Fetal sex specific differences in human placentation: a prospective cohort study.
BACKGROUND
Our objective was to assess fetal sex specific differences in first trimester placental biomarkers of both physiological and pathological pregnancies and their interaction with environmental influences. This study is embedded in the Generation R Study, a prospective cohort study.


METHODS
Only live singleton births were included. Linear regression was performed to assess the effect of sex on first trimester placental biomarkers. Interaction analyses were performed to assess interaction of fetal sex with environmental influences. First trimester soluble fms-like tyrosine kinase (s-Flt1), placental growth factor (PLGF), plasminogen activator inhibitor (PAI-2) and homocysteine levels were assessed.


RESULTS
Significant fetal sex specific differences in placental biomarkers were observed. S-Flt1, PAI-2 and PLGF log transformated concentrations were 0.08 ng/mL (95% CI 0.05; 0.11), 0.07 ng/mL (95% CI 0.06; 0.09) and 0.04 pg/mL (95% CI 0.01; 0.06) higher in case of female as compared to male placentas. In pregnancies complicated by pre-eclampsia (PE), preterm birth (PTB) or a newborn being small for gestational age (SGA) no fetal sex specific differences were observed. Interaction analyses suggest that concentrations of s-Flt1, PLGF and PAI-2 decrease in male placentas in the case of hyperhomocysteinemia but remain equal in female placentas.


CONCLUSIONS
Fetal sex affects early placentation processes with discrepancies regarding pregnancies complicated by PE, PTB or a newborn being SGA. This suggests that other mechanisms causing these complications may dominate the fetal sex effect. The differences concerning homocysteine suggest that fetal sex dependent placental gene-environment interactions exist.


CONCLUSIONS
Fetal sex specific differences in placental biomarkers exist.
The Generation R Study Group, Erasmus Medical Centre, Rotterdam, The Netherlands; Department of Obstetrics and Gynecology, Erasmus Medical Centre, Rotterdam, The Netherlands. Electronic address: z.brown@erasmusmc.nl.
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ZA
Brown
The Generation R Study Group, Erasmus Medical Centre, Rotterdam, The Netherlands; Department of Obstetrics and Gynecology, Erasmus Medical Centre, Rotterdam, The Netherlands.
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Schalekamp-Timmermans
Department of Epidemiology, Erasmus Medical Centre, Rotterdam, The Netherlands; Department of Psychiatry, Erasmus Medical Centre, Rotterdam, The Netherlands.
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Tiemeier
Department of Epidemiology, Erasmus Medical Centre, Rotterdam, The Netherlands.
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A
Hofman
The Generation R Study Group, Erasmus Medical Centre, Rotterdam, The Netherlands; Department of Epidemiology, Erasmus Medical Centre, Rotterdam, The Netherlands.
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VW
Jaddoe
Department of Obstetrics and Gynecology, Erasmus Medical Centre, Rotterdam, The Netherlands.
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Steegers
D015415:Biomarkers / Q000032:analysis*; D015331:Cohort Studies; D005260:Female; D006710:Homocysteine / Q000097:blood; D006801:Humans; D016014:Linear Models; D008297:Male; D010920:Placenta / Q000502:physiology*; D000072483:Placenta Growth Factor; D010929:Placentation / Q000502:physiology*; D017396:Plasminogen Activator Inhibitor 2 / Q000097:blood; D011247:Pregnancy; D011248:Pregnancy Complications / Q000097:blood; D011257:Pregnancy Proteins / Q000097:blood; D011261:Pregnancy Trimester, First; D011446:Prospective Studies; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000097:blood; D012737:Sex Factors; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000097:blood
D015415:Biomarkers; C000608036:PGF protein, human; D017396:Plasminogen Activator Inhibitor 2; D011257:Pregnancy Proteins; D006710:Homocysteine; D000072483:Placenta Growth Factor; C501162:FLT1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; D040281:Vascular Endothelial Growth Factor Receptor-1
Fetal sex; placental biomarkers