Original Article
Mid-Trimester Maternal ADAM12 Levels Differ According to Fetal Gender in Pregnancies Complicated by Preeclampsia
Reproductive Sciences 2015, Vol. 22(2) 235-241 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/1933719114537713 rs.sagepub.com
Jenny E. Myers, PhD1, Gre´goire Thomas, PhD2, Robin Tuytten, PhD2, Yven Van Herrewege, PhD2, Raoul O. Djiokep, MSc2, Claire T. Roberts, PhD3, Louise C. Kenny, PhD4, Nigel A. B. Simpson, MD5, Robyn A. North, PhD6, and Philip N. Baker, DM1,7
Abstract An overrepresentation of adverse pregnancy outcomes has been observed in pregnancies associated with a male fetus. We investigated the association between fetal gender and candidate biomarkers for preeclampsia. Proteins were quantified in samples taken at 20 weeks from women recruited to the SCreening fOr Pregnancy Endpoints (SCOPE) study (preeclampsia n ¼ 150; no preeclampsia n ¼ 450). In contrast to placental growth factor, soluble endoglin, and insulin-like growth factor acid labile subunit, levels of metallopeptidase domain 12 (ADAM12) at 20 weeks were dependent on fetal gender in pregnancies complicated by preeclampsia, for male (n ¼ 73) fetuses the multiples of the median (MoM; interquartile range [IQR] 1.1-1.5) was 1.3, whereas for female fetuses (n ¼ 75) MoM was 1.1 (1.0-1.3); P < .01. Prediction of preeclampsia using ADAM12 levels was improved for pregnancies associated with a male fetus (area under receiver–operator curve [AUC] 0.73 [95% confidence interval [CI] 0.67-0.80]) than that of a female fetus (AUC 0.62 [0.55-0.70]); P ¼ .03. The data presented here fit a contemporary hypothesis that there is a difference between the genders in response to an adverse maternal environment and suggest that an alteration in ADAM12 may reflect an altered placental response in pregnancies subsequently complicated by preeclampsia. Keywords preeclampsia, mass spectrometry, biomarkers, fetal sex, ADAM12
Introduction Many investigators have observed disparities between male and female fetuses in relation to a number of adverse pregnancy outcomes. The ratio of male fetuses to female fetuses has been shown to be increased in fetal loss due to miscarriage1 and stillbirths.2 Disorders of pregnancy associated with poor placentation such as abruption,2 preeclampsia,3 and fetal growth restriction (FGR) associated with placental insufficiency4,5 have also been shown to occur more frequently when the fetus is male. Furthermore, sex-specific alterations in placental genes (eg, JAK1, IL2RB, Clusterin, LTBP, CXCL1 and IL1RL1, and tumor necrosis factor receptor)6 have been observed to be upregulated in female placentas suggesting that aberrations in placental function can occur in a sex-specific manner.7 Placental complications such as preeclampsia and FGR represent highly significant but potentially modifiable health and economic burdens throughout the world. Preeclampsia continues to be a major cause of maternal mortality,8 and there are strong associations between both conditions and stillbirth.9,10 Effects of preeclampsia and FGR are not limited to
very early life; surviving babies are at increased risk of cardiovascular disease, chronic hypertension, type 2 diabetes, and
1 Maternal & Fetal Heath Research Centre, Manchester Academic Health Science Centre, University of Manchester, Central Manchester NHS Trust, Manchester, United Kingdom 2 Pronota, Zwijnaarde, Belgium 3 Discipline of Obstetrics and Gynaecology, University of Adelaide, Adelaide, Australia 4 The Irish Centre for Fetal and Neonatal Translational Research (INFANT), University College Cork, Ireland 5 Department of Obstetrics and Gynaecology, University of Leeds, Leeds, United Kingdom 6 Women’s Health Academic Centre, King’s College London, London, United Kingdom 7 Gravida: National Centre for Growth and Development, Liggins Institute, University of Auckland, New Zealand
Corresponding Author: Jenny E. Myers, Maternal & Fetal Health Research Centre, 5th Floor (Research), St Mary’s Hospital, Oxford Rd, Manchester, M13 9WL, United Kingdom. Email: [email protected]
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Table 1. Demographic Characteristics. Characteristics Maternal age, years Fetal gender male Caucasian ethnicity Smoker at 15 wks Body mass index at 15 wks (kg/m2) Gestation at sampling, wks Systolic blood pressure, mm Hg Diastolic blood pressure, mm Hg Gestation age at delivery, weeks Preterm birth,
