VU Research Portal

VU Research Portal

Studying the effects of periconceptional folic acid supplementation

Blom, F.

2015

document version

Publisher's PDF, also known as Version of record

Link to publication in VU Research Portal

citation for published version (APA)

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

General rights

Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain

• You may freely distribute the URL identifying the publication in the public portal ?

Take down policy

If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.

E-mail address:

vuresearchportal.ub@vu.nl

ϱϳ DWƌĞŐŶĂŶĐLJΘŚŝůĚďŝƌƚŚϮϬϭϰ͖ϭϰ͗ϭϲϲ ϱϳ ϱϳ

4

PHOTOGRAPHY BY FENNEKE BLOM

Renata Bortolus Fenneke Blom Francesca Filippini DŝƌĞŝůůĞEDǀĂŶWŽƉƉĞů ŵĂŶƵĞůĞ>ĞŽŶĐŝŶŝ ĞŶŚĂƌĚ:ĚĞ^ŵŝƚ

PREVENTION OF CONGENITAL MALFORMATIONS

AND OTHER ADVERSE PREGNANCY

KhdKD^t/d,ϰ͘ϬD'K&&K>//͗

KDDhE/dzͳ^ZEKD/>/E/>

WĂƌƚ/& ŽůŝĐĂĐŝĚƐƵƉƉůĞŵĞŶ ƚĂ ƟŽŶĂŶĚĐ ŽŶŐ ĞŶŝƚ ĂůĂŶŽŵĂůŝĞƐĂŶĚ Ɖƌ ĞŐŶĂŶĐLJŽƵƚ ĐŽ ŵĞƐ ϲϲ 4 ŬŶŽǁŶƌŝƐŬĨĂĐƚŽƌ͘/ĨĂĚŽƐĞŽĨϰʹϱŵŐͬĚĂLJĐĂŶƉƌĞǀĞŶƚƌĞĐƵƌƌĞŶĐĞŽƌŽĐĐƵƌƌĞŶĐĞŝŶǁŽŵĞŶ ǁŝƚŚǁĞůůͲŬŶŽǁŶƌŝƐŬĨĂĐƚŽƌƐ͕ŝƚƐŚŽƵůĚďĞƚŚĞƐĂŵĞĨŽƌƚŚĞŽĐĐƵƌƌĞŶĐĞĂŶĚŝŶǁŽŵĞŶǁŝƚŚŶŽ ŬŶŽǁŶƌŝƐŬĨĂĐƚŽƌƐ͘ dŚĞƋƵĞƐƟŽŶƌĞŵĂŝŶƐĐŽŶĐĞƌŶŝŶŐƚŚĞďĞƐƚĚŽƐĞŽĨ&ƐƵƉƉůĞŵĞŶƚĂƟŽŶ͕ĂƐƚŚĞƉƌĞǀĂůĞŶĐĞŽĨ DƐǁŽƌůĚǁŝĚĞŝƐƐƟůůŚŝŐŚ͘ KǀĞƌĂůů͕ĨƌŽŵĂůůƚŚĞƐĞƐƚƵĚŝĞƐŝƚĐĂŶďĞƐƉĞĐƵůĂƚĞĚƚŚĂƚĂŶŝŶĐƌĞĂƐĞĚƉĞƌŝͲĐŽŶĐĞƉƟŽŶĂůŝŶƚĂŬĞ ŽĨ&ĐĂŶĐĂƵƐĞĂŐƌĞĂƚĞƌƌĞĚƵĐƟŽŶŝŶƚŚĞƌŝƐŬŽĨEdƐĂƐǁĞůůĂƐĂŐƌĞĂƚĞƌĂŶĚŵĞĂƐƵƌĂďůĞ ƌĞĚƵĐƟŽŶŝŶƚŚĞƌŝƐŬŽĨŽƚŚĞƌDƐ͕ŝŶĐůƵĚŝŶŐƚƌŝƐŽŵLJϮϭƐLJŶĚƌŽŵĞ͘ dŚĞŚLJƉŽƚŚĞƐŝƐƚŚĂƚĂŚŝŐŚĞƌŝŶƚĂŬĞŽĨ&ŝƐƌĞůĂƚĞĚƚŽĂŚŝŐŚĞƌƌŝƐŬƌĞĚƵĐƟŽŶŽĨEdƐĂŶĚŽĨ ŽƚŚĞƌDƐŝƐƚŚĞŵĂŝŶƌĂƟŽŶĂůĞĨŽƌƚŚĞ/ƚĂůŝĂŶĂŶĚƵƚĐŚZdƐ͘ &ƐƵƉƉůĞŵĞŶƚĂƟŽŶŝŶƐĞĐŽŶĚĂŶĚƚŚŝƌĚƚƌŝŵĞƐƚĞƌŽĨƉƌĞŐŶĂŶĐLJ ƵƌŝŶŐ ƉƌĞŐŶĂŶĐLJ͕ ŝŶĐƌĞĂƐĞĚ ĨŽůĂƚĞ ŝŶƚĂŬĞ ŝƐ ƌĞƋƵŝƌĞĚ ĨŽƌ ƌĂƉŝĚ ĐĞůů ƉƌŽůŝĨĞƌĂƟŽŶ ĂŶĚ ƟƐƐƵĞ ŐƌŽǁƚŚŽĨƚŚĞƵƚĞƌƵƐĂŶĚƉůĂĐĞŶƚĂ͕ŐƌŽǁƚŚŽĨƚŚĞĨŽĞƚƵƐ͕ĂŶĚĞdžƉĂŶƐŝŽŶŽĨƚŚĞŵĂƚĞƌŶĂůďůŽŽĚ ǀŽůƵŵĞ͘ ŽŶƟŶƵĞĚ&ƐƵƉƉůĞŵĞŶƚĂƟŽŶǁŝƚŚϬ͘ϰŵŐͬĚĂLJŝŶƚƌŝŵĞƐƚĞƌƐϮĂŶĚϯŽĨƉƌĞŐŶĂŶĐLJĐĂŶŝŶ-ĐƌĞĂƐĞ ŵĂƚĞƌŶĂů ĂŶĚ ĐŽƌĚ ďůŽŽĚ ĨŽůĂƚĞ ƐƚĂƚƵƐ ĂŶĚ ƉƌĞǀĞŶƚ ƚŚĞ ŝŶŽŶƟŶƵĞĚ&ƐƵƉƉůĞŵĞŶƚĂƟŽŶǁŝƚŚϬ͘ϰŵŐͬĚĂLJŝŶƚƌŝŵĞƐƚĞƌƐϮĂŶĚϯŽĨƉƌĞŐŶĂŶĐLJĐĂŶŝŶ-ĐƌĞĂƐĞ ŝŶ ŚŽŵŽĐLJƐƚĞŝŶĞ ĐŽŶĐĞŶƚƌĂƟŽŶƚŚĂƚŽƚŚĞƌǁŝƐĞŽĐĐƵƌƐŝŶůĂƚĞƉƌĞŐŶĂŶĐLJϭϮϴ_͘ ,ŽǁĞǀĞƌ͕ƚŚĞĞīĞĐƚŽĨĨŽůĂƚĞƐƵƉƉůĞŵĞŶƚĂƟŽŶƚŚƌŽƵŐŚŽƵƚƉƌĞŐŶĂŶĐLJŽŶƐĞǀĞƌĂůŽƚŚĞƌŚĞĂůƚŚ ŽƵƚĐŽŵĞƐŝƐƵŶĐůĞĂƌ͘KďƐĞƌǀĂƟŽŶĂůƐƚƵĚŝĞƐƐƵŐŐĞƐƚĂƉŽƚĞŶƟĂůďĞŶĞĮƚŽĨŐŽŽĚŵĂƚĞƌŶĂůĨŽůĂƚĞ ƐƚĂƚƵƐŽŶďŝƌƚŚǁĞŝŐŚƚ͕ƉůĂĐĞŶƚĂůǁĞŝŐŚƚŽƌůĞŶŐƚŚŽĨŐĞƐƚĂƟŽŶϭϮϵ͕ϭϯϬ ͘/ŶĐŽŶƚƌĂƐƚ͕ƐƵƉƉůĞŵĞŶƚĂ-ƟŽŶƚƌŝĂůƐŚĂǀĞƐŚŽǁŶĞƋƵŝǀŽĐĂůƌĞƐƵůƚƐ͘

