DOI: 10.1002/pd.4423
EDITORIAL
Can prenatal screening reduce the adverse obstetric outcomes related to abnormal placentation? Alessandro Ghidini1* and Eduard Gratacos2 1
Perinatal Diagnostic Center, Inova Alexandria Hospital, Alexandria, VA, USA BCNatal, Barcelona Center for Maternal-Fetal and Neonatal Medicine, Hospital Clinic and Hospital Sant Joan de Deu, IDIBAPS, CIBERER and Universitat de Barcelona, Spain *Correspondence to: Alessandro Ghidini. E-mail: [email protected]
2
Funding sources: None Conflicts of interest: None declared
Over the past several decades, the focus of research in prenatal diagnosis and screening has been the fetus and its congenital structural or genetic anomalies. Only more recently has it become apparent that obstetric complications affecting the outcome of otherwise normal fetuses are due to pathologic events in the placenta, which precede and are likely causally linked to the clinical manifestations. The placenta has thus become the focus of an entire new field of prenatal screening and diagnosis. Preterm adverse pregnancy outcomes (APO), including preeclampsia, placental abruption, and fetal growth restriction (FGR), leading in the most severe cases to fetal death, occur in 5% to 10% of pregnancies, but they are among the leading causes of maternal morbidity and mortality, as well as perinatal morbidity and mortality in non-malformed infants.1 As their placental histological features overlap,2 these APOs are grouped under the term ‘placental dysfunction disorders’.3,4 The most frequent pattern of placental lesions visible at histopathology examination (uteroplacental vessel fibrinoid necrosis or atherosis, absence of physiologic conversion, syncytiotrophoblast knotting, cyto-trophoblast X-cell proliferation, and circulating nucleated red blood cell) indicates inadequate uteroplacental blood perfusion.5 Such patterns have been designated in different ways (placental vascular disease or pathology, ischemic placental disease, and uteroplacental insufficiency), but there is agreement among placenta pathology experts that it is secondary to defective placental implantation.2,6 Even thrombotic placental lesions (uteroplacental vessel thrombosis; intervillous thrombus; perivillous fibrin deposition; infarcts), which are often found in cases of preterm FGR or preeclampsia,7–9 are in most cases superimposed on preexisting abnormal placental development or differentiation.9,10
NORMAL AND ABNORMAL PLACENTATION Central to the development and continuation of a normal healthy pregnancy is the optimal development of the placenta. Prenatal Diagnosis 2014, 34, 613–617
Normal placentation involves trophoblast cell invasion of the spiral arteries resulting in reversible changes in the normal arterial wall architecture.11–13 The spiral arteries, which are high-impedance vessels, are transformed into large caliber, low resistance uteroplacental vessels by a process of extravillous trophoblast infiltration.12–14 This trophoblastic invasion of the spiral arteries develops from 8 weeks’ gestation and is completed in the majority of cases by 22 weeks of gestation.12,13,15,16 Failure of conversion of the spiral arteries leads to underperfusion of the placenta;17 the hypoxic placenta can manifest clinically weeks or months later with preterm APOs (Figure 1). The severity of placenta dysfunction is inversely related to the gestational age at onset of the clinical manifestations, so that the most severe cases manifest as early as the second trimester. Identification of abnormal placentation can be carried out with confidence after delivery by histologic placental examination. The cumulative burden of placental lesions determines the probability of the clinical manifestations18 as well as the gestational age at their onset.19,20 Occurrence of a preterm APO with features of abnormal placentation in a previous pregnancy indicates an increased risk of the same recurring in a subsequent pregnancy. Rates of recurrence in subsequent pregnancies have been quoted as 26% for severe preeclampsia, 16% for FGR less than fifth centile, 5% for abruption, 8.5% for fetal death at ≥20 weeks, and 61% to 85% for one or more APOs.21 The recurrence risk increases with the number of complicated pregnancies: in a published trial of low-dose aspirin for prevention of recurrent APO, control patients with prior poor outcome defined as FGR, fetal demise, or placental abruption had a recurrence risk of 26% with one prior complication and 46% with two or more prior APOs, without regard to thrombophilia.22 Recurrences can manifest clinically with different APOs from one pregnancy to the next: a large retrospective cohort study found that women with preeclampsia, FGR, and placental abruption in their first © 2014 John Wiley & Sons, Ltd.
