Screening for Abnormal Placentation and Adverse Pregnancy Outcomes with Maternal Serum Biomarkers in the Second Trimester
Katherine R. Goetzinger M.D., M.S.C.I. Anthony O. Odibo M.D., M.S.C.E. Department of Obstetrics & Gynecology, Washington University in St. Louis
Corresponding Author: Anthony O. Odibo, M.D., M.S.C.E. Department of Obstetrics and Gynecology Washington University in St. Louis 4911 Barnes-Jewish Hospital Plaza Campus Box 8064 St. Louis, MO 63110 Phone: 314-362-8895; Fax: 314-747-1720 Email: [email protected]
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/pd.4370
This article is protected by copyright. All rights reserved.
Abstract Second-trimester biomarkers were initially introduced with the intent of screening for neural tube defects, and then subsequently for Down syndrome. It was soon realized that these markers can be indirect evidence of abnormal placentation and, therefore, can be used for screening for adverse pregnancy outcomes. Several new biomarkers have subsequently been described with conflicting findings regarding their efficiency for screening for adverse pregnancy outcomes. While a biologically feasible mechanism has been proposed for the role of these biomarkers, they still fall short of an ideal screening test to be clinically useful.
This article is protected by copyright. All rights reserved.
Introduction Second trimester maternal serum biomarker screening was first introduced into the field of obstetrics in the 1970s with the discovery of elevated levels of alpha-fetoprotein (AFP) in the maternal serum of pregnancies affected by fetal open neural tube defects (NTD). Approximately one decade later, low maternal serum levels of AFP were identified in pregnancies with fetal trisomy 21. Since that time, AFP has been combined with other maternal serum biomarkers, including human chorionic gonadotropin (hCG), unconjugated estriol, and inhibin A, in order to improve the detection rate of fetal aneuploidy in the second trimester of pregnancy. These biomarkers are secreted by the placenta and enter the maternal bloodstream in small amounts throughout gestation. The detection of abnormal biomarker levels in fetal trisomies suggest that aneuploid fetuses demonstrate a degree of fetal-plaacnetal immaturity which results in both unregulated hypersecretion and under-secretion of both fetal and placental products.1 This suggests that abnormal levels of this biomarkers may be representative of abnormal placentation and, thus, associated with adverse pregnancy outcomes such as pre-eclampsia, fetal growth restriction (FGR), preterm delivery and fetal loss. Abnormal maternal serum markers obtained during the first trimester of pregnancy are also risk factors for subsequent adverse pregnancy outcomes; however, these first-trimester markers will not be addressed in this review. The objective of this review is to critically evaluate the current literature regarding abnormal levels of maternal serum biomarker in the second trimester of pregnancy and their association with and screening efficiency for adverse pregnancy outcomes.
This article is protected by copyright. All rights reserved.
Routine Second Trimester Serum Biomarkers Alpha-Fetoprotein (AFP) AFP was the first maternal serum biomarker identified as a screening tool for fetal structural malformations and chromosomal anomalies. Subsequently, it is the most studied biomarker to be associated with adverse pregnancy outcome. AFP is an oncofetal protein which is synthesized by the yolk sac early in gestation and later by the fetal liver. The placenta transports small amounts of AFP into the maternal circulation during early gestation, where it reaches peak concentrations between between 28-32 weeks.2 Elevated levels of maternal serum AFP >2.5 multiples of the median (MoMs) between 16-18 weeks’ gestation are associated with an ~80% detection rate for open neural tube defects.3 In the absence of a neural tube defect, the differential diagnosis for elevated levels of AFP in maternal serum in the second trimester of pregnancy includes false positive test reading, inaccurate pregnancy dating, multiple gestations, intrauterine fetal demise, maternal-fetal hemorrhage, aneuploidy, congenital infection such as Parvovirus and other fetal structural malformations, most commonly abdominal wall defects. However, approximately 1% of women persistently will have an abnormally elevated serum level of AFP which cannot be accounted for by these diagnoses.4 It has been demonstrated that these women remain at increased risk for adverse pregnancy outcomes, with an incidence as high as 20-38% in some studies.5 In 1988, Barbara Burton demonstrated that patients with an unexplained elevated maternal serum AFP level ≥2.5 MoMs were at significantly increased risk for fetal loss beyond 20 weeks’ gestation, low birth weight, and neonatal death as compared to controls with a normal maternal serum AFP level.6 Milunsky and colleagues further quantified these risks demonstrating that patients with unexplained elevated maternal serum AFP levels ≥2.0 MoMs were at a 2-fold increased risk for pre-eclampsia, a 3-fold increased risk for placental abruption, a 4-fold increased risk for low birth weight, and an 8-fold increased risk for fetal
This article is protected by copyright. All rights reserved.