The meta-analysis of Fekete et al.ϭϯϭ

Wƌ Ğǀ ĞŶ ƟŽŶŽĨĂŶĚŽƚŚĞƌĂĚǀ Ğƌ ƐĞƉƌ ĞŐŶĂŶĐLJŽƵƚ ĐŽ ŵĞƐǁŝƚŚϰ͘Ϭŵ ŐŽĨ& ͗ϮZ d Ɛ ϲϳ 4 ƚŚĞŝŵƉĂĐƚŽĨ&ƐƵƉƉůĞŵĞŶƚĂƟŽŶŽŶŵŝƐĐĂƌƌŝĂŐĞŽƌƉƌĞͲĞĐůĂŵƉƐŝĂ͘ WƌĞͲĞĐůĂŵƉƐŝĂŝƐĂůĞĂĚŝŶŐĐĂƵƐĞŽĨŝŶĚŝĐĂƚĞĚƉƌĞƚĞƌŵĚĞůŝǀĞƌLJĂŶĚĂĐĐŽƵŶƚƐĨŽƌϮϱйŽĨǀĞƌLJ ůŽǁďŝƌƚŚǁĞŝŐŚƚŝŶĨĂŶƚƐ͘&ƵƌƚŚĞƌŵŽƌĞ͕ƉƌĞͲĞĐůĂŵƉƐŝĂŵĂLJĂůƐŽŝŶĐƌĞĂƐĞƚŚĞƌŝƐŬŽĨĐĂƌĚŝŽǀĂƐ-ĐƵůĂƌĚŝƐĞĂƐĞŝŶƚŚĞŽīƐƉƌŝŶŐƚŚƌŽƵŐŚ͞ĨŽĞƚĂůŽƌŝŐŝŶŽĨĂĚƵůƚĚŝƐĞĂƐĞƐ͟ϭϯϯ _{and women with a}

ŚŝƐƚŽƌLJŽĨƉƌĞͲĞĐůĂŵƉƐŝĂĐŽŶƟŶƵĞƚŽďĞĂƚŝŶĐƌĞĂƐĞĚƌŝƐŬĨŽƌĨƵƚƵƌĞĐĂƌĚŝŽǀĂƐĐƵůĂƌĞǀĞŶƚƐϭϰ͕ϭϱ_͘

