Periconceptional maternal biomarkers of one-carbon metabolism and embryonic growth trajectories: the Rotterdam Periconceptional Cohort (Predict Study)

Periconceptional maternal vitamin B12 and total homocysteine concentrations are associated with longitudinal crown-rump length and embryonic volume measurements, resulting in opposite effects on embryonic growth trajectories.

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Volume 107, Issue 3, Pages 691–698


Francesca Parisi, M.D., Melek Rousian, Ph.D., Anton H.J. Koning, Ph.D., Sten P. Willemsen, M.Sc., Irene Cetin, Ph.D., Eric A.P. Steegers, Ph.D., Régine P.M. Steegers-Theunissen, Ph.D.



To study the associations between the periconceptional maternal biomarkers of one-carbon metabolism and embryonic growth.


Prospective, periconceptional hospital-based birth cohort.


Tertiary medical care center.


Between 2010 and 2014, 236 women with early singleton ongoing pregnancies that resulted in 139 strictly dated spontaneous pregnancies and 97 pregnancies conceived after assisted reproductive technology.



Main Outcome Measure(s)

Maternal serum vitamin B12 and plasma total homocysteine (tHcy) assessed at enrollment, and longitudinal first-trimester crown-rump length (CRL), embryonic volume (EV), and absolute growth rates obtained via three-dimensional ultrasound (3D-US) and virtual reality.


In early pregnancy, we performed a median of five 3D-US scans (range: 1–7). Vitamin B12 concentrations were positively associated with CRL and EV measurements in the total population (CRL: β 5ˆ10−4 (1ˆ10−4 to 9ˆ10−4) √mm; EV: β 2ˆ10−4 (0ˆ10−4 to 4ˆ10−4) 3√cm3) and in the strictly dated spontaneous pregnancy subgroup. The tHcy concentration was negatively associated with embryonic growth in all study groups. High tHcy concentrations (+2 standard deviation [SD], 10.3 μmol/L) were associated with a 1.7 mm smaller CRL (−13.4%) at 7 weeks and a 3.6-mm smaller CRL (−7.1%) at 11 weeks compared with −2 SD tHcy (−3.0 μmol/L). A high tHcy concentration was also associated with a 0.10 cm3 smaller EV (−33.3%) at 7 weeks and a 1.65 cm3smaller EV (−16.1%) at 11 weeks. The embryonic growth rate was positively associated with vitamin B12 and negatively associated with tHcy.


Minor variations in periconceptional maternal concentrations of one-carbon metabolism biomarkers are associated with human embryonic growth.

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Fertility and Sterility

Editorial Office, American Society for Reproductive Medicine

Fertility and Sterility® is an international journal for obstetricians, gynecologists, reproductive endocrinologists, urologists, basic scientists and others who treat and investigate problems of infertility and human reproductive disorders.