Mid-Trimester Maternal ADAM12 Levels Differ According to Fetal Gender in Pregnancies Complicated by Preeclampsia
Reproductive Sciences 2015, Vol. 22(2) 235-241 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/1933719114537713 rs.sagepub.com
Jenny E. Myers, PhD1, Gre´goire Thomas, PhD2, Robin Tuytten, PhD2, Yven Van Herrewege, PhD2, Raoul O. Djiokep, MSc2, Claire T. Roberts, PhD3, Louise C. Kenny, PhD4, Nigel A. B. Simpson, MD5, Robyn A. North, PhD6, and Philip N. Baker, DM1,7
Abstract An overrepresentation of adverse pregnancy outcomes has been observed in pregnancies associated with a male fetus. We investigated the association between fetal gender and candidate biomarkers for preeclampsia. Proteins were quantified in samples taken at 20 weeks from women recruited to the SCreening fOr Pregnancy Endpoints (SCOPE) study (preeclampsia n ¼ 150; no preeclampsia n ¼ 450). In contrast to placental growth factor, soluble endoglin, and insulin-like growth factor acid labile subunit, levels of metallopeptidase domain 12 (ADAM12) at 20 weeks were dependent on fetal gender in pregnancies complicated by preeclampsia, for male (n ¼ 73) fetuses the multiples of the median (MoM; interquartile range [IQR] 1.1-1.5) was 1.3, whereas for female fetuses (n ¼ 75) MoM was 1.1 (1.0-1.3); P < .01. Prediction of preeclampsia using ADAM12 levels was improved for pregnancies associated with a male fetus (area under receiver–operator curve [AUC] 0.73 [95% confidence interval [CI] 0.67-0.80]) than that of a female fetus (AUC 0.62 [0.55-0.70]); P ¼ .03. The data presented here fit a contemporary hypothesis that there is a difference between the genders in response to an adverse maternal environment and suggest that an alteration in ADAM12 may reflect an altered placental response in pregnancies subsequently complicated by preeclampsia. Keywords preeclampsia, mass spectrometry, biomarkers, fetal sex, ADAM12
Introduction Many investigators have observed disparities between male and female fetuses in relation to a number of adverse pregnancy outcomes. The ratio of male fetuses to female fetuses has been shown to be increased in fetal loss due to miscarriage1 and stillbirths.2 Disorders of pregnancy associated with poor placentation such as abruption,2 preeclampsia,3 and fetal growth restriction (FGR) associated with placental insufficiency4,5 have also been shown to occur more frequently when the fetus is male. Furthermore, sex-specific alterations in placental genes (eg, JAK1, IL2RB, Clusterin, LTBP, CXCL1 and IL1RL1, and tumor necrosis factor receptor)6 have been observed to be upregulated in female placentas suggesting that aberrations in placental function can occur in a sex-specific manner.7 Placental complications such as preeclampsia and FGR represent highly significant but potentially modifiable health and economic burdens throughout the world. Preeclampsia continues to be a major cause of maternal mortality,8 and there are strong associations between both conditions and stillbirth.9,10 Effects of preeclampsia and FGR are not limited to
very early life; surviving babies are at increased risk of cardiovascular disease, chronic hypertension, type 2 diabetes, and
1 Maternal & Fetal Heath Research Centre, Manchester Academic Health Science Centre, University of Manchester, Central Manchester NHS Trust, Manchester, United Kingdom 2 Pronota, Zwijnaarde, Belgium 3 Discipline of Obstetrics and Gynaecology, University of Adelaide, Adelaide, Australia 4 The Irish Centre for Fetal and Neonatal Translational Research (INFANT), University College Cork, Ireland 5 Department of Obstetrics and Gynaecology, University of Leeds, Leeds, United Kingdom 6 Women’s Health Academic Centre, King’s College London, London, United Kingdom 7 Gravida: National Centre for Growth and Development, Liggins Institute, University of Auckland, New Zealand
Corresponding Author: Jenny E. Myers, Maternal & Fetal Health Research Centre, 5th Floor (Research), St Mary’s Hospital, Oxford Rd, Manchester, M13 9WL, United Kingdom. Email: [email protected]
Downloaded from rsx.sagepub.com at Apollo Group - UOP on February 15, 2015
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Reproductive Sciences 22(2)
Table 1. Demographic Characteristics. Characteristics Maternal age, years Fetal gender male Caucasian ethnicity Smoker at 15 wks Body mass index at 15 wks (kg/m2) Gestation at sampling, wks Systolic blood pressure, mm Hg Diastolic blood pressure, mm Hg Gestation age at delivery, weeks Preterm birth,
