Elsevier

The Lancet

Volume 358, Issue 9298, 15 December 2001, Pages 2074-2077
The Lancet

Hypothesis
Short interpregnancy intervals and unfavourable pregnancy outcome: role of folate depletion

https://doi.org/10.1016/S0140-6736(01)07105-7Get rights and content

Summary

There is no generally accepted explanation for the excess risk of adverse pregnancy outcome after short interpregnancy intervals. In this paper, we present a hypothesis that is both biologically plausible, empirically testable, and able to explain many observations. Maternal serum and erythrocyte concentrations of folate decrease from the fifth month of pregnancy onwards and remain low for a fairly long time after delivery. Women who become pregnant before folate restoration is complete have a raised risk of folate insufficiency at the time of conception and during pregnancy. As a consequence, their offspring have higher risks of neural tube defects, intrauterine growth retardation, and preterm birth. We make several predictions based on our hypothesis and suggest ways of testing them empirically. The proposed mechanism implies, among other things, that postpartum supplementation with folic acid might prevent excess risk of unfavourable pregnancy outcome in women with short interpregnancy intervals.

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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