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Studying the effects of periconceptional folic acid supplementation

Blom, F.

2015

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

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Fenneke Blom :ƵĚŝƚŚDĂŶŶŝģŶ ǀĞůŝĞŶ^ƉĞůƚĞŶ

THIRD TRIMESTER FOLIC ACID USE

ASSOCIATED WITH REDUCED RISK FOR PRETERM BIRTH:

A DUTCH COHORT STUDY

dŚŝƌ ĚƚƌŝŵĞƐ ƚĞ ƌĨ ŽůŝĐĂĐŝĚƵƐĞĂƐƐŽĐŝĂ ƚĞĚǁŝƚŚƌ ĞĚƵĐĞĚƌŝƐŬĨ Žƌ Ɖƌ Ğƚ ĞƌŵďŝƌƚŚ͗ĂƵƚ ĐŚĐ ŽŚŽƌƚƐ ƚƵĚLJ ϰϳ 3 ďŽƌŶ ĂďƌŽĂĚͿ͘ ĚƵĐĂƟŽŶ ůĞǀĞů ǁĂƐ ĐĂƚĞŐŽƌŝnjĞĚ ŝŶƚŽ ůŽǁ ;ƵƉ ƚŽ >ŽǁĞƌ 'ĞŶĞƌĂů ^ĞĐŽŶĚĂƌLJ ĚƵĐĂƟŽŶͿ͕ŝŶƚĞƌŵĞĚŝĂƚĞ;ŝŶƚĞƌŵĞĚŝĂƚĞǀŽĐĂƟŽŶĂůĞĚƵĐĂƟŽŶĂŶĚh<'^͛ƐĂƚůĞǀĞůŽƌh<'^ ͬϮͿĂŶĚŚŝŐŚ;ƵŶŝǀĞƌƐŝƚLJŽĨĂƉƉůŝĞĚƐĐŝĞŶĐĞͬƉƌŽĨĞƐƐŝŽŶĂůĞĚƵĐĂƟŽŶŽƌƵŶŝǀĞƌƐŝƚLJŽĨƐĐŝĞŶĐĞͿ͘ WƌĞƉƌĞŐŶĂŶĐLJ D/ ǁĂƐ ĐĂůĐƵůĂƚĞĚ ĨƌŽŵ ƐĞůĨͲƌĞƉŽƌƚĞĚ ŚĞŝŐŚƚ ĂŶĚ ǁĞŝŐŚƚ ďĞĨŽƌĞ ƉƌĞŐŶĂŶĐLJ ;ǁĞŝŐŚƚ ;ŬŐͿͬŚĞŝŐŚƚ ;ŵͿϮͿ ĂŶĚ ĐĂƚĞŐŽƌŝnjĞĚ ŝŶƚŽ ƵŶĚĞƌǁĞŝŐŚƚ ;фϭϴͿ͕ ŚĞĂůƚŚLJ ǁĞŝŐŚƚ ;ϭϴͲϮϱͿ͕ ŽǀĞƌǁĞŝŐŚƚ ;ϮϱͲϯϬͿ ĂŶĚ ŽďĞƐĞ ;хϯϬͿ͘ DĂƌŝƚĂů ƐƚĂƚƵƐ ǁĂƐ ĚŝĐŚŽƚŽŵŝnjĞĚ ŝŶƚŽ ƐŝŶŐůĞ Žƌ ĐŽͲ ŚĂďŝƚĂŶƚ͕ĂŶĚǁŽƌŬƐƚĂƚƵƐŝŶƚŽǁŽƌŬŝŶŐ;ƐƚƵĚĞŶƚƐĂůƐŽŝŶĐůƵĚĞĚͿŽƌƵŶĞŵƉůŽLJĞĚ;Ğ͘Ő͘ŚŽƵƐĞ-ǁŝĨĞ͕ǀŽůƵŶƚĂƌLJǁŽƌŬŽƌŽƵƚŽĨǁŽƌŬͿ͘ĂƟŶŐŚĂďŝƚƐǁĞƌĞĐŽŶƐŝĚĞƌĞĚŚĞĂůƚŚLJǁŚĞŶĂůůŽĨƚŚĞ ĨŽůůŽǁŝŶŐŝƚĞŵƐǁĞƌĞƉŽƐŝƟǀĞ͗ĚĂŝůLJŚĂǀŝŶŐĂǁĂƌŵŵĞĂů͖ŚĂǀŝŶŐǀĞŐĞƚĂďůĞƐĚĂŝůLJ͕ŚĂǀŝŶŐĨƌƵŝƚ ĚĂŝůLJ͖ŚĂǀŝŶŐďƌĞĂŬĨĂƐƚŵŽƐƚŽĨƚŚĞĚĂLJƐ͖ŶŽƚŚĂǀŝŶŐƐŶĂĐŬƐĚĂŝůLJ͘ ^ƚĂƟƐƟĐĂůĂŶĂůLJƐĞƐ &ŽƌƚŚĞĂŶĂůLJƐĞƐ͕ǁŽŵĞŶŽĨǁŚŽŵŝŶĨŽƌŵĂƟŽŶǁĂƐůĂĐŬŝŶŐŽŶ&ƐƵƉƉůĞŵĞŶƚĂƟŽŶ;ŶсϮϲϲͿ͕ ƉƌĞŐŶĂŶĐLJŽƵƚĐŽŵĞƐ;ŶсϭϲϵϴͿŽƌĐŽǀĂƌŝĂƚĞƐ;ŶсϭϬϮϰͿǁĞƌĞĞdžĐůƵĚĞĚ͘dŚĞĮŶĂůƐƚƵĚLJƉŽƉƵůĂ- ƟŽŶĐŽŶƐŝƐƚĞĚŽĨϯϳϳϱƉƌĞŐŶĂŶĐŝĞƐ͕ŽĨǁŚŝĐŚϮϬϱϬŝŶĐůƵĚĞĚŝŶĨŽƌŵĂƟŽŶĂďŽƵƚ&ƐƵƉƉůĞŵĞŶ-ƚĂƟŽŶŝŶƚŚĞƐĞĐŽŶĚƋƵĞƐƟŽŶŶĂŝƌĞ;ϯϰͲϰϯǁĞĞŬƐƉƌĞŐŶĂŶƚͿ;&ŝŐƵƌĞϯ͘ϭͿ͘ &ŝŐƵƌĞϯ͘ϭ &ůŽǁĐŚĂƌƚŽĨƚŚŝƐƐƚƵĚLJ FA Folic Acid