death.7 In 1991, Waller and colleagues published a case-control study of 612 women whose pregnancies ended in fetal death and compared them to 2501 live births. After controlling for confounders, this study demonstrated a 10.4-fold increased risk for fetal death in women with a serum AFP level greater than 3.0 MoMs and a 2.4-fold increased risk for fetal death in women with a serum AFP level between 2.0 and 2.9 MoMs. Most interestingly, this study also demonstrated that the increased risk for fetal death persisted throughout gestation, months after the second trimester AFP level was obtained.8 Most recently, Smith and colleagues published data suggesting an increased risk for sudden infant death syndrome (odds ratio (OR) 2.8, 95% confidence interval (CI) 1.4-5.4) in children born to women with a maternal serum AFP level in the highest quintile as compared to those in the lowest quintile; however, this finding may be partially mediated by FGR and preterm birth.9 The mechanism for these associations remains unclear. Elevated AFP levels have been found in women who have experienced early vaginal bleeding which may occur in the setting of recent or impending fetal death. However, the fact that the risk for fetal death persists far into the third trimester of pregnancy suggests an alternative mechanism. It has been hypothesized that a disruption in the maternal-fetal interface allows increased transfer of AFP into the maternal circulation.10 Others suggest that elevated AFP levels are a surrogate marker for abnormal implantation and placental malfunction which are the underlying pathologic mechanisms for many adverse obstetric outcomes.11,12 This is further substantiated by research demonstrating a large range of both sonographic and pathologic abnormalities in both the placenta and umbilical cord in patients with an elevated maternal serum AFP level.13 Salafia and colleagues identified distinct placental lesions including chronic villitis, thrombosis and infarction in women with elevated maternal serum AFP levels.14 Furthermore, an increased risk for abnormal placental adherence (i.e. placenta
This article is protected by copyright. All rights reserved.
accreta/increta/percreta) also has been demonstrated in women with an elevated maternal serum AFP level, especially in the presence of a placenta previa.15,16 Risk stratification has been evaluated to identify those women at highest risk for adverse pregnancy outcome among those with an elevated AFP level. Using maternal characteristics and medical co-morbidities, Chandra and colleagues assigned women into high and low-risk groups based on their a priori risk of having an obstetric complication. They found that women with an unexplained elevated maternal serum AFP level were at increased risk for obstetric complications regardless of their pre-pregnancy risk status.12 Biophysical measurements such as uterine artery Doppler also have been combined with serum levels of AFP in order to improve screening efficiency. Multiple small studies have reported an increased risk for adverse pregnancy outcomes in patients with abnormal second trimester uterine artery Doppler studies in the setting of an unexplained elevated maternal serum AFP level.17-21 Bromley and colleagues demonstrated that severe grade II uterine artery notching was associated with a greater than 3 fold increased risk for a composite perinatal morbidity including preterm delivery2.0 MoMs) was not associated with any adverse pregnancy outcome.36 Furthermore, Walton and colleagues showed only a slight association between maternal serum hCG levels >2.0 MoMs and the adverse outcomes of pregnancyinduced hypertension and preterm delivery and no association with premature rupture of membranes nor FGR. However, that study did show that higher levels of hCG were associated with stillbirth with an odds ratio of 1.4 (95% CI 1.1-1.9) for every increase of one multiple of the median.37 . In rare case of elevated levels of both maternal serum AFP and hCG, it is more apparent that the risk for adverse pregnancy outcome is significant12,36,38. Spencer and colleagues observed a 6-fold increased risk for preterm delivery as well as a 7-fold increased risk for stillbirth when both AFP and free hCG were >2.0 MoMs.36 Chandra and colleagues demonstrated a risk increase for FGR from a RR of 1.28 in the setting of an isolated maternal hCG level to a RR of 4.11 in the setting of elevated levels of both AFP and hCG. Similarly, the risk of intrauterine fetal demise was reported to increase to 13.8 when both AFP and hCG levels are elevated.12 Unconjugated Estriol and Inhibin A Unconjugated estriol and Inhibin A are the other two serum analytes which comprise the quadruple second trimester aneuploidy screen. Unconjugated estriol levels are typically 1.6-1.8 MoMs in trisomy 21.39-41 Low unconjugated estriol levels have been associated with a number of adverse pregnancy outcomes.42-46 Yaron and colleagues observed that unconjugated estriol levels
Katherine R. Goetzinger M.D., M.S.C.I. Anthony O. Odibo M.D., M.S.C.E. Department of Obstetrics & Gynecology, Washington University in St. Louis
Corresponding Author: Anthony O. Odibo, M.D., M.S.C.E. Department of Obstetrics and Gynecology Washington University in St. Louis 4911 Barnes-Jewish Hospital Plaza Campus Box 8064 St. Louis, MO 63110 Phone: 314-362-8895; Fax: 314-747-1720 Email: [email protected]
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/pd.4370
This article is protected by copyright. All rights reserved.
Abstract Second-trimester biomarkers were initially introduced with the intent of screening for neural tube defects, and then subsequently for Down syndrome. It was soon realized that these markers can be indirect evidence of abnormal placentation and, therefore, can be used for screening for adverse pregnancy outcomes. Several new biomarkers have subsequently been described with conflicting findings regarding their efficiency for screening for adverse pregnancy outcomes. While a biologically feasible mechanism has been proposed for the role of these biomarkers, they still fall short of an ideal screening test to be clinically useful.
This article is protected by copyright. All rights reserved.
Introduction Second trimester maternal serum biomarker screening was first introduced into the field of obstetrics in the 1970s with the discovery of elevated levels of alpha-fetoprotein (AFP) in the maternal serum of pregnancies affected by fetal open neural tube defects (NTD). Approximately one decade later, low maternal serum levels of AFP were identified in pregnancies with fetal trisomy 21. Since that time, AFP has been combined with other maternal serum biomarkers, including human chorionic gonadotropin (hCG), unconjugated estriol, and inhibin A, in order to improve the detection rate of fetal aneuploidy in the second trimester of pregnancy. These biomarkers are secreted by the placenta and enter the maternal bloodstream in small amounts throughout gestation. The detection of abnormal biomarker levels in fetal trisomies suggest that aneuploid fetuses demonstrate a degree of fetal-plaacnetal immaturity which results in both unregulated hypersecretion and under-secretion of both fetal and placental products.1 This suggests that abnormal levels of this biomarkers may be representative of abnormal placentation and, thus, associated with adverse pregnancy outcomes such as pre-eclampsia, fetal growth restriction (FGR), preterm delivery and fetal loss. Abnormal maternal serum markers obtained during the first trimester of pregnancy are also risk factors for subsequent adverse pregnancy outcomes; however, these first-trimester markers will not be addressed in this review. The objective of this review is to critically evaluate the current literature regarding abnormal levels of maternal serum biomarker in the second trimester of pregnancy and their association with and screening efficiency for adverse pregnancy outcomes.
This article is protected by copyright. All rights reserved.
Routine Second Trimester Serum Biomarkers Alpha-Fetoprotein (AFP) AFP was the first maternal serum biomarker identified as a screening tool for fetal structural malformations and chromosomal anomalies. Subsequently, it is the most studied biomarker to be associated with adverse pregnancy outcome. AFP is an oncofetal protein which is synthesized by the yolk sac early in gestation and later by the fetal liver. The placenta transports small amounts of AFP into the maternal circulation during early gestation, where it reaches peak concentrations between between 28-32 weeks.2 Elevated levels of maternal serum AFP >2.5 multiples of the median (MoMs) between 16-18 weeks’ gestation are associated with an ~80% detection rate for open neural tube defects.3 In the absence of a neural tube defect, the differential diagnosis for elevated levels of AFP in maternal serum in the second trimester of pregnancy includes false positive test reading, inaccurate pregnancy dating, multiple gestations, intrauterine fetal demise, maternal-fetal hemorrhage, aneuploidy, congenital infection such as Parvovirus and other fetal structural malformations, most commonly abdominal wall defects. However, approximately 1% of women persistently will have an abnormally elevated serum level of AFP which cannot be accounted for by these diagnoses.4 It has been demonstrated that these women remain at increased risk for adverse pregnancy outcomes, with an incidence as high as 20-38% in some studies.5 In 1988, Barbara Burton demonstrated that patients with an unexplained elevated maternal serum AFP level ≥2.5 MoMs were at significantly increased risk for fetal loss beyond 20 weeks’ gestation, low birth weight, and neonatal death as compared to controls with a normal maternal serum AFP level.6 Milunsky and colleagues further quantified these risks demonstrating that patients with unexplained elevated maternal serum AFP levels ≥2.0 MoMs were at a 2-fold increased risk for pre-eclampsia, a 3-fold increased risk for placental abruption, a 4-fold increased risk for low birth weight, and an 8-fold increased risk for fetal
This article is protected by copyright. All rights reserved.
