrink JB, Koopmanschap MA, Rutten FFH. Handleiding voor kostenonderzoek. Methoden
en richtlijnen voor economische evaluaties in de gezondheidszorg. CVZ 2000
8