included in this study     ĞdžĐůƵĚĞĚĨƌŽŵƚŚŝƐƐƚƵĚLJ

7685 pregnant women in the DELIVER cohort

920 did not fill in 1st _{or 2}nd

questionnaire 6765 filled in at least 1st _{or 2}nd questionnaire Not included No data on - FA supplementation: n=266 - Pregnancy outcomes: n=1698 - Covariates: n=1024 Not included

3775 included in this study

2050 reported on FA use in 2nd _{questionnaire}

(34-43 weeks pregnant)

Included in analyses of FA use ‘at any time’ during or prior to pregnancy

WĂƌƚ/& ŽůŝĐĂĐŝĚƐƵƉƉůĞŵĞŶ ƚĂ ƟŽŶĂŶĚĐ ŽŶŐ ĞŶŝƚ ĂůĂŶŽŵĂůŝĞƐĂŶĚ Ɖƌ ĞŐŶĂŶĐLJŽƵƚ ĐŽ ŵĞƐ ϱϮ 3 ŽĨĐŽŶƟŶƵĞĚ&ƐƵƉƉůĞŵĞŶƚĂƟŽŶŝŶƐĞĐŽŶĚĂŶĚƚŚŝƌĚƚƌŝŵĞƐƚĞƌŽŶƉƌĞŐŶĂŶĐLJŽƵƚĐŽŵĞƐϮϬ_͕ǁĂƐ ĞŶĚĞĚƉƌĞŵĂƚƵƌĞůLJďĞĐĂƵƐĞŽĨůŽƐƐŽĨĨƵŶĚŝŶŐĚƵĞƚŽůŽǁƉĂƌƟĐŝƉĂƟŽŶƌĂƚĞƐ͘^ŝŶĐĞŝƚŝƐŶŽƚ ůŝŬĞůLJƚŚĂƚZdƐǁŝůůƉƌŽǀŝĚĞĚĞĮŶŝƚĞĂŶƐǁĞƌƐŝŶĂƌĞĂƐŽŶĂďůĞƉĞƌŝŽĚŽĨƟŵĞ͕ƌĞƐƵůƚƐĨƌŽŵůĞƐƐ ŽƉƟŵĂůƐƚƵĚLJĚĞƐŝŐŶƐƐŚŽƵůĚʹĂůƚŚŽƵŐŚŝŶƚĞƌƉƌĞƚĞĚǁŝƚŚĐĂƵƟŽŶͲďĞĂĐŬŶŽǁůĞĚŐĞĚĨŽƌƚŚĞŝƌ ǀĂůƵĞƚŽƚŚĞĂĐĐƵŵƵůĂƟŶŐĞǀŝĚĞŶĐĞ͘ dŚĞ ůŝƚĞƌĂƚƵƌĞ ŽŶ & ƐƵƉƉůĞŵĞŶƚĂƟŽŶ ĂŶĚ ƉƌĞƚĞƌŵ ďŝƌƚŚ ŝƐ ŝŶĐŽŶĐůƵƐŝǀĞ͘ dŚĞƌĞĨŽƌĞ͕ ŽƚŚĞƌƐ ŚĂǀĞƌĞĐŽŵŵĞŶĚĞĚĨƵƌƚŚĞƌƌĞƐĞĂƌĐŚŝŶƉƌŽƐƉĞĐƟǀĞŽďƐĞƌǀĂƟŽŶĂůƐƚƵĚŝĞƐϴ_{͕ĂŶĚůĂƌŐĞƌĐŽŚŽƌƚƐ} ŽĨǁĞůůͲŶŽƵƌŝƐŚĞĚƉŽƉƵůĂƟŽŶƐϭϭ_{͕ƐƵĐŚĂƐƚŚĞ>/sZĐŽŚŽƌƚ͘tŝƚŚƚŚŝƐƐƚƵĚLJ͕ǁĞĐŽŶƚƌŝďƵƚĞ} ƚŽ ƚŚĞ ŐĞŶĞƌĂůŝnjĂďŝůŝƚLJ ŽĨ ƚŚĞ ƌĞƐƵůƚƐ ŽŶ & ƐƵƉƉůĞŵĞŶƚĂƟŽŶ ĂŶĚ ƉƌĞƚĞƌŵ ďŝƌƚŚ͕ ďLJ ĂĚĚŝŶŐ ĂŶŽƚŚĞƌĐŽŚŽƌƚƚŽƚŚĞĞǀŝĚĞŶĐĞ͘KƵƌƌĞƐƵůƚƐĂƌĞŝŶůŝŶĞǁŝƚŚƚŚĞ,ƵŶŐĂƌŝĂŶƉŽƉƵůĂƟŽŶͲďĂƐĞĚ ƐƚƵĚLJ͕ǁŚŝĐŚĨŽƵŶĚƚŚĂƚ&ƐƵƉƉůĞŵĞŶƚĂƟŽŶŝŶƚŚĞƚŚŝƌĚƚƌŝŵĞƐƚĞƌƌĞĚƵĐĞƐƚŚĞƌŝƐŬŽĨƉƌĞƚĞƌŵ birthϭϮ_{͘dŚŝƐŝƐŝŶĐŽŶƚƌĂĚŝĐƟŽŶǁŝƚŚƚŚĞŝŶĐƌĞĂƐĞĚƌŝƐŬůǁĂŶ et al.;ϮϬϭϬͿĨŽƵŶĚ}ϭϭ_{͘/ŶŽƚŚĞƌ} ƐƚƵĚŝĞƐƉƌĞǀĞŶƟǀĞĞīĞĐƚƐǁĞƌĞĨŽƵŶĚŽĨ&ƵƐĞŝŶƚŚĞƉƌĞͲͬƉĞƌŝĐŽŶĐĞƉƟŽŶĂůƉĞƌŝŽĚϯͲϱ͕ϳ͕ϴ͕ϭϬ_͕

in the second trimesterϵ_{͕ŽƌŶŽƐŝŐŶŝĮĐĂŶƚĂƐƐŽĐŝĂƟŽŶƐǁĞƌĞĨŽƵŶĚ}ϭϯͲϭϲ_{͘^ŝŶĐĞĂůŵŽƐƚĂůůǁŽŵĞŶ}