death.7 In 1991, Waller and colleagues published a case-control study of 612 women whose pregnancies ended in fetal death and compared them to 2501 live births. After controlling for confounders, this study demonstrated a 10.4-fold increased risk for fetal death in women with a serum AFP level greater than 3.0 MoMs and a 2.4-fold increased risk for fetal death in women with a serum AFP level between 2.0 and 2.9 MoMs. Most interestingly, this study also demonstrated that the increased risk for fetal death persisted throughout gestation, months after the second trimester AFP level was obtained.8 Most recently, Smith and colleagues published data suggesting an increased risk for sudden infant death syndrome (odds ratio (OR) 2.8, 95% confidence interval (CI) 1.4-5.4) in children born to women with a maternal serum AFP level in the highest quintile as compared to those in the lowest quintile; however, this finding may be partially mediated by FGR and preterm birth.9 The mechanism for these associations remains unclear. Elevated AFP levels have been found in women who have experienced early vaginal bleeding which may occur in the setting of recent or impending fetal death. However, the fact that the risk for fetal death persists far into the third trimester of pregnancy suggests an alternative mechanism. It has been hypothesized that a disruption in the maternal-fetal interface allows increased transfer of AFP into the maternal circulation.10 Others suggest that elevated AFP levels are a surrogate marker for abnormal implantation and placental malfunction which are the underlying pathologic mechanisms for many adverse obstetric outcomes.11,12 This is further substantiated by research demonstrating a large range of both sonographic and pathologic abnormalities in both the placenta and umbilical cord in patients with an elevated maternal serum AFP level.13 Salafia and colleagues identified distinct placental lesions including chronic villitis, thrombosis and infarction in women with elevated maternal serum AFP levels.14 Furthermore, an increased risk for abnormal placental adherence (i.e. placenta
This article is protected by copyright. All rights reserved.
accreta/increta/percreta) also has been demonstrated in women with an elevated maternal serum AFP level, especially in the presence of a placenta previa.15,16 Risk stratification has been evaluated to identify those women at highest risk for adverse pregnancy outcome among those with an elevated AFP level. Using maternal characteristics and medical co-morbidities, Chandra and colleagues assigned women into high and low-risk groups based on their a priori risk of having an obstetric complication. They found that women with an unexplained elevated maternal serum AFP level were at increased risk for obstetric complications regardless of their pre-pregnancy risk status.12 Biophysical measurements such as uterine artery Doppler also have been combined with serum levels of AFP in order to improve screening efficiency. Multiple small studies have reported an increased risk for adverse pregnancy outcomes in patients with abnormal second trimester uterine artery Doppler studies in the setting of an unexplained elevated maternal serum AFP level.17-21 Bromley and colleagues demonstrated that severe grade II uterine artery notching was associated with a greater than 3 fold increased risk for a composite perinatal morbidity including preterm delivery2.0 MoMs) was not associated with any adverse pregnancy outcome.36 Furthermore, Walton and colleagues showed only a slight association between maternal serum hCG levels >2.0 MoMs and the adverse outcomes of pregnancyinduced hypertension and preterm delivery and no association with premature rupture of membranes nor FGR. However, that study did show that higher levels of hCG were associated with stillbirth with an odds ratio of 1.4 (95% CI 1.1-1.9) for every increase of one multiple of the median.37 . In rare case of elevated levels of both maternal serum AFP and hCG, it is more apparent that the risk for adverse pregnancy outcome is significant12,36,38. Spencer and colleagues observed a 6-fold increased risk for preterm delivery as well as a 7-fold increased risk for stillbirth when both AFP and free hCG were >2.0 MoMs.36 Chandra and colleagues demonstrated a risk increase for FGR from a RR of 1.28 in the setting of an isolated maternal hCG level to a RR of 4.11 in the setting of elevated levels of both AFP and hCG. Similarly, the risk of intrauterine fetal demise was reported to increase to 13.8 when both AFP and hCG levels are elevated.12 Unconjugated Estriol and Inhibin A Unconjugated estriol and Inhibin A are the other two serum analytes which comprise the quadruple second trimester aneuploidy screen. Unconjugated estriol levels are typically 1.6-1.8 MoMs in trisomy 21.39-41 Low unconjugated estriol levels have been associated with a number of adverse pregnancy outcomes.42-46 Yaron and colleagues observed that unconjugated estriol levels