A. Ghidini and E. Gratacos
614
Figure 1 Temporal sequence of events leading to placental dysfunction and related adverse pregnancy outcomes
pregnancy are at substantially increased risk of recurrence for any or all of these conditions in their second pregnancy.23,24 The earlier in pregnancy APOs occur, the higher the risk of recurrence.25 Another large study found that delivery of a small-for-gestational age child in a woman’s first pregnancy is associated with increased risk of fetal death in the subsequent pregnancy, with the risk increasing with decreasing gestational age at the first pregnancy (i.e. with the severity of FGR and of the underlying placental dysfunction), with odds ratios ranging from 2.1 when the first delivery was at term to 5.0 when the first delivery occurred before 32 weeks.26 It should be noted that such odds ratios are higher than the overall risk of recurrence of stillbirth itself. It would be obviously desirable to evaluate placental implantation in ongoing pregnancies, in order to appropriately identify cases departing from the normal placentation, monitor them more closely, and wherever possible, institute preventative strategies aimed at reducing the odds of APO. It has become progressively clear that this can be accomplished with the same tools that have been used successfully for prenatal screening and diagnosis of congenital fetal anomalies. Ongoing placental implantation can be assessed indirectly by interrogating the uteroplacental circulation with Doppler, evaluating placental shape, size, and cord insertion using ultrasonography, and evaluating placental or feto-placental markers released into the maternal circulation.27,28 Indeed, the observation that maternal serum markers may be abnormal in cases destined to poor placentation even before spiral arteries conversion takes place has suggested the hypothesis that disorders of deep placentation may be due to primary insults to the extravillous trophoblast in the first trimester (Figure 1).29 Insults to the villous trophoblast may lead to a failure to elaborate the placental vascular tree, with subsequent FGR.13
EX UNO, PLURES Clinicians are quite familiar with several medical syndromes resulting from an underlying pathologic process that manifests Prenatal Diagnosis 2014, 34, 613–617
clinically with different features. Why and how abnormalities in placental implantation can become manifest with maternal symptoms (as in preterm preeclampsia, abruption, preterm labor, or premature rupture of membranes), fetal symptoms (typically FGR or stillbirth), or a combination of both is presently unknown. It is likely that maternal characteristics (e.g. determined by immunologic, inflammatory, proangiogenic, or thrombophilic milieus, often determined by genetic predispositions) and fetal characteristics interplay with the placental disease, mitigating or worsening it, and ultimately contributing to the cascade of events which determine the gestational age at onset and the various clinical manifestations. This can also explain why similar clinical manifestations (e.g. preeclampsia) can occur (particularly at or near term) in the absence of evidence of placental dysfunction. For example, maternal susceptibility due to microvascular disease (e.g. in diabetes) or systemic inflammation (e.g. in obesity) may lead to term/late-onset preeclampsia in the absence of significant placental pathology.30 Typically, this entity is not associated with FGR. This has led to the hypothesis that preterm and term preeclampsia may be two different nosologic entities with different fetal involvement and different rates of recurrence.20,29–35 Fetal vulnerability or resilience to ongoing placental ischemia and hypoxia may determine the coexistence of FGR with other APOs, its severity and gestational age at onset, and fetal survival. Fetal manifestations may also be greatly affected by whether the initial placental insult in the first trimester (Figure 1) was primarily or exclusively confined to the villous trophoblast, affecting its subsequent development and resulting in restricted transfer of nutrients and oxygen to the fetus.29 Although likely to play a role, the contribution of fetal characteristics (e.g. genetically determined immunologic, inflammatory, pro-angiogenic, or thrombophilic responses) to the ongoing placental villous damage has been poorly explored.36 As for preeclampsia, it appears that early © 2014 John Wiley & Sons, Ltd.
Can prenatal screening reduce the adverse obstetric outcomes related to abnormal placentation?
gestational age at onset identifies a placental dysfunction more likely related to abnormal placentation. Finally, the placenta itself has its own capacity to overcome initial difficulties at implantation, with differential expansion on the decidual surface, witnessed at ultrasonography and at birth by abnormalities in placental shape and size, as well as marginal or velamentous insertion of the umbilical cord. Such changes are already evident at 11 to 14 weeks’ gestation.37 Although such placental survival mechanisms are successful in most cases, leading to a favorable pregnancy outcome, they witness to the problematic initial implantation, and indeed, their presence increases significantly the odds of subsequent APOs.38 Placenta dynamic plasticity is quite relevant in the prenatal diagnosis and screening of APOs due to abnormal placentation: for example, cases flagged as high risk for APO because of uterine artery Doppler findings but who subsequently present normalization of the Doppler uterine waveforms (suggesting a delayed but eventually appropriate placental implantation and perfusion) result in a more favorable pregnancy outcome than those which maintain abnormal Doppler findings.39–41 Conversely, persistence of abnormal uterine artery Doppler findings between the first and second trimester identifies the group with the highest risk for APO.42 It should also be noted that placentas normally implanted (as evidenced by normal maternal serum markers and uterine artery Doppler findings in the first and second trimester) may subsequently develop acquired lesions (e.g. chronic villitis) ultimately resulting in APOs, which cannot be predicted or prevented.43 A placenta pathology study on preterm preeclampsia showed that such lesions can be found in one third of cases.44 Prenatal diagnosis and screening of ongoing placentation may shed light on the complex interplay of trophoblastic and maternal characteristics, and the relative contribution of each to the genesis of abnormal placentation.
PREVENTION Because interventions after the diagnosis of the clinical manifestations of preterm APOs have limited impact on the outcome, it has become clearer that the optimal timing for interventions should be much earlier in pregnancy, namely, at the time of placental implantation. Randomized clinical trials have shown that prophylaxis using low-molecular-weight heparin in women with history of preterm and severe APOs can be effective at reducing recurrences, with little heterogeneity among the studies.45,46 Similarly, low-dose aspirin has been shown to effectively reduce the risk of preterm APOs (more effectively for preeclampsia than FGR) not only in pregnancies flagged by a poor obstetric history but also in those identified prospectively by abnormal uterine artery Doppler findings.47,48 Of interest, a small placenta histology study has shown no effect of low-dose aspirin on histologic evidence of uterine vascular pathology, suggesting that the benefit of the prophylaxis may not be mediated by an effect on placental implantation.49 The efficacy of low-dose aspirin for late-onset APOs is quite inconsistent. The success of the same preventative strategy to reduce the risk of subsequent preeclampsia, preterm birth, or FGR Prenatal Diagnosis 2014, 34, 613–617
615
provides indirect support to the relevance of placental vascular disease in the genesis of preterm and severe APOs. It is intriguing to note that although placental vascular disease accounts for only one third of placenta pathology in preeclampsia cases delivered at
EDITORIAL
Can prenatal screening reduce the adverse obstetric outcomes related to abnormal placentation? Alessandro Ghidini1* and Eduard Gratacos2 1
Perinatal Diagnostic Center, Inova Alexandria Hospital, Alexandria, VA, USA BCNatal, Barcelona Center for Maternal-Fetal and Neonatal Medicine, Hospital Clinic and Hospital Sant Joan de Deu, IDIBAPS, CIBERER and Universitat de Barcelona, Spain *Correspondence to: Alessandro Ghidini. E-mail: [email protected]
2
Funding sources: None Conflicts of interest: None declared
Over the past several decades, the focus of research in prenatal diagnosis and screening has been the fetus and its congenital structural or genetic anomalies. Only more recently has it become apparent that obstetric complications affecting the outcome of otherwise normal fetuses are due to pathologic events in the placenta, which precede and are likely causally linked to the clinical manifestations. The placenta has thus become the focus of an entire new field of prenatal screening and diagnosis. Preterm adverse pregnancy outcomes (APO), including preeclampsia, placental abruption, and fetal growth restriction (FGR), leading in the most severe cases to fetal death, occur in 5% to 10% of pregnancies, but they are among the leading causes of maternal morbidity and mortality, as well as perinatal morbidity and mortality in non-malformed infants.1 As their placental histological features overlap,2 these APOs are grouped under the term ‘placental dysfunction disorders’.3,4 The most frequent pattern of placental lesions visible at histopathology examination (uteroplacental vessel fibrinoid necrosis or atherosis, absence of physiologic conversion, syncytiotrophoblast knotting, cyto-trophoblast X-cell proliferation, and circulating nucleated red blood cell) indicates inadequate uteroplacental blood perfusion.5 Such patterns have been designated in different ways (placental vascular disease or pathology, ischemic placental disease, and uteroplacental insufficiency), but there is agreement among placenta pathology experts that it is secondary to defective placental implantation.2,6 Even thrombotic placental lesions (uteroplacental vessel thrombosis; intervillous thrombus; perivillous fibrin deposition; infarcts), which are often found in cases of preterm FGR or preeclampsia,7–9 are in most cases superimposed on preexisting abnormal placental development or differentiation.9,10
