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VU Research Portal

Studying the effects of periconceptional folic acid supplementation

Blom, F.

2015

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citation for published version (APA)

Blom, F. (2015). Studying the effects of periconceptional folic acid supplementation: Travel the world and the

seven seas.

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Gener

al discussion

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9

ART BY MARIEKE VAN HELLENBERG HUBAR

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Part IV Gener

al discussion and Addendum

ϭϱϮ

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Part IV Gener

ϭϱϰ 9 >ĞǀĞů / ĞǀŝĚĞŶĐĞ ĐĂŶ ďĞ ƵƐĞĚ ƚŽ ĚĞŵŽŶƐƚƌĂƚĞ ĐĂƵƐĂů ƌĞůĂƟŽŶƐŚŝƉƐ͘ Ɛ ƐŚŽǁŶ ŝŶ ƚŚŝƐ ƚŚĞƐŝƐ ŚŽǁĞǀĞƌ͕ŝƚŝƐĚŝĸĐƵůƚƚŽƉĞƌĨŽƌŵƌĞƐĞĂƌĐŚĂƚƚŚŝƐŚŝŐŚůĞǀĞů͘ƐƉĞĐŝĂůůǇĨŽƌƚŚĞƐƚƵĚǇŽĨĂŶĚ & ƐƵƉƉůĞŵĞŶƚĂƟŽŶ ƚŚŝƐ ŝƐ ĐŚĂůůĞŶŐŝŶŐ ďĞĐĂƵƐĞ ůĂƌŐĞ ŶƵŵďĞƌƐ ŽĨ ƉĂƌƟĐŝƉĂŶƚƐ ĂƌĞ ƌĞƋƵŝƌĞĚ ĚƵĞƚŽƚŚĞůŽǁƉƌĞǀĂůĞŶĐĞŽĨ͕ĂŶĚďĞĐĂƵƐĞƚŚĞƚĂƌŐĞƚƉŽƉƵůĂƟŽŶĨŽƌ&ƐƵƉƉůĞŵĞŶƚĂƟŽŶŝƐ ĚŝĸĐƵůƚƚŽŝĚĞŶƟĨǇĂŶĚƌĞĂĐŚĂƚƚŚĞƌŝŐŚƚŵŽŵĞŶƚǁŝƚŚƚŚĞƌŝŐŚƚŵĞƐƐĂŐĞ͘ ZĞƐĞĂƌĐŚĂůƚĞƌŶĂƟǀĞƐ tŚĞŶ ůĞǀĞů ϭ ĞǀŝĚĞŶĐĞ ŝƐ ŶŽƚ ƉŽƐƐŝďůĞ ƚŽ ĂĐŚŝĞǀĞ͕ ƚŚĞƌĞ ĂƌĞ ƉůĞŶƚǇ ĂůƚĞƌŶĂƟǀĞƐ ŽĨ ŽƚŚĞƌ ůĞǀĞůƐ͕ƐƵĐŚĂƐƵŶĐŽŶƚƌŽůůĞĚŝŶƚĞƌǀĞŶƟŽŶƐƚƵĚŝĞƐ͕ĐŽŚŽƌƚĂŶĚĐĂƐĞͲĐŽŶƚƌŽůƐƚƵĚŝĞƐ͘ŶĚǁŚĞŶ ƚŚĞƌĞƐƵůƚƐĂƌĞŝŶƚŚĞƐĂŵĞĚŝƌĞĐƟŽŶ͕ƐǇƐƚĞŵĂƟĐƌĞǀŝĞǁƐŽĨƚŚĞƐĞƚǇƉĞƐŽĨƐƚƵĚŝĞƐĐĂŶƉƌŽǀŝĚĞ ĂŐŽŽĚĞƐƟŵĂƚĞŽĨƚŚĞƚƌƵĞĞīĞĐƚ͘/ŶƚŚĞĚĞǀĞůŽƉŵĞŶƚŽĨƉƵďůŝĐŚĞĂůƚŚƉŽůŝĐǇ͕ŝƚŝƐŝŵƉŽƌƚĂŶƚ ƚŽƚĂŬĞŝŶƚŽĂĐĐŽƵŶƚĂůůďĞŶĞĮĐŝĂůĂŶĚƉŽƚĞŶƟĂůůǇĂĚǀĞƌƐĞĞīĞĐƚƐϱ_{͘ŝīĞƌĞŶƚŽƵƚĐŽŵĞƐĐĂŶďĞ} ĚŝĸĐƵůƚƚŽǁĞŝŐŚĂŐĂŝŶƐƚĞĂĐŚŽƚŚĞƌ͕ĞƐƉĞĐŝĂůůǇĐŽŶƐŝĚĞƌŝŶŐƚŚĞƟŵŝŶŐŽĨƚŚĞŽƵƚĐŽŵĞ͕Ğ͘Ő͘ ĐŽŶŐĞŶŝƚĂůĂŶŽŵĂůŝĞƐǀĞƌƐƵƐŝŶĐƌĞĂƐĞĚŝŶĐŝĚĞŶĐĞŽĨĐŚŝůĚŚŽŽĚĂƐƚŚŵĂŽƌŝŶƐƵůŝŶƌĞƐŝƐƚĂŶĐĞŝŶ ƚŚĞŽīƐƉƌŝŶŐϲ_{͘ƵƚĂůƐŽĨŽƌŽŶĞŽƵƚĐŽŵĞĐŽŶŇŝĐƟŶŐƌĞƐƵůƚƐŚĂǀĞƚŽďĞǁĞŝŐŚĞĚĐĂƌĞĨƵůůǇ͘&Žƌ} ĞǆĂŵƉůĞ͕ŝŶĂƉƌŽƐƉĞĐƟǀĞĐŽŚŽƌƚƐƚƵĚǇŽŶŽƌŽĨĂĐŝĂůĐůĞŌƐŝŶŚŝŶĂ͕Ϭ͘ϰŵŐ&ǁĂƐĂƐƐŽĐŝĂƚĞĚ ǁŝƚŚĂƌĞĚƵĐĞĚƌŝƐŬĨŽƌĐůĞŌůŝƉǁŝƚŚŽƌǁŝƚŚŽƵƚĐůĞŌƉĂůĂƚĞϳ_{͕ǁŚŝůĞĂƵƚĐŚĐĂƐĞͲĐŽŶƚƌŽůƐƚƵĚǇ} ƌĞƉŽƌƚĞĚŝŶĐƌĞĂƐĞĚƌŝƐŬƐŽĨĐůĞŌůŝƉͬĂůǀĞŽůƵƐĂƐƐŽĐŝĂƚĞĚǁŝƚŚ&ƐƵƉƉůĞŵĞŶƚĂƟŽŶϴ_{͘dŚĞŶĞǆƚ} ůŽŐŝĐĂůƐƚĞƉǁŽƵůĚďĞƚŽƉĞƌĨŽƌŵĂŶZd͘dŽĐůĞĂƌƚŚŝƐŝŵƉĂƐƐĞ͕ŝƚŝƐŶĞĐĞƐƐĂƌǇƚŽƌĞƉĞĂƚƐƚƵĚǇ protocols in other countriesϵ_{͕ĂŶĚƚŽĨƵƌƚŚĞƌĞǆƉůŽƌĞƉŽƚĞŶƟĂůƌĞŐŝŽŶĂůĞīĞĐƚƐ͘dŚĞƌĞĂƌĞƐŽŵĞ}

