Premature Birth Clinical Trial
Official title:
Docosahexaenoic Acid (DHA) Supplementation During Pregnancy to Prevent Deep Placentation Disorders: A Randomized Clinical Trial and a Study of the Molecular Pathways of Abnormal Placentation Prevention
This study evaluates the effectiveness of maternal supplementation with Docosahexaenoic acid (DHA) early in pregnancy to reduce the incidence of deep placentation disorders: preterm birth, preterm labor, preterm premature rupture of membranes, preeclampsia and fetal growth restriction. Half of the participants in early pregnancy will receive DHA 600 mg per day, while the other half will receive placebo. Investigators will study also the ability of DHA supplementation, early in pregnancy, to enhance invasion and transformation of spiral arteries by trophoblast, as deep placentation indicators.
Introduction: uteroplacental ischemia may cause preterm birth, either due to preterm labor,
preterm premature rupture of membranes, or medical indication (in the presence of
preeclampsia or fetal growth restriction). Uteroplacental ischemia is the product of
defective deep placentation, that is a failure of invasion and transformation of the spiral
arteries by the trophoblast. It has been reported that the failure of normal placentation
generates a series of clinical abnormalities nowadays called "deep placentation disorders";
they include preeclampsia (PE), fetal growth restriction (FGR), preterm labor (PL), preterm
premature rupture of membranes (PPROM), in utero fetal death and placental abruption.
Strategies to prevent deep placentation disorders have been just partially effective.
Docosahexaenoic acid (DHA) is an essential fatty acid of the family of long chain
polyunsaturated fatty acids (LC-PUFAs) or omega-3 fatty acids. Early reports, suggested that
a LC-PUFAs rich diet reduces the incidence of deep placentation disorders. Recent randomized
controlled trials are inconsistent to show the benefit of DHA supplementation during
pregnancy to prevent deep placentation disorders; but most of them showed that DHA
supplementation was associated to lower risk of early preterm birth.
Hypothesis: investigators propose that Docosahexaenoic acid (DHA) supplementation, early in
pregnancy, reduces the incidence of deep placentation disorders (preterm birth, preterm
labor, preterm premature rupture of membranes, preeclampsia and fetal growth restriction),
by improving deep placentation physiology: invasion and transformation of spiral arteries by
trophoblast.
General Goals: in this proposal investigators aimed to
1. Assess the effectiveness of maternal supplementation with Docosahexaenoic acid (DHA)
early in pregnancy to reduce the incidence of deep placentation disorders: preterm
birth, preterm labor, preterm premature rupture of membranes, preeclampsia and fetal
growth restriction.
2. Study the ability of DHA supplementation, early in pregnancy, to enhance invasion and
transformation of spiral arteries by trophoblast, as deep placentation indicators.
Methodology: investigators will conduct a randomized, placebo controlled, double blind,
clinical trial of maternal supplementation with DHA (Docosahexaenoic acid) to prevent
deep placentation disorders. Women will be recruited before 16 weeks of pregnancy from
5 ambulatory centers, 2.400 pregnant women will be assigned to 600 mg DHA per day or
placebo. A composite outcome will be the primary outcome of the study. The components
of the composite outcome will be: preterm birth < 34+0 weeks gestation; early
preeclampsia (<34+0 weeks) and severe fetal growth restriction (lower than the 2
percentile and < 34+0 weeks). Each of the outcomes of the composite outcome and other
clinically relevant maternal and fetal outcomes will be evaluated as the secondary
outcomes of the study. Clinical samples will be obtained from pregnant women on both
groups, including: plasma, trophoblast, placental bed and myometrium, to study changes
of deep placentation or defective placentation markers. Trophoblast cell lines will be
used to study the effect of DHA on trophoblast function in vitro.
Expected outcome: In the randomized clinical trial, a 50% reduction in the incidence of the
composite outcome in the DHA group (4% placebo vs. 2% DHA) is expected. Investigators expect
to decrease defective deep placentation (placental bed biopsies) and defective placentation
markers in DHA supplemented women. Investigators expect also to demonstrate that DHA
enhances trophoblast migration and invasion in vitro and decreases production of
inflammatory cytokines and anti-vasculogenic mediators.
Relevance: if the findings are positive, DHA supplementation, early in pregnancy, will
become a safe and effective strategy for primary prevention of highly relevant pregnancy
diseases, such as preterm birth, preeclampsia and fetal growth restriction.
;
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Prevention
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