The purpose of this study is to examine whether treatment of pregnant Malawian women with repeated doses of sulfadoxine-pyrimethamine and azithromycin antibiotics will prevent preterm deliveries and result in other health benefits both for the mother and the foetus/newborn.
Maternal anaemia, preterm deliveries and low birth weight are common in Sub-Saharan Africa and contribute significantly to the ill-health of pregnant women and infants. The present study is based on the assumption that these adverse outcomes can be prevented by improved antimicrobial management of malaria and sexually transmitted infections (STI) among pregnant women. To test the hypothesis, a randomised clinical trial following Good Clinical Practice (GCP) is being carried out in Malawi, South-Eastern Africa. A total of 1320 consenting women who present at a rural antenatal clinic after 14 but before 26 completed gestation weeks will be enrolled. One third of the women will receive antenatal care according to national recommendations, including regular visits to health centre, screening for pregnancy complications, haematinic and vitamin A supplementation and two doses of presumptive malaria treatment with sulfadoxine-pyrimethamine. Another third will receive otherwise the same care, but sulfadoxine-pyrimethamine treatment is given at monthly intervals. The final third receives standard antenatal care, sulfadoxine-pyrimethamine treatment at monthly intervals and two doses of presumptive STI treatment with azithromycin. Women are monitored throughout pregnancy and delivery and newborn growth will be followed up for five years. The primary outcome measure is proportion of preterm births in the three study groups. Secondary maternal outcomes include anaemia and malaria parasitaemia during pregnancy, at delivery and at 1, 3, and 6 months after delivery, gestational weight gain and morbidity and STI prevalence after delivery. Secondary child outcomes consist of proportion of babies with low birth weight, mean birth weight, growth in infancy and childhood, incidence of malnutrition in infancy and childhood, and mortality. Additionally, information is collected on the development of malaria-specific humoral immunity in pregnancy and participant experiences from the study. Participant safety is systematically monitored throughout the intervention. There have been two edits two the trial protocol, since the original approval. In the first one, there was an amendment to follow child growth and mortality until and child development at 5 years of age, with visits at 1, 3, 6, 9, 12, 15, 18, 21, 24, 30, 36, 48, and 60 months. In the second amendment, there was an addition to monitor child antropometrics, physical, mental, and social health at and mortality by 10-12 years of age.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
SINGLE
Enrollment
1,320
Sulfadoxine-pyrimethamine, 3 tablets (each containing 500mg of sulfadoxine and 25mg of pyrimethamine), taken once at antenatal care enrolment (14.0-25.9 gestation weeks) and another time between 28.0 and 33.9 gestation weeks. 2 placebo tablets for azithromycin taken at the same time points.
Sulfadoxine-pyrimethamine, 3 tablets (each containing 500mg of sulfadoxine and 25mg of pyrimethamine), taken once at antenatal care enrolment (14.0-25.9 gestation weeks) and then at 4 week intervals until 37.0 gestation weeks. 2 placebo tablets for azithromycin taken once at antenatal care enrolment (14.0-25.9 gestation weeks) and another time between 28.0 and 33.9 gestation weeks.
College of Medicine, University of Malawi
Mangochi, Mangochi District, Malawi
Proportion of preterm births
Proportion of babies who are born before 37 completed gestation weeks
Time frame: once, after delivery
Number of serious adverse events
Death, life-threatening event, hospitalization, congenital anomaly, or any othe condition consedered an SAE by a study physician
Time frame: Cumulative during pregnancy and neonatal period
Percentage of low birth weight babies
Birth weight \< 2500 g
Time frame: Once, after delivery
Mean birth weight
Measured in grams
Time frame: Once, after delivery
Mean duration of gestation
Measured in gestation weeks, expressed to one deciman,
Time frame: Once, after delivery
Percentage of low head circumference at birth
Below 2 standard deviations of the mean of international reference population
Time frame: Once, after delivery
Incidence of moderate underweight during infancy or childhood
weight for age Z-score \< -2
Time frame: Cumulative during infancy and childhood
Perinatal mortality
Stillbirths after 22 gestation weeks or within first 7 days of life / 1000 live births
Time frame: Cumulative until 7 days of post-natal life
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Sulfadoxine-pyrimethamine, 3 tablets (each containing 500mg of sulfadoxine and 25mg of pyrimethamine), taken once at antenatal care enrolment (14.0-25.9 gestation weeks) and then at 4 week intervals until 37.0 gestation weeks. 2 azithromycin tablets (each 500 mg) taken once at antenatal care enrolment (14.0-25.9 gestation weeks) and another time between 28.0 and 33.9 gestation weeks.
