Maternal Homocysteine before Conception and throughout Pregnancy Predicts Fetal Homocysteine and Birth Weight Michelle M. Murphy, 1* John M. Scott, 2 Victoria Arija, 1 Anne M. Molloy, 3 and Joan D. Fernandez-Ballart 1 Background: Increased homocysteine has been associ- ated with pregnancy complications. Methods: We investigated prospectively the effect of maternal homocysteine on normal pregnancy outcome. The study included 93 women and their offspring; 39 of the women took folic acid during the second and/or third trimesters of pregnancy. We measured homocys- teine at preconception; at weeks 8, 20, and 32 of preg- nancy; during labor; and in the fetal cord; we also recorded birth weight. Results: Geometric mean (SE) maternal total homocys- teine (tHcy) increased between 32 weeks of pregnancy and labor [7.98 (1.05) mol/L in unsupplemented women and 6.26 (1.07) mol/L in supplemented women; P <0.0001 for both]. Fetal tHcy was lower than maternal tHcy [6.39 (1.06) mol/L in unsupplemented pregnan- cies (P <0.0001), and 5.18 (1.06) mol/L in supplemented pregnancies (P <0.05)]. Maternal tHcy was correlated from preconception throughout pregnancy (8 weeks, r  0.708; 20 weeks, r  0.637; 32 weeks, r  0.537; labor, r  0.502; P <0.0001 for all time points) and with fetal tHcy [preconception, r  0.255 (P <0.05); 8 weeks, r  0.321 (P <0.01); 20 weeks, r  0.469; 32 weeks, r  0.550; labor, r  0.624 (P <0.0001)]. Mothers in the highest tHcy tertile at 8 weeks of pregnancy were three times [odds ratio, 3.26 (95% confidence interval, 1.05–10.13); P <0.05] and at labor were four times [3.65 (1.15–11.56); P <0.05] more likely to give birth to a neonate in the lowest birth weight tertile. Neonates of mothers in the highest tHcy tertile at labor weighed, on average, 227.98 g less than those of mothers in the low and medium tertiles (P  0.014). Conclusions: Supplemented mothers had lower tHcy at labor than unsupplemented mothers, as did their neo- nates. Maternal and fetal tHcy was significantly corre- lated throughout the study. Neonates of mothers in the highest tertile of homocysteine weighed less. © 2004 American Association for Clinical Chemistry Several case– control studies have reported an association between increased maternal plasma total homocysteine (tHcy) 4 and pregnancy complications (1–6). Such studies have been repeatedly quoted as demonstrating an associ- ation between increased maternal tHcy and pregnancy complications. However, many of them have concluded this by relating a tHcy measurement in the nonpregnant state with a previous pregnancy complication (1, 2, 4). To the best of our knowledge, no studies have investigated the effect of tHcy measured longitudinally at preconcep- tion and during each trimester of pregnancy on outcome. It is not clear whether increased tHcy is the cause or consequence of these complications. It is possible that underlying mechanisms that occur when tHcy is in- creased preconceptionally are expressed during preg- nancy. This is difficult to investigate because, typically, the first blood sample available for analysis is at the end of the first trimester of pregnancy and because tHcy is not routinely analyzed. tHcy is significantly decreased as a physiologic response to pregnancy and is decreased even further in mothers who use folic acid supplements (7). The aim of this study was to investigate the effect of maternal tHcy, preconceptionally and throughout preg- 1 Unit of Preventive Medicine and Public Health, Rovira i Virgili Univer- sity, Reus, Spain. Departments of 2 Biochemistry and 3 Clinical Medicine, Trinity College, Dublin, Ireland. *Address correspondence to this author at: Unitat Medicina Preventiva, Facultat de Medicina, Universitat Rovira i Virgili, C/Sant Llorenc ¸, 21, 43201 Reus, Spain. Fax 34-977–759-322; e-mail mm@fmcs.urv.es. Received February 16, 2004; accepted May 4, 2004. Previously published online at DOI: 10.1373/clinchem.2004.032904 4 Nonstandard abbreviations: tHcy, total homocysteine; BMI, body mass index, 95% CI, 95% confidence interval; and OR, odds ratio. Clinical Chemistry 50:8 1406 –1412 (2004) Nutrition 1406