ƐƚŚĞƌĞǀŝĞǁŽĨtĞŶ et al.ϭϯϰ_{ƐƵŐŐĞƐƚƐ͕ǁŚŝůĞĞĂƌůŝĞƌƐƚƵĚŝĞƐƐŚŽǁĞĚƉƌŽƚĞĐƟǀĞĞīĞĐƚŽĨ&ŽŶ}

reduced risk of pre-eclampsiaϴϭͲϴϰ_{͕ƐŽŵĞƌĞĐĞŶƚƐƚƵĚŝĞƐĨĂŝůĞĚƚŽĮŶĚƐƵĐŚĂŶĞīĞĐƚ}ϴϳ͕ϴϴ

Wƌ Ğǀ ĞŶ ƟŽŶŽĨĂŶĚŽƚŚĞƌĂĚǀ Ğƌ ƐĞƉƌ ĞŐŶĂŶĐLJŽƵƚ ĐŽ ŵĞƐǁŝƚŚϰ͘Ϭŵ ŐŽĨ& ͗ϮZ d Ɛ ϴϯ 4 ϭ͘ hZKd ƉƌĞǀĂůĞŶĐĞ ƚĂďůĞƐ͘ ŚƩƉ͗ͬͬǁǁǁ͘ĞƵ-ƌŽĐĂƚͲŶĞƚǁŽƌŬ͘ĞƵͬ^^WZs>Edͬ WƌĞǀĂůĞŶĐĞdĂďůĞƐ͘ Ϯ͘ zŝz͕>ŝŶĚĞŵĂŶŶD͕ŽůůŝŐƐ͕^ŶŽǁďĂůů͗ĐŽ-nomic burden of neural tube defects and im-ƉĂĐƚŽĨƉƌĞǀĞŶƟŽŶǁŝƚŚĨŽůŝĐĂĐŝĚ͗ĂůŝƚĞƌĂƚƵƌĞ ƌĞǀŝĞǁ͘Ƶƌ:WĞĚŝĂƚƌϮϬϭϭ͕ϭϳϬ͗ϭϯϵϭʹϭϰϬϬ͘ ϯ͘ ^ƵƩŽŶ D͕ ĂůLJ >͕ <ŝƌŬĞ WE͗ ^ƵƌǀŝǀĂů ĂŶĚ