Neonatal mortality
Deaths within first 28 days of life / 1000 live births
Time frame: Cumulative until 28 days of post-natal life
Infant mortality
Deaths within first 265 days of life / 1000 live births
Time frame: Cumulative until 365 days of post-natal life
Mean maternal blood haemoglobin concentration at each antenatal visit and at 1, 3, and 6 months after delivery
Measured with hemocue meter, expressed as grams / liter
Time frame: Several antenatal and postnatal visits
Percentage of women with mild, moderate or severe anaemia at every antenatal visit and at 1, 3, and 6 months after delivery
Cut-offs for mild, moderate and severa anaemia 110 g / l - 80 g / l - 50 g / l
Time frame: Several antenatal and postnatal visits
Percentage of women with peripheral blood malaria parasitaemia at 32 gestational weeks and at delivery
Measured with microscopy from fresh blood slides and with real-time PCR from dried blood spots
Time frame: At enrolment, every 4 weeks thereafter and at delivery
Maternal weight gain during pregnancy
grams / gestation week
Time frame: Cumulative during pregnancy
Mean number of maternal illness days during pregnancy
Self reported illness symptoms
Time frame: Cumulative during pregnancy
Prevalence of maternal chlamydia trachomatis, neisseria gonorrhoea, and vaginal trichomoniasis infection at 4 weeks after delivery
Chlamydia and gonorhoea measured from urine samples with a PCR, vaginal trichomoniasis measures with a wet microscopy
Time frame: At 4 weeks after delivery
Attained lenght / height
Measured as length until 2 years of age, then height; expressed in cm (one decimal) and as length / heigh for age Z-score
Time frame: 1, 3, 6, 9, 12, 15, 18, 21, 24, 30, 36, 48, 60 months and 10-12 years of age
Attained weight
Expressed in kg with two decimals and as weight for age Z-score
Time frame: 1, 3, 6, 9, 12, 15, 18, 21, 24, 30, 36, 48, 60 months and 10-12 years of age
Nutritional status
Mid-upper arm circumference, in mm (no decimals)
Time frame: 1, 3, 6, 9, 12, 15, 18, 21, 24, 30, 36, 48, 60 months and 10-12 years of age
Attained head circumference
Head circumference, in mm, no decimals
Time frame: 1, 3, 6, 9, 12, 15, 18, 21, 24, 30, 36, 48, 60 months and 10-12 years of age
Childhood mortality, % of subjects who have died by the 10-12 year follow-up visit
Deaths, information obtained from parents or other adults who have lived in the same household with the child
Time frame: Cumulative incidence by 10-12 years of age
Motor development, Griffiths test, sub-score
Summary score from questions in the gross motor and fine motor domain questions
Time frame: 5 years of age
Social development, Griffiths test, sub-score
Summary score from questions in the social development domain questions
Time frame: 5 years of age
Cognitive development, Raven's colour matrix, score
Summary score from 36 questions in the Raven's colour matrix test
Time frame: 10-12 years of age
Reaction time, milliseconds
This will be tested with an eye-tracking device (Tobii). Participants are asked to look from the fixation point to different directions or fixate the gaze at one point. We will measure the horizontal eye-movements (saccades) and calculate the reaction times, scoring the task correct/incorrect (direction). This eye-tracking system is based on a Pupil Centre Corneal Reflection (PCCR) technique, in which near infrared illumination is reflected on the cornea relative to the center of the pupil. The eye-tracking cameras capture the light reflections and create a 3D model of the eye and head-position to track the participant's point of gaze at high temporal and spatial accuracy (60 Hz/0.4°). The results will be stored automatically into a data base.
Time frame: 10-12 years of age
Systolic blood pressure, mmHg
Will use oscillometric Mobil o Graph blood pressure monitoring system (accuracy +/- 3 mmHg), when the child is first sitting, then standing and last lying down.
Time frame: 10-12 years of age
Diastolic blood pressure, mmHg
Will use oscillometric Mobil o Graph blood pressure monitoring system (accuracy +/- 3 mmHg), when the child is first sitting, then standing and last lying down.
Time frame: 10-12 years of age
Central blood pressure, mmHg
Will use oscillometric Mobil o Graph blood pressure monitoring system (accuracy +/- 3 mmHg), when the child is first sitting, then standing and last lying down.
Time frame: 10-12 years of age
Pulse rate, beats / minutes
Will use oscillometric Mobil o Graph blood pressure monitoring system. We will measure pulse rate / minutes, when the child is first sitting, then standing and last lying down.
Time frame: 10-12 years of age
Vascular resistance, mmHg·min/l
Will use oscillometric Mobil o Graph blood pressure monitoring system. We will measure vascular resistance, when the child is first sitting, then standing and last lying down.
Time frame: 10-12 years of age
Lean body mass, expressed in kg, with one decimal
Body composition measured with 8-polar biompedance method (Seca® mBCA 515 Medical Body Composition Analyser), validated with Deuterium Dilution Technique with Analysis of Saliva Samples by Fourier Transform Infrared Spectrometry (FTIR)
Time frame: 10-12 years of age
Fat mass, expressed in kg, with one decimal
Body composition measured with 8-polar biompedance method (Seca® mBCA 515 Medical Body Composition Analyser), validated with Deuterium Dilution Technique with Analysis of Saliva Samples by Fourier Transform Infrared Spectrometry (FTIR)
Time frame: 10-12 years of age
Fat percentage, expressed proportion of body weight (per cent, with one decimal)
Body composition measured with 8-polar biompedance method (Seca® mBCA 515 Medical Body Composition Analyser), validated with Deuterium Dilution Technique with Analysis of Saliva Samples by Fourier Transform Infrared Spectrometry (FTIR)
Time frame: 10-12 years of age
Self-rated well-being, score
Self-reported well-being will be measured with 11 question panel with rating from 1-5 expressed as smileys. The questions consider about "how happy you are about the things you own, school, house you live, food, clothes, other pupils, friends, the family, safety feeling, the way you look, with yourself". Score for self-reported well-being will be calculated as a sum of ratings for each item divided by the number of items with non-missing data. There are two items related to the child's school and they are not applicable if the child does not go to school. The minimum score for self-reported well-being is 1 and the maximum is 5, and the score will be expressed with one decimal.
Time frame: 10-12 years of age