WĂƌƚ/& ŽůŝĐĂĐŝĚƐƵƉƉůĞŵĞŶ ƚĂ ƟŽŶĂŶĚĐ ŽŶŐ ĞŶŝƚ ĂůĂŶŽŵĂůŝĞƐĂŶĚ Ɖƌ ĞŐŶĂŶĐLJŽƵƚ ĐŽ ŵĞƐ ϱϰ 3 ϭ͘ ŽƌŶĞůD͕ƌŝĐŬƐŽŶ:͘ŽŵƉĂƌŝƐŽŶŽĨŶĂƟŽŶ-ĂůƉŽůŝĐŝĞƐŽŶƉĞƌŝĐŽŶĐĞƉƟŽŶĂůƵƐĞŽĨĨŽůŝĐĂĐŝĚ ƚŽƉƌĞǀĞŶƚƐƉŝŶĂďŝĮĚĂĂŶĚĂŶĞŶĐĞƉŚĂůLJ;^Ϳ͘ dĞƌĂƚŽůŽŐLJϭϵϵϳ͖ϱϱ;ϮͿ͗ϭϯϰͲϭϯϳ͘ Ϯ͘ tĞƌůĞƌ DD͕ ^ŚĂƉŝƌŽ ^͕ DŝƚĐŚĞůů ͘ WĞƌŝ-ĐŽŶĐĞƉƟŽŶĂů &ŽůŝĐ ĐŝĚ džƉŽƐƵƌĞ ĂŶĚ ZŝƐŬ ŽĨ KĐĐƵƌƌĞŶƚ EĞƵƌĂů dƵďĞ ĞĨĞĐƚƐ͘ :D͗ dŚĞ :ŽƵƌŶĂů ŽĨ ƚŚĞ ŵĞƌŝĐĂŶ DĞĚŝĐĂů ƐƐŽĐŝĂƟŽŶ ϭϵϵϯ͖Ϯϲϵ;ϭϬͿ͗ϭϮϱϳͲϭϮϲϭ͘ ϯ͘ ƵŬŽǁƐŬŝZ͕DĂůŽŶĞ&͕WŽƌƚĞƌ&d͕ELJďĞƌŐ͕ ŽŵƐƚŽĐŬ,͕,ĂŶŬŝŶƐ' et al.WƌĞĐŽŶĐĞƉƟŽŶ- ĂůĨŽůĂƚĞƐƵƉƉůĞŵĞŶƚĂƟŽŶĂŶĚƚŚĞƌŝƐŬŽĨƐƉŽŶ-ƚĂŶĞŽƵƐ ƉƌĞƚĞƌŵ ďŝƌƚŚ͗ Ă ĐŽŚŽƌƚ ƐƚƵĚLJ͘ W>Ž^ DĞĚŝĐŝŶĞϮϬϬϵ͖ϲ;ϱͿ͗ĞϭϬϬϬϬϲϭ͘ ϰ͘ ^ŚĂǁ '͕ ĂƌŵŝĐŚĂĞů ^͕ zĂŶŐ t͕ ^ŝĞŐĂͲZŝnj ͘ WĞƌŝĐŽŶĐĞƉƟŽŶĂů/ŶƚĂŬĞŽĨ&ŽůŝĐĐŝĚĂŶĚ&ŽŽĚ &ŽůĂƚĞĂŶĚZŝƐŬƐŽĨWƌĞƚĞƌŵĞůŝǀĞƌLJ͘ŵĞƌŝĐĂŶ ũŽƵƌŶĂůŽĨƉĞƌŝŶĂƚŽůŽŐLJϮϬϭϭ͖Ϯϴ;ϭϬͿ͗ϳϰϳͲ ϱ͘ ^ĐŚŽůůdK͕,ĞĚŝŐĞƌD>͕^ĐŚĂůů:/͕<ŚŽŽ^͕&ŝƐĐŚ-ĞƌZ>͘ŝĞƚĂƌLJĂŶĚƐĞƌƵŵĨŽůĂƚĞ͗ƚŚĞŝƌŝŶŇƵĞŶĐĞ ŽŶƚŚĞŽƵƚĐŽŵĞŽĨƉƌĞŐŶĂŶĐLJ͘ŵĞƌŝĐĂŶ:ŽƵƌ-ŶĂůŽĨůŝŶŝĐĂůEƵƚƌŝƟŽŶϭϵϵϲ͖ϲϯ͗ϱϮϬͲϱϮϱ͘ ϲ͘ ĞƌŐĞŶ E͕ :ĂĚĚŽĞ sts͕ dŝŵŵĞƌŵĂŶƐ ^͕ ,ŽĨŵĂŶ͕>ŝŶĚĞŵĂŶƐ:͕ZƵƐƐĐŚĞƌ, et al.,Ž-ŵŽĐLJƐƚĞŝŶĞ ĂŶĚ ĨŽůĂƚĞ ĐŽŶĐĞŶƚƌĂƟŽŶƐ ŝŶ ĞĂƌůLJ ƉƌĞŐŶĂŶĐLJ ĂŶĚ ƚŚĞ ƌŝƐŬ ŽĨ ĂĚǀĞƌƐĞ ƉƌĞŐŶĂŶĐLJ ŽƵƚĐŽŵĞƐ͗ ƚŚĞ 'ĞŶĞƌĂƟŽŶ Z ^ƚƵĚLJ͘ :K'͗ Ŷ /ŶƚĞƌŶĂƟŽŶĂů:ŽƵƌŶĂůŽĨKďƐƚĞƚƌŝĐƐΘ'LJŶĂĞĐŽů-ŽŐLJϮϬϭϮ͖ϭϭϵ;ϲͿ͗ϳϯϵͲϳϱϭ͘ ϳ͘ >ŝ͕zĞZ͕ŚĂŶŐ>͕>ŝ,͕>ŝƵ:͕ZĞŶ͘WĞƌŝĐŽŶĐĞƉ-ƟŽŶĂů ĨŽůŝĐ ĂĐŝĚ ƐƵƉƉůĞŵĞŶƚĂƟŽŶ ĂŶĚ ƚŚĞ ƌŝƐŬ ŽĨƉƌĞƚĞƌŵďŝƌƚŚƐŝŶŚŝŶĂ͗ĂůĂƌŐĞƉƌŽƐƉĞĐƟǀĞ ĐŽŚŽƌƚƐƚƵĚLJ͘/ŶƚĞƌŶĂƟŽŶĂů:ŽƵƌŶĂůŽĨ ϴ͘ ĂƚŽǀ :D͕ ŽĚŶĂƌ >D͕ KůƐĞŶ :͕ KůƐĞŶ ^͕ EŽŚƌ ͘ WĞƌŝĐŽŶĐĞƉƟŽŶĂů ŵƵůƟǀŝƚĂŵŝŶ ƵƐĞ ĂŶĚ ƌŝƐŬ ŽĨ ƉƌĞƚĞƌŵ Žƌ ƐŵĂůůͲĨŽƌͲŐĞƐƚĂƟŽŶĂůͲĂŐĞ ďŝƌƚŚƐ ŝŶ ƚŚĞ ĂŶŝƐŚ EĂƟŽŶĂů ŝƌƚŚ ŽŚŽƌƚ͘ dŚĞ ŵĞƌŝĐĂŶ :ŽƵƌŶĂů ŽĨ ůŝŶŝĐĂů EƵƚƌŝƟŽŶ ϮϬϭϭ͖ϵϰ;ϯͿ͗ϵϬϲͲϵϭϮ͘ ϵ͘ ^ŝĞŐĂͲZŝnj D͕ ^Ăǀŝƚnj ͕ ĞŝƐĞů ^,͕ dŚŽƌƉ :D͕ ,ĞƌƌŝŶŐ ͘ ^ĞĐŽŶĚ ƚƌŝŵĞƐƚĞƌ ĨŽůĂƚĞ ƐƚĂƚƵƐ ĂŶĚ ƉƌĞƚĞƌŵ ďŝƌƚŚ͘ŵĞƌŝĐĂŶ :ŽƵƌŶĂůŽĨ KďƐƚĞƚƌŝĐƐ ĂŶĚ'LJŶĞĐŽůŽŐLJϮϬϬϰ͖ϭϵϭ;ϲͿ͗ϭϴϱϭͲϭϴϱϳ͘ ϭϬ͘ ^ŚĂǁ'D͕>ŝďĞƌŵĂŶZ&͕dŽĚŽƌŽī<͕tĂƐƐĞƌŵĂŶ Z͘ >Žǁ ďŝƌƚŚ ǁĞŝŐŚƚ͕ ƉƌĞƚĞƌŵ ĚĞůŝǀĞƌLJ͕ ĂŶĚ ƉĞƌŝĐŽŶĐĞƉƟŽŶĂů ǀŝƚĂŵŝŶ ƵƐĞ͘ dŚĞ :ŽƵƌŶĂů ŽĨ WĞĚŝĂƚƌŝĐƐϭϵϵϳ͖ϭϯϬ;ϲͿ͗ϭϬϭϯͲϭϬϭϰ͘ ϭϭ͘ ůǁĂŶ E͕ 'ƌĞĞŶǁŽŽĚ ͕ ^ŝŵƉƐŽŶ E͕ DĐƌĚůĞ,:͕ĂĚĞ:͘dŚĞƌĞůĂƟŽŶƐŚŝƉďĞƚǁĞĞŶ ĚŝĞƚĂƌLJƐƵƉƉůĞŵĞŶƚƵƐĞŝŶůĂƚĞƉƌĞŐŶĂŶĐLJĂŶĚ ďŝƌƚŚŽƵƚĐŽŵĞƐ͗ĂĐŽŚŽƌƚƐƚƵĚLJŝŶƌŝƟƐŚǁŽŵ-ĞŶ͘ :K'͗ Ŷ /ŶƚĞƌŶĂƟŽŶĂů :ŽƵƌŶĂů ŽĨ KďƐƚĞƚ-ƌŝĐƐΘ'LJŶĂĞĐŽůŽŐLJϮϬϭϬ͖ϭϭϳ;ϳͿ͗ϴϮϭͲϴϮϵ͘ ϭϮ͘ njĞŝnjĞů ͕ WƵŚſ ,͕ >ĂŶŐŵĂƌ ͕ ĐƐ E͕ ĄŶ- ŚŝĚLJ&͘WŽƐƐŝďůĞĂƐƐŽĐŝĂƟŽŶŽĨĨŽůŝĐĂĐŝĚƐƵƉƉůĞ-ŵĞŶƚĂƟŽŶĚƵƌŝŶŐƉƌĞŐŶĂŶĐLJǁŝƚŚƌĞĚƵĐƟŽŶŽĨ ƉƌĞƚĞƌŵďŝƌƚŚ͗ĂƉŽƉƵůĂƟŽŶͲďĂƐĞĚƐƚƵĚLJ͘ƵƌŽ-ƉĞĂŶ :ŽƵƌŶĂů ŽĨ KďƐƚĞƚƌŝĐƐ Θ 'LJŶĞĐŽůŽŐLJ ĂŶĚ ZĞƉƌŽĚƵĐƟǀĞŝŽůŽŐLJϮϬϭϬ͖ϭϰϴ;ϮͿ͗ϭϯϱͲϭϰϬ͘ ϭϯ͘ njĞŝnjĞů ͕ ƵĚĂƐ /͕ DĞƚŶĞŬŝ :͘ WƌĞŐŶĂŶĐLJ