ĚŝƐ-ability in a cohort of neural tube defect births ŝŶƵďůŝŶ͕/ƌĞůĂŶĚ͘ŝƌƚŚĞĨĞĐƚƐZĞƐĞĂƌĐŚ;WĂƌƚ ͿϮϬϬϴ͕ϴϮ͗ϳϬϭʹϳϬϵ͘ ϰ͘ ůĞŶĐŽǁĞ,͕ŽƵƐĞŶƐ^͕KĞƐƚĞƌŐĂĂƌĚD͕ŚŽƵ ͕ DŽůůĞƌ ͕ EĂƌǁĂů Z͕ ĚůĞƌ ͕ 'ĂƌĐŝĂ s͕ ZŽŚĚĞ^͕^ĂLJ>͕>ĂǁŶ:͗EĂƟŽŶĂů͕ƌĞŐŝŽŶĂů͕ĂŶĚ ǁŽƌůĚǁŝĚĞĞƐƟŵĂƚĞƐŽĨƉƌĞƚĞƌŵďŝƌƚŚƌĂƚĞƐŝŶ ƚŚĞLJĞĂƌϮϬϭϬǁŝƚŚƟŵĞƚƌĞŶĚƐƐŝŶĐĞϭϵϵϬĨŽƌ ƐĞůĞĐƚĞĚ ĐŽƵŶƚƌŝĞƐ͗ Ă ƐLJƐƚĞŵĂƟĐ ĂŶĂůLJƐŝƐ ĂŶĚ ŝŵƉůŝĐĂƟŽŶƐ͘>ĂŶĐĞƚϮϬϭϮ͕ϯϳϵ͗ϮϭϲϮʹϮϭϳϮ͘ ϱ͘ ^ĂŝŐĂů ^͕ ŽLJůĞ >t͗ WƌĞƚĞƌŵ ŝƌƚŚ ϯ͘ Ŷ ŽǀĞƌ-ǀŝĞǁ ŽĨ ŵŽƌƚĂůŝƚLJ ĂŶĚ ƐĞƋƵĞůĂĞ ŽĨ ƉƌĞƚĞƌŵ ďŝƌƚŚĨƌŽŵŝŶĨĂŶĐLJƚŽĂĚƵůƚŚŽŽĚ͘>ĂŶĐĞƚϮϬϬϴ͕ ϯϳϭ͗ϮϲϭʹϮϲϵ͘ ϲ͘ 'ůƵĐŬŵĂŶ W͕ ,ĂŶƐŽŶ D͕ ŽŽƉĞƌ ͕ dŚŽƌŶ- ďƵƌŐ<>͗īĞĐƚŽĨŝŶƵƚĞƌŽĂŶĚĞĂƌůLJͲůŝĨĞĐŽŶĚŝ-ƟŽŶƐŽŶĂĚƵůƚŚĞĂůƚŚĂŶĚĚŝƐĞĂƐĞ͘EŶŐů:DĞĚ ϮϬϬϴ͕ϯϱϵ͗ϲϭʹϳϯ͘ ϳ͘ ŚĂŶŐ ,,͕ >ĂƌƐŽŶ :͕ ůĞŶĐŽǁĞ ,͕ ^ƉŽŶŐ z͕ ,ŽǁƐŽŶ W͕ ĂŝŵƐͲ^ŵŝƚŚ ^͕ >ĂĐŬƌŝƚnj D͕ >ĞĞ ^<͕ DĂƐŽŶ ͕ ^ĞƌĂnjŝŶ ͕ tĂůĂŶŝ ^͕ ^ŝŵƉƐŽŶ :>͕ >ĂǁŶ :͕ ŽŶ ďĞŚĂůĨ ŽĨ ƚŚĞ ŽƌŶ dŽŽ ^ŽŽŶ ƉƌĞƚĞƌŵƉƌĞǀĞŶƟŽŶĂŶĂůLJƐŝƐŐƌŽƵƉ͗WƌĞǀĞŶƟŶŐ ƉƌĞƚĞƌŵďŝƌƚŚƐ͗ĂŶĂůLJƐŝƐŽĨƚƌĞŶĚƐĂŶĚƉŽƚĞŶƟĂů ƌĞĚƵĐƟŽŶƐ ǁŝƚŚ ŝŶƚĞƌǀĞŶƟŽŶƐ ŝŶ ϯϵ ĐŽƵŶƚƌŝĞƐ ǁŝƚŚǀĞƌLJŚŝŐŚŚƵŵĂŶĚĞǀĞůŽƉŵĞŶƚŝŶĚĞdž͘>ĂŶ-ĐĞƚϮϬϭϯ͕ϯϴϭ͗ϮϮϯʹϮϯϰ͘ ϴ͘ DĂŶŐŚĂŵ >:͕ WĞƚƌŽƵ ^͕ ŽLJůĞ >t͕ ƌĂƉĞƌ ^͕ DĂƌůŽǁE͗dŚĞĐŽƐƚŽĨƉƌĞƚĞƌŵďŝƌƚŚƚŚƌŽƵŐŚ-ŽƵƚĐŚŝůĚŚŽŽĚŝŶŶŐůĂŶĚĂŶĚtĂůĞƐ͘WĞĚŝĂƚƌŝĐƐ ϮϬϬϵ͕ϭϮϯ͗ϯϭϮʹϯϮϳ͘ ϵ͘ DĐ/ŶƟƌĞ͕ůŽŽŵ^>͕ĂƐĞLJD͕>ĞǀĞŶŽ<:͗ ŝƌƚŚǁĞŝŐŚƚŝŶƌĞůĂƟŽŶƚŽŵŽƌďŝĚŝƚLJĂŶĚŵŽƌ-ƚĂůŝƚLJ ĂŵŽŶŐ ŶĞǁďŽƌŶ ŝŶĨĂŶƚƐ͘ E ŶŐů : DĞĚ ϭϵϵϵ͕ϯϰϬ͗ϭϮϯϰʹϭϮϯϴ͘ ϭϬ͘ ZŝĐŚĂƌĚƐD͕,ĂƌĚLJZ͕<ƵŚ͕tĂĚƐǁŽƌƚŚD:͗ ŝƌƚŚǁĞŝŐŚƚĂŶĚĐŽŐŶŝƟǀĞĨƵŶĐƟŽŶŝŶƚŚĞƌŝƚ-ŝƐŚϭϵϰϲďŝƌƚŚĐŽŚŽƌƚ͗ůŽŶŐŝƚƵĚŝŶĂůƉŽƉƵůĂƟŽŶ ďĂƐĞĚƐƚƵĚLJ͘D:ϮϬϬϭ͕ϯϮϮ͗ϭϵϵʹϮϬϯ͘ ϭϭ͘ ^ƚƌĞŝŵŝƐŚ/'͕ŚƌĞŶŬƌĂŶnjZ͕ůůƌĞĚE͕K͛^ŚĞĂ dD͕ <ƵďĂŶ <͕ WĂŶĞƚŚ E͕ >ĞǀŝƚŽŶ ͕ ƚŚĞ >-'E^ƚƵĚLJ/ŶǀĞƐƟŐĂƚŽƌƐ͗ŝƌƚŚǁĞŝŐŚƚĂŶĚĨĞƚĂů ǁĞŝŐŚƚͲŐƌŽǁƚŚƌĞƐƚƌŝĐƟŽŶ͗/ŵƉĂĐƚŽŶŶĞƵƌŽĚĞ-ǀĞůŽƉŵĞŶƚ͘ĂƌůLJ,ƵŵĞǀϮϬϭϮ͕ϴϴ͗ϳϲϱʹϳϳϭ͘ ϭϮ͘ ^ŝďĂŝ͕ĞŬŬĞƌ'͕<ƵƉĨĞƌŵŝŶĐD͗WƌĞͲĞĐůĂŵƉ-ƐŝĂ͘>ĂŶĐĞƚϮϬϬϱ͕ϯϲϱ͗ϳϴϱʹϳϵϵ͘ ϭϯ͘ ^ƚĞĞŐĞƌƐ͕ǀŽŶĂĚĞůƐnjĞŶW͕ƵǀĞŬŽƚ:͕WŝũŶĞŶ-ďŽƌŐZ͗WƌĞͲĞĐůĂŵƉƐŝĂ͘>ĂŶĐĞƚϮϬϭϬ͕ϯϳϲ͗ϲϯϭʹ ϲϰϰ͘ ϭϰ͘ /ƌŐĞŶƐ,h͕ZĞŝƐĂĞƚĞƌ>͕/ƌŐĞŶƐ>D͕>ŝĞZd͗>ŽŶŐ ƚĞƌŵ ŵŽƌƚĂůŝƚLJ ŽĨ ŵŽƚŚĞƌƐ ĂŶĚ ĨĂƚŚĞƌƐ ĂŌĞƌ ƉƌĞͲĞĐůĂŵƉƐŝĂ͗ƉŽƉƵůĂƟŽŶďĂƐĞĚĐŽŚŽƌƚƐƚƵĚLJ͘ D:ϮϬϬϭ͕ϯϮϯ͗ϭϮϭϯʹϭϮϭϲ͘ ϭϱ͘ tŝůƐŽŶ:͕tĂƚƐŽŶD^͕WƌĞƐĐŽƩ':͕^ƵŶĚĞƌůĂŶĚ ^͕ ĂŵƉďĞůů D͕ ,ĂŶŶĂĨŽƌĚ W͕ ^ŵŝƚŚ t͗ ,LJ-ƉĞƌƚĞŶƐŝǀĞ ĚŝƐĞĂƐĞƐ ŽĨ ƉƌĞŐŶĂŶĐLJ ĂŶĚ ƌŝƐŬ ŽĨ ŚLJƉĞƌƚĞŶƐŝŽŶ ĂŶĚ ƐƚƌŽŬĞ ŝŶ ůĂƚĞƌ ůŝĨĞ͗ ƌĞƐƵůƚƐ ĨƌŽŵĐŽŚŽƌƚƐƚƵĚLJ͘D:ϮϬϬϯ͕ϯϮϲ͗ϴϰϱʹϴϰϵ͘ ϭϲ͘ ,ĂƵŬŬĂŵĂĂ>͕^ĂůŵŝŶĞŶD͕>ĂŝǀƵŽƌŝ,͕>ĞŝŶŽŶ-ĞŶ,͕,ŝŝůĞƐŵĂĂs͕<ĂĂũĂZ͗ZŝƐŬĨŽƌƐƵďƐĞƋƵĞŶƚ ĐŽƌŽŶĂƌLJĂƌƚĞƌLJĚŝƐĞĂƐĞĂŌĞƌƉƌĞĞĐůĂŵƉƐŝĂ͘ŵ :ĂƌĚŝŽůϮϬϬϰ͕ϵϯ͗ϴϬϱʹϴϬϴ͘ ϭϳ͘ ĞůůĂŵLJ>͕ĂƐĂƐ:W͕,ŝŶŐŽƌĂŶŝ͕tŝůůŝĂŵƐ:͗ WƌĞͲĞĐůĂŵƉƐŝĂ ĂŶĚ ƌŝƐŬ ŽĨ ĐĂƌĚŝŽǀĂƐĐƵůĂƌ ĚŝƐ-ĞĂƐĞĂŶĚĐĂŶĐĞƌŝŶůĂƚĞƌůŝĨĞ͗ƐLJƐƚĞŵĂƟĐƌĞǀŝĞǁ ĂŶĚŵĞƚĂͲĂŶĂůLJƐŝƐ͘D:ϮϬϬϳ͕ϯϯϱ͗ϵϳϰʹϵϳϳ͘ ϭϴ͘ DĂƌĐŚŽĨŝŵĞƐ͕dŚĞWĂƌƚŶĞƌƐŚŝƉŽĨDĂƚĞƌŶĂů͕ EĞǁďŽƌŶĂŶĚŚŝůĚ,ĞĂůƚŚ͕^ĂǀĞƚŚĞŚŝůĚƌĞŶ͕ tŽƌůĚ,ĞĂůƚŚKƌŐĂŶŝnjĂƟŽŶ͗ŽƌŶƚŽŽƐŽŽŶ͗ƚŚĞ ŐůŽďĂůĂĐƟŽŶƌĞƉŽƌƚŽŶƉƌĞƚĞƌŵďŝƌƚŚ͘'ĞŶĞǀĂ͗ tŽƌůĚ,ĞĂůƚŚKƌŐĂŶŝnjĂƟŽŶ͖ϮϬϭϮ͘ ϭϵ͘ ŚƵƩĂ ͕ ĂƐ :<͕ Zŝnjǀŝ ͕ 'ĂīĞLJ D&͕ tĂůŬĞƌ E͕,ŽƌƚŽŶ^͕tĞďďW͕>ĂƌƚĞLJ͕ůĂĐŬZ͗>ĂŶ-ĐĞƚ/ŶƚĞƌǀĞŶƟŽŶƐZĞǀŝĞǁ'ƌŽƵƉ͕DĂƚĞƌŶĂůĂŶĚ ŚŝůĚ EƵƚƌŝƟŽŶ ^ƚƵĚLJ 'ƌŽƵƉ͗ ǀŝĚĞŶĐĞ ďĂƐĞĚ ŝŶƚĞƌǀĞŶƟŽŶƐ ĨŽƌ ŝŵƉƌŽǀĞŵĞŶƚ ŽĨ ŵĂƚĞƌŶĂů ĂŶĚ ĐŚŝůĚ ŶƵƚƌŝƟŽŶ͗ ǁŚĂƚ ĐĂŶ ďĞ ĚŽŶĞ ĂŶĚ Ăƚ ǁŚĂƚĐŽƐƚ͍>ĂŶĐĞƚϮϬϭϯ͕ϯϴϮ͗ϰϱϮʹϰϳϳ͘ ϮϬ͘ dĂŵƵƌĂ d͕ WŝĐĐŝĂŶŽ D&͗ &ŽůĂƚĞ ĂŶĚ ŚƵŵĂŶ ƌĞ-ƉƌŽĚƵĐƟŽŶ͘ŵ:ůŝŶEƵƚƌϮϬϬϲ͕ϴϯ͗ϵϵϯʹϭϬϭϲ͘ Ϯϭ͘ ĂŝůĞLJ >͕ 'ƌĞŐŽƌLJ :& ϯƌĚ͗ &ŽůĂƚĞ ŵĞƚĂďŽůŝƐŵ ĂŶĚƌĞƋƵŝƌĞŵĞŶƚƐ͘:EƵƚƌϭϵϵϵ͕ϭϮϵ͗ϳϳϵʹϳϴϮ͘ ϮϮ͘ ŚĂŶĂƌŝŶ /͗ dŚĞ ĨŽůĂƚĞƐ͘ /Ŷ sŝƚĂŵŝŶƐ ŝŶ ŵĞĚŝ-ĐŝŶĞ͘ sŽůƵŵĞ ϭ͘ ϰƚŚ ĞĚŝƟŽŶ͘ ĚŝƚĞĚ ďLJ ĂƌŬĞƌ D͕ ĞŶĚĞƌ ͘ >ŽŶĚŽŶ͗ tŝůůŝĂŵ ,ĞŝŶĞŵĂŶŶ DĞĚŝĐĂůŽŽŬƐ͖ϭϵϴϬ͗Ϯϰϳʹϯϭϰ͘ Ϯϯ͘ ^ƚĞŝŶďĞƌŐ^͗DĞĐŚĂŶŝƐŵƐŽĨĨŽůĂƚĞŚŽŵĞŽƐƚĂ-ƐŝƐ͘ŵ:WŚLJƐŝŽůϭϵϴϰ͕Ϯϰϲ͗ϯϭϵʹϯϮϰ͘ Ϯϰ͘ ^ĐŚŽůů dK͕ :ŽŚŶƐŽŶ t'͗ &ŽůŝĐ ĂĐŝĚ͗ ŝŶŇƵĞŶĐĞ ŽŶƚŚĞŽƵƚĐŽŵĞŽĨƉƌĞŐŶĂŶĐLJ͘ŵ:ůŝŶEƵƚƌ ϮϬϬϬ͕ϳϭ͗ϭϮϵϱ^ʹϭϯϬϯ^͘ Ϯϱ͘ ZĂLJ :'͕ >ĂƐŬŝŶ ͗ &ŽůŝĐ ĂĐŝĚ ĂŶĚ ŚŽŵŽĐLJƐƚĞ-ine metabolic defects and the risk of placental ĂďƌƵƉƟŽŶ͕ ƉƌĞͲĞĐůĂŵƉƐŝĂ ĂŶĚ ƐƉŽŶƚĂŶĞŽƵƐ ƉƌĞŐŶĂŶĐLJ ůŽƐƐ͗ Ă ƐLJƐƚĞŵĂƟĐ ƌĞǀŝĞǁ͘ WůĂĐĞŶƚĂ ϭϵϵϵ͕ϮϬ͗ϱϭϵʹϱϮϵ͘

