Gestational Sulfadoxine-pyrimethamine and Azithromycin Treatment to Prevent Preterm Birth

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.

Eligibility Criteria:
Inclusion Criteria:

* Signed informed consent
* Age \>= 15 years
* Ultrasound confirmed pregnancy
* Quickening
* Foetal age 14-26 gestation weeks
* Maternal availability for follow-up during the entire study period

Exclusion Criteria:

* Known maternal tuberculosis, diabetes, kidney disease or liver disease
* Any severe acute illness warranting hospital referral at enrollment visit
* Mental disorder that may affect comprehension of the study or success of follow-up
* Twin pregnancy
* Pregnancy complications evident at enrollment visit (moderate to severe oedema, blood hemoglobin \[Hb\] concentration \< 50 g/l, systolic blood pressure \[BP\] \> 160 mmHg or diastolic BP \> 100 mmHg)
* Prior receipt of azithromycin during this pregnancy
* Receipt of sulfadoxine and pyrimethamine within 28 days of enrollment
* Known allergy to drugs containing sulfonamides, macrolides or pyrimethamine
* History of anaphylaxis
* History of any serious allergic reaction to any substance, requiring emergency medical care
* Concurrent participation in any other clinical trial