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Gener al discussion ϭϱϱ 9 ĂŶĚŝŶĚŝīĞƌĞŶƚƌĞŐŝƐƚƌŝĞƐŝƐŶĞĞĚĞĚƚŽƐŚĞĚůŝŐŚƚŽŶƚŚĞĂĚĚŝƟǀĞǀĂůƵĞŽĨƚŚŝƐŵĞƚŚŽĚƚŽƚŚĞ ĐůĂƌŝĮĐĂƟŽŶŽĨƚŚĞĞīĞĐƚƐŽĨ&͘ dŚŝƐůĂƐƚŚǇƉŽƚŚĞƐŝƐŝƐŶŽƚďĂƐĞĚŽŶƚŚĞƵƐĞŽĨ&͕ďƵƚŽŶƚŚĞƉƌŽďĂďůĞůĂĐŬŽĨ&ƚŚĂƚůĞĂĚƐƚŽ ƚŚĞ&ͲƌĞůĂƚĞĚƚŽŽĐĐƵƌ͘ƉĂƌƚĨƌŽŵĞƉŝĚĞŵŝŽůŽŐŝĐĂůĚĂƚĂŽŶ͕ƚŚĞ&ƐƚĂƚƵƐĐŽƵůĚďĞĂ ďĂƐŝƐ ĨŽƌ ĨƵƚƵƌĞ ƌĞƐĞĂƌĐŚ͘ dŚĞ & ƐƚĂƚƵƐ ĐĂŶ ďĞ ǀŝĞǁĞĚ ŝŶ Ă ďƌŽĂĚ ƐĞŶƐĞ͕ Ğ͘Ő͘ ŽŶ ŶĂƟŽŶĂů ůĞǀĞů͕ Žƌ ǀĞƌǇ ĐůŽƐĞ ƚŽ ƚŚĞ ƟŵŝŶŐ ĂŶĚ ŽƌŝŐŝŶ ŽĨ ƚŚĞ ƐƚƵĚŝĞĚ ĞīĞĐƚ͗ ŝŶ ƚŚĞ ŵŽƚŚĞƌͲƚŽͲďĞ͘ ^ĞƌƵŵůĞǀĞůƐŽĨĨŽůŝĐĂĐŝĚŝŶǁŽŵĞŶ͕ďĞĨŽƌĞĐŽŶĐĞƉƟŽŶŽƌĞĂƌůǇŝŶƉƌĞŐŶĂŶĐǇ͕ƌĞŇĞĐƚĨŽůĂƚĞ ƐƚĂƚƵƐ͘ KŶ ŶĂƟŽŶĂů ůĞǀĞů͕ ŵŽƌĞ ĂŶĚ ŵŽƌĞ ĐŽƵŶƚƌŝĞƐ ŝŶƚƌŽĚƵĐĞ ŵĂŶĚĂƚŽƌǇ ĨŽŽĚ ĨŽƌƟĮĐĂƟŽŶ ǁŝƚŚ&ƚŽĚĞĐƌĞĂƐĞƚŚĞƉƌĞǀĂůĞŶĐĞŽĨEd͘/ŶĐŝĚĞŶĐĞƟŵĞͲƚƌĞŶĚĂŶĂůǇƐŝƐ͕ƉƌŝŽƌƚŽĂŶĚĂŌĞƌ ƚŚĞŝŵƉůĞŵĞŶƚĂƟŽŶŽĨĨŽŽĚĨŽƌƟĮĐĂƟŽŶ͕ĂŶĚĂĐŽŵƉĂƌŝƐŽŶŽĨŝŶĐŝĚĞŶĐĞƌĂƚĞƐŝŶĐŽƵŶƚƌŝĞƐǁŝƚŚ ŽƌǁŝƚŚŽƵƚŵĂŶĚĂƚŽƌǇĨŽŽĚĨŽƌƟĮĐĂƟŽŶƉƌŽŐƌĂŵƐĐĂŶƐŚĞĚŶĞǁ͕ŽƌĂůƚĞƌŶĂƟǀĞ͕ůŝŐŚƚŽŶƚŚĞ ĞīĞĐƚŽĨ&ŽŶƚŚĞŽĐĐƵƌƌĞŶĐĞŽĨ͘ &ŽĐƵƐƐŝŶŐŽŶƚŚĞ&ƐƚĂƚƵƐǀĞƌǇĐůŽƐĞƚŽƚŚĞƟŵŝŶŐĂŶĚŽƌŝŐŝŶŽĨƚŚĞƐƚƵĚŝĞĚĞīĞĐƚ͕ŵŝŐŚƚĂůƐŽ ůŝŵŝƚƚŚĞŝŶŇƵĞŶĐĞŽĨĐŽŶĨŽƵŶĚĞƌƐ͘ŽŶĨŽƵŶĚŝŶŐĨĂĐƚŽƌƐŵŝŐŚƚŝŶĐƌĞĂƐĞƚŚĞƉƌĞǀĂůĞŶĐĞŽĨ& ƐƵƉƉůĞŵĞŶƚĂƟŽŶŽƌŝŶŇƵĞŶĐĞƚŚĞŵĞƚĂďŽůŝƐŵŽĨ&͕ĂŶĚƚŚĞƌĞĨŽƌĞŝŶƚĞƌĨĞƌĞǁŝƚŚƚŚĞƌĞůĂƟŽŶ-ƐŚŝƉďĞƚǁĞĞŶ&ƐƵƉƉůĞŵĞŶƚĂƟŽŶĂŶĚƚŚĞďŝƌƚŚŽƵƚĐŽŵĞ͘dŚĞĞīĞĐƚŽĨƐǇŶƚŚĞƟĐ&ŝƐĂĐƚƵĂůůǇ caused by metabolites of FA in the bodyi_{;ĨŽůĂƚĞƐͿ}ϭϬ_{͘ǇƐƚƵĚǇŝŶŐƚŚĞďůŽŽĚĨŽůĂƚĞůĞǀĞůƐ;Ğ͘Ő͘}