WĂƌƚ/& ŽůŝĐĂĐŝĚƐƵƉƉůĞŵĞŶ ƚĂ ƟŽŶĂŶĚĐ ŽŶŐ ĞŶŝƚ ĂůĂŶŽŵĂůŝĞƐĂŶĚ Ɖƌ ĞŐŶĂŶĐLJŽƵƚ ĐŽ ŵĞƐ ϴϰ 4 Ϯϲ͘ &ŽǁůĞƌ͗dŚĞĨŽůĂƚĞĐLJĐůĞĂŶĚĚŝƐĞĂƐĞŝŶŚƵ-ŵĂŶƐ͘<ŝĚŶĞLJ/Ŷƚ^ƵƉƉůϮϬϬϭ͕ϳϴ͗^ϮϮϭʹ^ϮϮϵ͘ Ϯϳ͘ sŽůůƐĞƚ^͕ZĞĨƐƵŵ,͕/ƌŐĞŶƐ>D͕ŵďůĞŵD͕ dǀĞƌĚĂů ͕ 'ũĞƐƐŝŶŐ ,<͗ WůĂƐŵĂ ƚŽƚĂů ŚŽŵŽ-ĐLJƐƚĞŝŶĞ͕ ƉƌĞŐŶĂŶĐLJ ĐŽŵƉůŝĐĂƟŽŶƐ͕ ĂŶĚ ĂĚ-ǀĞƌƐĞ ƉƌĞŐŶĂŶĐLJ ŽƵƚĐŽŵĞƐ͗ ƚŚĞ ,ŽƌĚĂůĂŶĚ ,ŽŵŽĐLJƐƚĞŝŶĞ ^ƚƵĚLJ͘ ŵ : ůŝŶ EƵƚƌ ϮϬϬϬ͕ ϳϭ͗ϵϲϮʹϵϲϴ͘ Ϯϴ͘ ĞƌŐĞŶ E͕ :ĂĚĚŽĞ st͕ dŝŵŵĞƌŵĂŶƐ ^͕ ,ŽĨŵĂŶ͕>ŝŶĚĞŵĂŶƐ:͕ZƵƐƐĐŚĞƌ,͕ZĂĂƚ,͕ ^ƚĞĞŐĞƌƐͲdŚĞƵŶŝƐƐĞŶZW͕^ƚĞĞŐĞƌƐ͗,ŽŵŽ-ĐLJƐƚĞŝŶĞ ĂŶĚ ĨŽůĂƚĞ ĐŽŶĐĞŶƚƌĂƟŽŶƐ ŝŶ ĞĂƌůLJ ƉƌĞŐŶĂŶĐLJ ĂŶĚ ƚŚĞ ƌŝƐŬ ŽĨ ĂĚǀĞƌƐĞ ƉƌĞŐŶĂŶ-ĐLJ ŽƵƚĐŽŵĞƐ͗ ƚŚĞ 'ĞŶĞƌĂƟŽŶ Z ^ƚƵĚLJ͘ :K' ϮϬϭϮ͕ϭϭϵ͗ϳϯϵʹϳϱϭ͘ Ϯϵ͘ DZsŝƚĂŵŝŶ^ƚƵĚLJZĞƐĞĂƌĐŚ'ƌŽƵƉ͗WƌĞǀĞŶ-ƟŽŶŽĨŶĞƵƌĂůƚƵďĞĚĞĨĞĐƚƐ͗ƌĞƐƵůƚƐŽĨƚŚĞDZ sŝƚĂŵŝŶ^ƚƵĚLJ͘>ĂŶĐĞƚϭϵϵϭ͕ϯϯϴ͗ϭϯϭʹϭϯϳ͘ ϯϬ͘