NORMAL AND ABNORMAL PLACENTATION Central to the development and continuation of a normal healthy pregnancy is the optimal development of the placenta. Prenatal Diagnosis 2014, 34, 613–617
Normal placentation involves trophoblast cell invasion of the spiral arteries resulting in reversible changes in the normal arterial wall architecture.11–13 The spiral arteries, which are high-impedance vessels, are transformed into large caliber, low resistance uteroplacental vessels by a process of extravillous trophoblast infiltration.12–14 This trophoblastic invasion of the spiral arteries develops from 8 weeks’ gestation and is completed in the majority of cases by 22 weeks of gestation.12,13,15,16 Failure of conversion of the spiral arteries leads to underperfusion of the placenta;17 the hypoxic placenta can manifest clinically weeks or months later with preterm APOs (Figure 1). The severity of placenta dysfunction is inversely related to the gestational age at onset of the clinical manifestations, so that the most severe cases manifest as early as the second trimester. Identification of abnormal placentation can be carried out with confidence after delivery by histologic placental examination. The cumulative burden of placental lesions determines the probability of the clinical manifestations18 as well as the gestational age at their onset.19,20 Occurrence of a preterm APO with features of abnormal placentation in a previous pregnancy indicates an increased risk of the same recurring in a subsequent pregnancy. Rates of recurrence in subsequent pregnancies have been quoted as 26% for severe preeclampsia, 16% for FGR less than fifth centile, 5% for abruption, 8.5% for fetal death at ≥20 weeks, and 61% to 85% for one or more APOs.21 The recurrence risk increases with the number of complicated pregnancies: in a published trial of low-dose aspirin for prevention of recurrent APO, control patients with prior poor outcome defined as FGR, fetal demise, or placental abruption had a recurrence risk of 26% with one prior complication and 46% with two or more prior APOs, without regard to thrombophilia.22 Recurrences can manifest clinically with different APOs from one pregnancy to the next: a large retrospective cohort study found that women with preeclampsia, FGR, and placental abruption in their first © 2014 John Wiley & Sons, Ltd.
A. Ghidini and E. Gratacos
614
Figure 1 Temporal sequence of events leading to placental dysfunction and related adverse pregnancy outcomes
pregnancy are at substantially increased risk of recurrence for any or all of these conditions in their second pregnancy.23,24 The earlier in pregnancy APOs occur, the higher the risk of recurrence.25 Another large study found that delivery of a small-for-gestational age child in a woman’s first pregnancy is associated with increased risk of fetal death in the subsequent pregnancy, with the risk increasing with decreasing gestational age at the first pregnancy (i.e. with the severity of FGR and of the underlying placental dysfunction), with odds ratios ranging from 2.1 when the first delivery was at term to 5.0 when the first delivery occurred before 32 weeks.26 It should be noted that such odds ratios are higher than the overall risk of recurrence of stillbirth itself. It would be obviously desirable to evaluate placental implantation in ongoing pregnancies, in order to appropriately identify cases departing from the normal placentation, monitor them more closely, and wherever possible, institute preventative strategies aimed at reducing the odds of APO. It has become progressively clear that this can be accomplished with the same tools that have been used successfully for prenatal screening and diagnosis of congenital fetal anomalies. Ongoing placental implantation can be assessed indirectly by interrogating the uteroplacental circulation with Doppler, evaluating placental shape, size, and cord insertion using ultrasonography, and evaluating placental or feto-placental markers released into the maternal circulation.27,28 Indeed, the observation that maternal serum markers may be abnormal in cases destined to poor placentation even before spiral arteries conversion takes place has suggested the hypothesis that disorders of deep placentation may be due to primary insults to the extravillous trophoblast in the first trimester (Figure 1).29 Insults to the villous trophoblast may lead to a failure to elaborate the placental vascular tree, with subsequent FGR.13
EX UNO, PLURES Clinicians are quite familiar with several medical syndromes resulting from an underlying pathologic process that manifests Prenatal Diagnosis 2014, 34, 613–617