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Part IV Gener

ϭϱϲ 9 &ŝŐƵƌĞϵ͘ϭ DĞĂƐƵƌĞŵĞŶƚŽĨ&ƐƵƉƉůĞŵĞŶƚĂƟŽŶƉƌĞĐĞĚĞƐƚŚĞŝŶŇƵĞŶĐĞŽĨ&ĂŶƚĂŐŽŶŝƐƚĚƌƵŐ;ĨŽƌĞǆ-ĂŵƉůĞͿŽŶƚŚĞĚĞǀĞůŽƉŵĞŶƚŽĨ͕ǁŚŝůĞŵĞĂƐƵƌĞŵĞŶƚŽĨďůŽŽĚĨŽůĂƚĞůĞǀĞůƐĨŽůůŽǁƐƚŚĞ& ŵĞƚĂďŽůŝƐŵ͘ /ŵƉůŝĐĂƟŽŶƐĨŽƌƉƵďůŝĐŚĞĂůƚŚƉŽůŝĐǇ ^ŝŶĐĞ ƚŚĞ ĐƵƌƌĞŶƚůǇ ƌĞĐŽŵŵĞŶĚĞĚ ĚŽƐĞ ŽĨ ƉĞƌŝĐŽŶĐĞƉƟŽŶĂů & ƐƵƉƉůĞŵĞŶƚĂƟŽŶ ƌĞĚƵĐĞƐ ƚŚĞƌŝƐŬŽĨEdŝŶƚŚĞŽīƐƉƌŝŶŐ͕ƚŚĞŝŵƉůĞŵĞŶƚĂƟŽŶŽĨƚŚĞƐƵƉƉůĞŵĞŶƚĂƟŽŶĂĚǀŝĐĞƐŚŽƵůĚ ďĞ ĐŽŶƟŶƵĞĚ͘ dŚŝƐ ŝƐ Ă ĐŚĂůůĞŶŐĞ͕ ĞǀĞŶ ŝŶ ƚŚĞ EĞƚŚĞƌůĂŶĚƐ ǁŚĞƌĞ Ă ůĂƌŐĞ ƉƌŽƉŽƌƟŽŶ ŽĨ ƉƌĞŐŶĂŶĐŝĞƐŝƐƉůĂŶŶĞĚϭϮ_{͘dŚĞƵƐĞŽĨ&ŝŶƚŚĞEĞƚŚĞƌůĂŶĚƐĚŝĚŶŽƚŝŶĐƌĞĂƐĞĚƵƌŝŶŐƚŚĞůĂƐƚ} ĚĞĐĂĚĞ͕ĂŶĚƚŚĞŬŶŽǁůĞĚŐĞŽĨ&ŝƐĚĞĐůŝŶŝŶŐϭϯ_{͘DŽƌĞŽǀĞƌ͕ŝŶƚŚĞůĂƐƚƌĞƉŽƌƚĞĚƐƵƌǀĞǇŽĨ&} ƵƐĞŝŶƚŚĞEŽƌƚŚĞƌŶEĞƚŚĞƌůĂŶĚƐ͕ϱϭ͘ϲйŽĨƚŚĞǁŽŵĞŶƌĞƉŽƌƚĞĚƚŽŚĂǀĞƵƐĞĚ&ǁŚŝůĞϴϳ͘Ϭй ŬŶĞǁŽĨ&ďĞĨŽƌĞƚŚĞŝƌƉƌĞŐŶĂŶĐǇϭϯ_{͘ZĞĐŽŵŵĞŶĚĂƟŽŶƐĂůŽŶĞĂƌĞŶŽƚĞŶŽƵŐŚƚŽƉƌĞǀĞŶƚƚŚĞ} ŽĐĐƵƌƌĞŶĐĞ ŽĨ Edϭϰ_{͘ ƐƉĞĐŝĂůůǇ ǇŽƵŶŐ ǁŽŵĞŶ ĂŶĚ ǁŽŵĞŶ ǁŝƚŚ Ă ůŽǁĞƌ ƐŽĐŝŽͲĞĐŽŶŽŵŝĐ} ƐƚĂƚƵƐ;^^ͿĂƌĞĂƚŚŝŐŚĞƌƌŝƐŬŽĨŶŽƚͲƵƐŝŶŐ&ϭϯ_{͕ĂŶĚƚŚŝƐĚŝīĞƌĞŶĐĞŝƐĚƵĞƚŽĂĚŝīĞƌĞŶĐĞŝŶ} ŬŶŽǁůĞĚŐĞĂďŽƵƚ&ϭϱ_{͘/ŶƚŚĞEĞƚŚĞƌůĂŶĚƐ͕ƚŚĞƌĞŝƐŶŽŵĂŶĚĂƚŽƌǇĨŽŽĚĨŽƌƟĮĐĂƟŽŶǁŝƚŚ&͕} ĂŶĚǁŝƚŚǀŽůƵŶƚĂƌǇĨŽƌƟĮĐĂƟŽŶŵĂŝŶůǇƐƵďƉŽƉƵůĂƟŽŶƐĂƌĞƌĞĂĐŚĞĚƚŚĂƚĂƌĞĂǁĂƌĞŽĨƚŚĞ& ƐƵƉƉůĞŵĞŶƚĂƟŽŶĂĚǀŝĐĞ͘dŚĞƌĞĨŽƌĞ͕ĂĚĚŝƟŽŶĂůƉƵďůŝĐŚĞĂůƚŚĂƉƉƌŽĂĐŚĞƐĂƌĞŶĞĞĚĞĚƚŽƌĞĂĐŚ ƚŚĞŵŽƌĞǀƵůŶĞƌĂďůĞƐƵďƉŽƉƵůĂƟŽŶƐϭϲ_{͘ƐƉƌŽƉŽƐĞĚďǇƌŝĚĞƌ et al.;ϮϬϭϰͿďůŽŽĚĨŽůĂƚĞůĞǀĞůƐ} ĂƐďŝŽŵĂƌŬĞƌĨŽƌEdƌŝƐŬ͕ĐĂŶďĞƵƐĞĚƚŽŝĚĞŶƟĨǇƐƵďƉŽƉƵůĂƟŽŶƐĂƚƌŝƐŬϭϳ_{͕ĂƐǁĞůůĂƐŵĞƚŚŽĚ} ĨŽƌƉŽƉƵůĂƟŽŶƐƵƌǀĞǇƐƚŽĞǀĂůƵĂƚĞƉƌĞǀĞŶƟŽŶƐƚƌĂƚĞŐŝĞƐĂŶĚƚŽŚĞůƉŐƵŝĚĞƉŽůŝĐǇĚĞĐŝƐŝŽŶƐϭϳ͕ϭϴ_͘ ii_{ZĞĐĞŶƚůǇ&ZdƐǁĞƌĞƚĞƌŵŝŶĂƚĞĚŝŶƌĂǌŝů͕/ƚĂůǇĂŶĚƚŚĞEĞƚŚĞƌůĂŶĚƐ;W͘DĂƐƚƌŽŝĂĐŽǀŽ͕ϮϬϭϯ͕ƉĞƌƐŽŶĂů} ĐŽŵŵƵŶŝĐĂƟŽŶͿ͘ Confounding factors Use of FA