ƉƌĞŐ-WĂƌƚ/& ŽůŝĐĂĐŝĚƐƵƉƉůĞŵĞŶ ƚĂ ƟŽŶĂŶĚĐ ŽŶŐ ĞŶŝƚ ĂůĂŶŽŵĂůŝĞƐĂŶĚ Ɖƌ ĞŐŶĂŶĐLJŽƵƚ ĐŽ ŵĞƐ ϴϲ 4 ŶĂŶĐLJ ĂŶĚ ďŝƌƚŚ ŽƵƚĐŽŵĞƐ͗ Ă ĐŽŚŽƌƚ ƐƚƵĚLJ ŝŶƌŝƟƐŚǁŽŵĞŶ͘ƌ:KďƐƚĞƚ'LJŶĞĐŽůϮϬϭϬ͕ ϭϭϳ͗ϴϮϭʹϴϮϵ͘ ϲϵ͘ njĞŝnjĞů ͕ WƵŚŽ͛ ,͕ >ĂŶŐŵĂƌ ͕ ĐƐ E͕ ĂŶŚŝĚLJ &͗ WŽƐƐŝďůĞ ĂƐƐŽĐŝĂƟŽŶ ŽĨ ĨŽůŝĐ ĂĐŝĚ ƐƵƉƉůĞŵĞŶƚĂƟŽŶ ĚƵƌŝŶŐ ƉƌĞŐŶĂŶĐLJ ǁŝƚŚ ƌĞ-ĚƵĐƟŽŶŽĨƉƌĞƚĞƌŵďŝƌƚŚ͗ĂƉŽƉƵůĂƟŽŶͲďĂƐĞĚ ƐƚƵĚLJ͘Ƶƌ:KďƐƚĞƚ'LJŶĞĐŽůZĞƉƌŽĚŝŽůϮϬϭϬ͕ ϭϰϴ͗ϭϯϱʹϭϰϬ͘

