Birth Asphyxia Clinical Trial
Official title:
Birth Asphyxia in Uganda: Prevalence, Associated Factors and Effect of Intrapartum Oxygen Administration on Fetal and Early Neonatal Outcomes
Introduction Birth asphyxia is one of leading causes of neonatal mortality in Uganda. It is
associated with long term neuro-developmental complications among the babies that survive.
Preventive measures for birth asphyxia intrauterine are not clearly understood and thus the
need for this study.
The aim of the study is to assess the effect of intrapartum oxygen administration on fetal
and early neonatal outcomes.
Methods A double-blind randomized clinical trial which will be conducted in Gulu regional
referral and Kawempe National referral hospitals in Uganda. A total sample size of 1108 women
in labour will be enrolled with 554 participants per group. The intervention will include
administration of 10 L/min of 100% oxygen for 15 minutes to women in established labor who
have signs of fetal distress with fetal heart rate of less than 120 or above 160 beats per
minute. The control group will receive medical air (21% oxygen) using the same criteria.
Women and babies will be followed up until 7 days after birth to document the outcomes.
Statistical analysis to identify difference in outcomes between the control and intervention
groups will be performed.
Ethical considerations Ethical approval and permission was received from relevant research
and ethics committees. Informed consent will be sought from the participants. A data and
safety monitoring board will be set up to review periodically the progress of the clinical
trial study. Participants will be monitored for adverse events and severe adverse events;
reporting will be done according to the research and ethics committee guidelines.
Background:
Foetal distress which refers to fetal heart rate of less than 120 or more than 160 beats per
minute(Pildner von Steinburg et al., 2013) during labour is one of the contributing factors
to poor newborn outcomes. A proportion of these newborns will require interventions after
birth such as resuscitation, oxygen therapy, antibiotics and prolonged hospital admissions.
According to a retrospective study in Nigeria, 23% of foetuses diagnosed with fetal distress
were born with asphyxia which is a major cause of newborn deaths(Adanikin & Awoleke, 2017).
Several interventions to optimise fetal wellbeing as preparations for birth are being
instituted have been suggested. These include amnio-infusion, maternal positioning,
tocolysis, oxygen administration and intravenous fluid bolus(Bullens, van Runnard Heimel, van
der Hout-van, & Oei, 2015; Simpson, 2007). Reviews of intrauterine resuscitation techniques
have reported sufficient evidence for use of tocolysis and maternal repositioning to improve
fetal pH and Apgar scores(Bullens et al., 2015; Velayudhareddy & Kirankumar, 2010). Although
oxygen is used in several settings for intrauterine resuscitation(Dawood & Al-Arnous, 2002;
Siriussawakul et al., 2014), its effect when used in labour for management of foetal distress
remains debatable. In a Cochrane review to evaluate efficacy of oxygen administration in
preventing fetal distress, only two clinical trials were found. There was evidence that the
fetal arterial partial pressures of oxygen were improved by oxygen administration although
there was a negative effect on pH levels. There is insufficient evidence to recommend or
disprove use of oxygen for intrauterine resuscitation(Fawole & Hofmeyr, 2012). This therefore
creates sufficient equipoise to undertake this study. In low resource setting where pregnant
women are most likely to have anaemia, suffer from malaria and other infections, the role of
oxygen for intrauterine resuscitation needs to be explored.
Aim: This study will assess the effect of administration of oxygen to women with fetal
distress in the first stage of labour on fetal and early neonatal outcomes in a low resource
setting.
Hypothesis: Administering 100% oxygen for 15 minutes to women with fetal distress will reduce
the rate of fetal distress by 30% in the first stage of labour.
Study design: A randomised clinical trial with parallel assignment will be conducted.
Setting: The trial will take place in Gulu regional and Kawempe National referral hospitals
in Uganda.
Study population: The study population will consist of pregnant women in the first stage of
labour (that is between 4-10 cm cervical dilation).
Sample size: Using the Kelsey formula for sample size calculation for randomized controlled
trials, with a ratio of intervention to controls of 1:1, 1108 women will be recruited.
Randomisation Block randomisation will be done to reduce the risk of bias in the study and
ensure that each of the two groups has equal numbers of participant. A sequence of variable
block sizes (4, 6 and 8) will be generated using STATA 15 by a statistician who will not be
part of the study team.
Allocation and concealment: The allocation concealment will be done by the pharmacist in
Uganda who will be in charge of storage of the control and intervention gas cylinders and
dressing them with similar tamper proof jackets. The pharmacist will receive the
randomization sequence from the statistician and label each masked cylinder with a set of
participant serial numbers. Copies of these serial numbers will be concealed in opaque
envelopes and given to research assistants.
Blinding/Masking: This will be a double blind study where the participants, the investigator,
research assistants, and outcome assessors will not know the participants allocated to either
intervention or control arm of the study. Unblinding of allocation will be done if the
occurrence of serious adverse events increase above the study site's rates warranting
investigation by the data safety monitoring board. In this case, the unblinding will be done
for the data safety monitoring board (DSMB) and not to the research team.