clinically with different features. Why and how abnormalities in placental implantation can become manifest with maternal symptoms (as in preterm preeclampsia, abruption, preterm labor, or premature rupture of membranes), fetal symptoms (typically FGR or stillbirth), or a combination of both is presently unknown. It is likely that maternal characteristics (e.g. determined by immunologic, inflammatory, proangiogenic, or thrombophilic milieus, often determined by genetic predispositions) and fetal characteristics interplay with the placental disease, mitigating or worsening it, and ultimately contributing to the cascade of events which determine the gestational age at onset and the various clinical manifestations. This can also explain why similar clinical manifestations (e.g. preeclampsia) can occur (particularly at or near term) in the absence of evidence of placental dysfunction. For example, maternal susceptibility due to microvascular disease (e.g. in diabetes) or systemic inflammation (e.g. in obesity) may lead to term/late-onset preeclampsia in the absence of significant placental pathology.30 Typically, this entity is not associated with FGR. This has led to the hypothesis that preterm and term preeclampsia may be two different nosologic entities with different fetal involvement and different rates of recurrence.20,29–35 Fetal vulnerability or resilience to ongoing placental ischemia and hypoxia may determine the coexistence of FGR with other APOs, its severity and gestational age at onset, and fetal survival. Fetal manifestations may also be greatly affected by whether the initial placental insult in the first trimester (Figure 1) was primarily or exclusively confined to the villous trophoblast, affecting its subsequent development and resulting in restricted transfer of nutrients and oxygen to the fetus.29 Although likely to play a role, the contribution of fetal characteristics (e.g. genetically determined immunologic, inflammatory, pro-angiogenic, or thrombophilic responses) to the ongoing placental villous damage has been poorly explored.36 As for preeclampsia, it appears that early © 2014 John Wiley & Sons, Ltd.
Can prenatal screening reduce the adverse obstetric outcomes related to abnormal placentation?
gestational age at onset identifies a placental dysfunction more likely related to abnormal placentation. Finally, the placenta itself has its own capacity to overcome initial difficulties at implantation, with differential expansion on the decidual surface, witnessed at ultrasonography and at birth by abnormalities in placental shape and size, as well as marginal or velamentous insertion of the umbilical cord. Such changes are already evident at 11 to 14 weeks’ gestation.37 Although such placental survival mechanisms are successful in most cases, leading to a favorable pregnancy outcome, they witness to the problematic initial implantation, and indeed, their presence increases significantly the odds of subsequent APOs.38 Placenta dynamic plasticity is quite relevant in the prenatal diagnosis and screening of APOs due to abnormal placentation: for example, cases flagged as high risk for APO because of uterine artery Doppler findings but who subsequently present normalization of the Doppler uterine waveforms (suggesting a delayed but eventually appropriate placental implantation and perfusion) result in a more favorable pregnancy outcome than those which maintain abnormal Doppler findings.39–41 Conversely, persistence of abnormal uterine artery Doppler findings between the first and second trimester identifies the group with the highest risk for APO.42 It should also be noted that placentas normally implanted (as evidenced by normal maternal serum markers and uterine artery Doppler findings in the first and second trimester) may subsequently develop acquired lesions (e.g. chronic villitis) ultimately resulting in APOs, which cannot be predicted or prevented.43 A placenta pathology study on preterm preeclampsia showed that such lesions can be found in one third of cases.44 Prenatal diagnosis and screening of ongoing placentation may shed light on the complex interplay of trophoblastic and maternal characteristics, and the relative contribution of each to the genesis of abnormal placentation.
PREVENTION Because interventions after the diagnosis of the clinical manifestations of preterm APOs have limited impact on the outcome, it has become clearer that the optimal timing for interventions should be much earlier in pregnancy, namely, at the time of placental implantation. Randomized clinical trials have shown that prophylaxis using low-molecular-weight heparin in women with history of preterm and severe APOs can be effective at reducing recurrences, with little heterogeneity among the studies.45,46 Similarly, low-dose aspirin has been shown to effectively reduce the risk of preterm APOs (more effectively for preeclampsia than FGR) not only in pregnancies flagged by a poor obstetric history but also in those identified prospectively by abnormal uterine artery Doppler findings.47,48 Of interest, a small placenta histology study has shown no effect of low-dose aspirin on histologic evidence of uterine vascular pathology, suggesting that the benefit of the prophylaxis may not be mediated by an effect on placental implantation.49 The efficacy of low-dose aspirin for late-onset APOs is quite inconsistent. The success of the same preventative strategy to reduce the risk of subsequent preeclampsia, preterm birth, or FGR Prenatal Diagnosis 2014, 34, 613–617
615
provides indirect support to the relevance of placental vascular disease in the genesis of preterm and severe APOs. It is intriguing to note that although placental vascular disease accounts for only one third of placenta pathology in preeclampsia cases delivered at