Awareness of FA FA metabolism _developmentEmbryonic

Measurement of FA supplementation

Measurement of blood folate levels

time

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Part IV Gener

ϭϱϴ 9 ϭ͘ ŽƌŶĞůD͕ƌŝĐŬƐŽŶ:͘ŽŵƉĂƌŝƐŽŶŽĨŶĂƟŽŶ-ĂůƉŽůŝĐŝĞƐŽŶƉĞƌŝĐŽŶĐĞƉƟŽŶĂůƵƐĞŽĨĨŽůŝĐĂĐŝĚ ƚŽƉƌĞǀĞŶƚƐƉŝŶĂďŝĮĚĂĂŶĚĂŶĞŶĐĞƉŚĂůǇ;^Ϳ͘ dĞƌĂƚŽůŽŐǇϭϵϵϳ͖ϱϱ;ϮͿ͗ϭϯϰͲϭϯϳ͘ Ϯ͘ ĞͲZĞŐŝů >D͕ &ĞƌŶĂŶĚĞǌͲ'ĂǆŝŽůĂ ͕ ŽǁƐǁĞůů d͕WĞŶĂͲZŽƐĂƐ:W͘īĞĐƚƐĂŶĚƐĂĨĞƚǇŽĨƉĞƌŝĐŽŶ-ĐĞƉƟŽŶĂů ĨŽůĂƚĞ ƐƵƉƉůĞŵĞŶƚĂƟŽŶ ĨŽƌ ƉƌĞǀĞŶƚ-ŝŶŐ ďŝƌƚŚ ĚĞĨĞĐƚƐ͘ ŽĐŚƌĂŶĞ ĂƚĂďĂƐĞ ŽĨ ^ǇƐ-ƚĞŵĂƟĐZĞǀŝĞǁƐϮϬϭϬ͖;ϭϬͿ͘

ϯ͘ ŽƌƚŽůƵƐ Z͕ ůŽŵ &͕ &ŝůŝƉƉŝŶŝ &͕ ǀĂŶ WŽƉƉĞů