outcomes in a randomised controlled trial of ƉĞƌŝĐŽŶĐĞƉƟŽŶĂů ŵƵůƟǀŝƚĂŵŝŶ ƐƵƉƉůĞŵĞŶ-ƚĂƟŽŶ͘ &ŝŶĂů ƌĞƉŽƌƚ͘ ƌĐŚ 'LJŶĞĐŽů KďƐƚĞƚ ϭϵϵϰ͖Ϯϱϱ͗ϭϯϭͲϭϯϵ͘ ϭϰ͘ ZŽŶŶĞŶďĞƌŐ'͕'ŽůĚŵĂŶD͕ŚĞŶ͕ŝƚŬĞŶ /t͕ tŝůůĞƩ t͕ ^ĞůŚƵď : et al. WƌĞĐŽŶĐĞƉƟŽŶ ŚŽŵŽĐLJƐƚĞŝŶĞ ĂŶĚ  ǀŝƚĂŵŝŶ ƐƚĂƚƵƐ ĂŶĚ ďŝƌƚŚ ŽƵƚĐŽŵĞƐ ŝŶ ŚŝŶĞƐĞ ǁŽŵĞŶ͘ dŚĞ ŵĞƌŝĐĂŶ :ŽƵƌŶĂů ŽĨ ůŝŶŝĐĂů EƵƚƌŝƟŽŶ ϮϬϬϮ͖ϳϲ;ϲͿ͗ϭϯϴϱͲ ϭϯϵϭ͘ ϭϱ͘ ŚĂƌůĞƐ ,͕ EĞƐƐ Z͕ ĂŵƉďĞůů ͕ ^ŵŝƚŚ '͕ tŚŝƚůĞLJ͕,ĂůůD,͘&ŽůŝĐĂĐŝĚƐƵƉƉůĞŵĞŶƚƐŝŶ ƉƌĞŐŶĂŶĐLJĂŶĚďŝƌƚŚŽƵƚĐŽŵĞ͗ƌĞͲĂŶĂůLJƐŝƐŽĨĂ ůĂƌŐĞ ƌĂŶĚŽŵŝƐĞĚ ĐŽŶƚƌŽůůĞĚ ƚƌŝĂů ĂŶĚ ƵƉĚĂƚĞ ŽĨŽĐŚƌĂŶĞƌĞǀŝĞǁ͘WĂĞĚŝĂƚƌWĞƌŝŶĂƚƉŝĚĞŵŝŽů ϮϬϬϱ͖ϭϵ͗ϭϭϮͲϭϮϰ͘ ϭϲ͘ dŝŵŵĞƌŵĂŶƐ ^͕ :ĂĚĚŽĞ st͕ ,ŽĨŵĂŶ ͕ ^ƚĞĞ-ŐĞƌƐͲdŚĞƵŶŝƐƐĞŶ ZW͕ ^ƚĞĞŐĞƌƐ ͘ WĞƌŝĐŽŶĐĞƉ-ƟŽŶ ĨŽůŝĐ ĂĐŝĚ ƐƵƉƉůĞŵĞŶƚĂƟŽŶ͕ ĨĞƚĂů ŐƌŽǁƚŚ ĂŶĚƚŚĞƌŝƐŬƐŽĨůŽǁďŝƌƚŚǁĞŝŐŚƚĂŶĚƉƌĞƚĞƌŵ ďŝƌƚŚ͗ ƚŚĞ 'ĞŶĞƌĂƟŽŶ Z ^ƚƵĚLJ͘ ƌ : EƵƚƌ ϮϬϬϵ͖ϭϬϮ;ϱͿ͗ϳϳϳͲϳϴϱ͘ ϭϳ͘ >ĂƐƐŝ ^͕ ^ĂůĂŵ Z͕ ,ĂŝĚĞƌ ͕ ŚƵƩĂ ͘ &Ž-ůŝĐĂĐŝĚƐƵƉƉůĞŵĞŶƚĂƟŽŶĚƵƌŝŶŐƉƌĞŐŶĂŶĐLJĨŽƌ ŵĂƚĞƌŶĂůŚĞĂůƚŚĂŶĚƉƌĞŐŶĂŶĐLJŽƵƚĐŽŵĞƐ͘Ž-ĐŚƌĂŶĞĂƚĂďĂƐĞ^LJƐƚZĞǀϮϬϭϯ͖ϯ͗ϬϬϲϴϵϲ͘ ϭϴ͘ DĂŶŶŝĞŶ:͕<ůŽŵƉd͕tŝĞŐĞƌƐd͕WĞƌĞŵD͕ ƌƵŐ:͕ĚĞ: et al.ǀĂůƵĂƟŽŶŽĨƉƌŝŵĂƌLJĐĂƌĞ ŵŝĚǁŝĨĞƌLJ ŝŶ dŚĞ EĞƚŚĞƌůĂŶĚƐ͗ ĚĞƐŝŐŶ ĂŶĚ ƌĂ-ƟŽŶĂůĞ ŽĨ Ă ĚLJŶĂŵŝĐ ĐŽŚŽƌƚ ƐƚƵĚLJ ;>/sZͿ͘ D,ĞĂůƚŚ^ĞƌǀZĞƐϮϬϭϮ͖ϭϮ͗ϲϵ͘ ϭϵ͘ ^ŝŬŬĞŶƐ ::͕ ǀĂŶ ŝũƐĚĞŶ D͕ ŽŶƐĞů ':͕ Žƌ-ŶĞů D͘ sĂůŝĚĂƟŽŶ ŽĨ ƐĞůĨͲƌĞƉŽƌƚĞĚ ĨŽůŝĐ ĂĐŝĚ ƵƐĞ ŝŶ Ă ŵƵůƟĞƚŚŶŝĐ ƉŽƉƵůĂƟŽŶ͗ ƌĞƐƵůƚƐ ŽĨ ƚŚĞ ŵƐƚĞƌĚĂŵ ŽƌŶ ŚŝůĚƌĞŶ ĂŶĚ ƚŚĞŝƌ Ğ-ǀĞůŽƉŵĞŶƚ ƐƚƵĚLJ͘ WƵďůŝĐ ,ĞĂůƚŚ EƵƚƌŝƟŽŶ ϮϬϭϭ͖ϭϰ;ϭϭͿ͗ϮϬϮϮͲϮϬϮϴ͘