Study procedures Women whose fetuses develop abnormal fetal heart rate on intermittent
auscultation will be evaluated for presence of fetal distress by a research assistant.
Diagnosis of fetal distress will be confirmed on the basis of fetal heart monitoring for 10
minutes using a Moyo fetal monitor by the trained study research assistants. A FHR below 120
or above 160 beats per minute will be considered fetal distress Standard care: All women with
fetal distress will receive current standard of care which may include, encouragement for
take oral fluids, administration of intravenous fluids such as Ringer's lactate, normal
saline or dextrose, maternal lateral positioning and stopping the oxytocin infusion if the
woman is undergoing induction or augmentation.
The intervention: Women allocated to the intervention arm will receive 100% oxygen, 10 liters
per minute via non re-breather face mask for 15 minutes. The control group will receive
medical air which contains 21% oxygen. 10 liters per minute via a non re-breather face mask
for 15 minutes.
Monitoring and follow up: Fetal heart rate will be monitored after the intervention is
commenced every 15 minutes for 1 hour or until the woman delivers the baby depending on which
one comes first. After one hour of monitoring, the fetal heart rate will be monitored
according to hospital protocols that is every 15 minutes if the fetal heart rate is still
abnormal or every 30 minutes if it normalizes. Follow up will be done until 7 days after
delivery.
Data collection Principal investigator and research assistants will collect personal,
socio-demographic and pregnancy related data. Case record forms(CRFs) will be used to collect
patient demographic data, maternal characteristics and results of the fetal heart rate
monitoring. These forms will be filled in by the research assistants allocated to the
particular shift. Data from laboratory tests will also be filled into the CRFs. A copy of
results will be kept in the patient's hospital records. A study coordinator at each study
site will ensure that all data for each patient has been properly captured daily and/or
before the woman is discharged.
Data management Daily electronic entry will be done from the paper CRFs by the research
assistants. Data will be entered into Epidata software 3.0 during the study period. This data
will be checked for completeness daily and any missing data retrieved before the participants
are discharged usually in 24 hours. The CRFs will be kept in a lockable cupboard placed in
the labor ward with the key only accessible to the research team. The electronic data will be
stored on a password protected computer accessible only by the principal investigator.
Data analysis Analysis will be according to intention to treat. Women in the control group
who for one reason or another require oxygen shall not be denied the treatment but will
however still be analysed according to their original assigned groups. All participants that
are randomized will be analysed including those who drop out for one reason or the other.
Reasons for dropout will be provided in the patient enrollment flow chart.
Data will be entered into STATA 15 software for analysis. Descriptive statistics will be
computed to analyse for similarities and differences in the intervention and control group.
Simple chi-squares will be used to assess differences in the study groups. The expected
outcome in the two groups will be categorically analysed and proportions of participants
whose fetal heart rate normalized within 30 minutes will be determined. The effect of oxygen
therapy on early neonatal outcomes will also be determined using a multi-variable logistic
regression model. Odds ratios will be calculated to determine associations between the
outcome and predictors variables.
Quality control: Allocation concealment and blinding will be done to improve the rigor and
methodological quality of the study. Fetal heart rate will be assessed objectively using the
Moyo fetal heart rate monitor. Research assistants will be trained before the study commences
and ongoing support supervision will be done. All procedures will follow the prescribed
standard operating procedures developed in consultation will available literature. Data
collected on the CRFs will be checked for completeness by the site coordinators and entered
into the software regularly for cleaning. Ongoing monitoring by the study monitor and the
DSMB will be done as well as visits from the ethics committee to ensure compliance with the
ethical principles.
Adverse events and serious adverse events reporting Normobaric Oxygen is a category A drug
for pregnant women and is therefore associated with minimal risks. Minor adverse events (AE)
may include; cough, chest pain, mild dyspnea/ hypo-ventilation, malaise, nausea or tingling
sensation on the skin. These signs and symptoms only occur if the oxygen is administered for
more than 6 hours.
Serious adverse events (SAE) will include but not limited to, serious maternal complications
such as antepartum hemorrhage, postpartum hemorrhage, disseminated intravascular coagulopathy
(DIC), still birth, neonatal death, and maternal death. The principal investigator(PI) will
be notified of any AE and SAE within 48 hours. In case of a SAE, it will be reported by the
PI to the primary ethics committee within 7 days. According to the Uganda National council of
science and technology guidelines, SAEs will be reported to the DSMB, National drug authority
and the ethics committee.
Ethical considerations Ethical approval was obtained from the higher degrees research and
ethics (HDREC) committee at the School of Health Sciences, Makerere University and the
National Council for higher education. Approval was also received from the Uganda National
drug authority and administrative clearances from both study sites. Verbal and written
informed consent will be obtained from participants in the study.
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