ŽŶǁŽŵĂŶĂŶĚĐŚŝůĚŚĞĂůƚŚ͗ĂƐLJƐƚĞŵĂƟĐƌĞ-WĂƌƚ/& ŽůŝĐĂĐŝĚƐƵƉƉůĞŵĞŶ ƚĂ ƟŽŶĂŶĚĐ ŽŶŐ ĞŶŝƚ ĂůĂŶŽŵĂůŝĞƐĂŶĚ Ɖƌ ĞŐŶĂŶĐLJŽƵƚ ĐŽ ŵĞƐ ϴϴ 4 ǀŝĞǁ͘^LJƐƚĞŵĂƟĐZĞǀŝĞǁƐϮϬϭϯ͕Ϯ͗ϲϳʹϵϬ͘ ϭϭϬ͘ƵƐďLJ ͕ ƌŵƐƚƌŽŶŐ ͕ ŽůŬ ,͕ ƌŵƐƚƌŽŶŐ ͕ ĚĚŽƌ D͕ ŶŶĞƌĞŶ '͕ ƌŵƐƚƌŽŶŐ E͕ Ă-ŐƵĞƩĞ͕ĂƌŝƐŝĐ/͕ĞƌŐŚŽůĚ͕ŝĂŶĐĂ^͕ƌĂnj W͕ĂůnjŽůĂƌŝ͕ŚƌŝƐƟĂŶƐĞŶD͕ŽĐĐŚŝ'͕Ăůƚ- ǀĞŝƚ<͕ĞtĂůůĞ,͕ĚǁĂƌĚƐ'͕'ĂƩD͕'Ğ-ŶĞƌ͕'ŝůůĞƌŽƚz͕'ũĞƌŐũĂZ͕'ŽƵũĂƌĚ:͕,ĂĞƵƐůĞƌ D͕>ĂƚŽƐͲŝĞůĞŶƐŬĂ͕DĐŽŶŶĞůůZ͕EĞǀŝůůĞ͕ KůĂƌƐ͕WŽƌƟůůŽ/͕ZŝƚǀĂŶĞŶ͕ZŽďĞƌƚͲ'ŶĂŶƐŝĂ ͕ZƂƐĐŚ͕^ĐĂƌĂŶŽ'͕^ƚĞŝŶďŝĐŬĞƌs͗WƌĞǀĞŶƚ-ŝŶŐ Ed^ ŝŶ ƵƌŽƉĞ͗ Ă ŵŝƐƐĞĚ ŽƉƉŽƌƚƵŶŝƚLJ͘ ZĞƉƌdŽdžŝĐŽůϮϬϬϱ͕ϮϬ͗ϯϵϯʹϰϬϮ͘ ϭϭϭ͘ŽƩŽ >͕ >ŝƐŝ ͕ ZŽďĞƌƚͲ'ŶĂŶƐŝĂ ͕ ƌŝĐŬƐŽŶ :͕sŽůůƐĞƚ^͕DĂƐƚƌŽŝĂĐŽǀŽW͕ŽƫŶŐ͕ŽĐ-ĐŚŝ'͕ĚĞsŝŐĂŶ͕ĚĞtĂůůĞ,͕&ĞŝũŽŽD͕/ƌŐĞŶƐ >D͕DĐŽŶŶĞůů͕DĞƌůŽďW͕ZŝƚǀĂŶĞŶ͕^ĐĂ-ƌĂŶŽ'͕^ŝīĞů͕DĞƚŶĞŬŝ:͕^ƚŽůů͕^ŵŝƚŚĞůůƐZ͕ 'ŽƵũĂƌĚ:͗/ŶƚĞƌŶĂƟŽŶĂůƌĞƚƌŽƐƉĞĐƟǀĞĐŽŚŽƌƚ ƐƚƵĚLJŽĨŶĞƵƌĂůƚƵďĞĚĞĨĞĐƚƐŝŶƌĞůĂƟŽŶƚŽĨŽůŝĐ ĂĐŝĚ ƌĞĐŽŵŵĞŶĚĂƟŽŶƐ͗ ĂƌĞ ƚŚĞ ƌĞĐŽŵŵĞŶ-ĚĂƟŽŶƐǁŽƌŬŝŶŐ͍D:ϮϬϬϱ͕ϯϯϬ͗ϱϳϭʹϱϳϴ͘ ϭϭϮ͘tĂůĚE:͕>ĂǁDZ͕DŽƌƌŝƐ:<͕tĂůĚ^͗YƵĂŶ-ƟĨLJŝŶŐ ƚŚĞ ĞīĞĐƚ ŽĨ ĨŽůŝĐ ĂĐŝĚ͘ >ĂŶĐĞƚ ϮϬϬϭ͕ ϯϱϴ͗ϮϬϲϵʹϮϬϳϯ͘ ϭϭϯ͘dŽůĂƌŽǀĂ D͕ ,ĂƌƌŝƐ :͗ ZĞĚƵĐĞĚ ƌĞĐƵƌƌĞŶĐĞ ŽĨ ŽƌŽĨĂĐŝĂůĐůĞŌƐĂŌĞƌƉĞƌŝĐŽŶĐĞƉƟŽŶĂůƐƵƉƉůĞ- ŵĞŶƚĂƟŽŶǁŝƚŚŚŝŐŚĚŽƐĞĨŽůŝĐĂĐŝĚĂŶĚŵƵůƟ-ǀŝƚĂŵŝŶƐ͘dĞƌĂƚŽůŽŐLJϭϵϵϱ͕ϱϭ͗ϳϭʹϳϴ͘ ϭϭϰ͘njĞŝnjĞů ͕ dŝŵĂƌ >͕ ^ĂƌŬŽnjŝ ͗ ŽƐĞͲĚĞƉĞŶ-ĚĞŶƚĞīĞĐƚŽĨĨŽůŝĐĂĐŝĚŽŶƚŚĞƉƌĞǀĞŶƟŽŶŽĨ ŽƌŽĨĂĐŝĂůĐůĞŌƐ͘WĞĚŝĂƚƌŝĐƐϭϵϵϵ͕ϭϬϰ͗Ğϲϲ͘ ϭϭϱ͘ĂůLJ >͕ <ŝƌŬĞ WE͕ DŽůůŽLJ ͕ tĞŝƌ '͕ ^ĐŽƩ :D͗ &ŽůĂƚĞ ůĞǀĞůƐ ĂŶĚ ŶĞƵƌĂů ƚƵďĞ ĚĞĨĞĐƚƐ͘ /ŵƉůŝĐĂƟŽŶƐ ĨŽƌ WƌĞǀĞŶƟŽŶ :D ϭϵϵϱ͕ Ϯϳϰ͗ϭϲϵϴʹϭϳϬϮ͘ ϭϭϲ͘WŝĞƚƌnjŝŬ <͕ >ĂŵĞƌƐ z͕ ƌĂŵƐǁŝŐ ^͕ WƌŝŶnjͲ>ĂŶ-ŐĞƌŽŚůZ͗ĂůĐƵůĂƟŽŶŽĨƌĞĚďůŽŽĚĐĞůůĨŽůĂƚĞ ƐƚĞĂĚLJƐƚĂƚĞĐŽŶĚŝƟŽŶƐĂŶĚĞůŝŵŝŶĂƟŽŶŬŝŶĞƚ-ŝĐƐ ĂŌĞƌ ĚĂŝůLJ ƐƵƉƉůĞŵĞŶƚĂƟŽŶ ǁŝƚŚ ǀĂƌŝŽƵƐ folate forms and doses in women of child-ďĞĂƌŝŶŐĂŐĞ͘ŵ:ůŝŶEƵƚƌϮϬϬϳ͕ϴϲ͗ϭϰϭϰʹ ϭϰϭϵ͘