HypothesisShort interpregnancy intervals and unfavourable pregnancy outcome: role of folate depletion
Section snippets
Course of folate concentrations during and after pregnancy
Human beings are fully dependent on dietary sources or dietary supplements for their folate supply. Folate is required for cell division because of its role in DNA synthesis.20 During pregnancy, folate demand is increased.21 Without adequate folate supplementation, concentrations of folate in maternal serum, plasma, and red blood cells decrease from the fifth month of pregnancy onwards.22, 23, 24 Concentrations continue to decrease for several weeks after pregnancy,22, 23, 25, 27 and by the
Folate deficiency-related adverse pregnancy outcome
A number of studies have addressed the relation between pregnancy outcome and either maternal blood folate concentrations, folate intake, or hyperhomocysteinaemia (the effect of inadequate folate intake or abnormal folate metabolism).
Periconceptional supplementation with folate has been shown to reduce the risk of neural tube defects by almost three-quarters.28 Studies in animals suggest that homocysteine is the teratogen which causes excess neural tube defects in folate deficiency.29 This
Our hypothesis
We hypothesise that the excess risk of adverse pregnancy outcome after short (<6 months), as opposed to longer, interpregnancy intervals is largely attributable to insufficient repletion of maternal folate resources.
The figure (parts A and B) gives a schematic representation of the expected course of folate concentrations in women with short and longer interpregnancy intervals. As of the fifth month of pregnancy, maternal folate concentrations decrease. They continue to do so during the first
Earlier observations in line with our hypothesis
Many earlier observations in studies of the effects of short interpregnancy intervals on pregnancy outcome can be explained by maternal folate depletion. A two-fold increase in the risk of neural tube defects was observed for conceptions within 6 months after a livebirth compared with conceptions 1 to 2 years after a livebirth.13 The investigators controlled for multivitamin use and other potential confounders. Within the group of pregnancies occurring after a (spontaneous or elective)
Predicted effects of our hypothesis
On the assumption that the hypothesis is true, several other effects can be expected. In breastfeeding women, the extra risk connected with short interpregnancy intervals is expected to be greater because of a higher probability of folate depletion during their first months postpartum. In addition, the excess risk is expected to last longer because of a longer duration of folate insufficiency.
In statistical analyses of the effects of the length of the interpregnancy interval on pregnancy
Testing the hypothesis
The most rigorous test of the hypothesis would be to do a randomised, placebo-controlled trial of folate supplementation in a large group of women who are at risk of becoming pregnant in the near future and who have delivered a baby in the recent past (so that short interpregnancy intervals might occur). These women would have to be followed until the relevant outcome could be measured. If the hypothesis is not true, short interpregnancy intervals would still be a factor explaining a large part
Conclusion
If the proposed mechanism correctly explains the excess unfavourable pregnancy outcome seen after short interpregnancy intervals, several types of preventive intervention are possible. First, women could be advised to take postpartum supplementation of folic acid to ensure adequate folate concentrations during the first months after delivery (figure). With supplementation, postpartum folate concentrations could be normalised within 1·5 to 3 months, even in lactating mothers.25 Overall, 6–12% of
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Influence of Medicaid expansion on short interpregnancy interval rates in the United States
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Interpregnancy interval and the risk of oppositional defiant disorder in offspring
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