The placenta and preeclampsia: villain or victim?

Preeclampsia is a disease whose characterization has not changed in the 150 years since the cluster of signs associated with the disorder were first described. Although our understanding of the pathophysiology of preeclampsia has advanced considerably since then, there is still little consensus regarding the true etiology of preeclampsia. As a consequence, preeclampsia has earned the moniker "disease of theories," predominantly because the underlying biological mechanisms linking clinical epidemiologic findings to observed organ dysfunction in preeclampsia are far from clear. Despite the lack of cohesive evidence, expert consensus favors the hypothesis that preeclampsia is a primary placental disorder. However, there is now emerging evidence that suboptimal maternal cardiovascular performance resulting in uteroplacental hypoperfusion is more likely to be the cause of secondary placental dysfunction in preeclampsia. Preeclampsia and cardiovascular disease share the same risk factors, preexisting cardiovascular disease is the strongest risk factor (chronic hypertension, congenital heart disease) for developing preeclampsia, and there are now abundant data from maternal echocardiography and angiogenic marker studies that cardiovascular dysfunction precedes the development of preeclampsia by several weeks or months. Importantly, cardiovascular signs and symptoms (hypertension, cerebral edema, cardiac dysfunction) predominate in preeclampsia at clinical presentation and persist into the postnatal period with a 30% risk of chronic hypertension in the decade after birth. Placental malperfusion caused by suboptimal maternal cardiovascular performance may lead to preeclampsia, thereby explaining the preponderance of cardiovascular drugs (aspirin, calcium, statins, metformin, and antihypertensives) in preeclampsia prevention strategies. Despite the seriousness of the maternal and fetal consequences, we are still developing sensitive screening, reliable diagnostic, effective therapeutic, or improvement strategies for postpartum maternal cardiovascular legacy in preeclampsia. The latter will only become clear with an acceptance and understanding of the cardiovascular etiology of preeclampsia.

Preventing term stillbirth: benefits and limitations of using fetal growth reference charts.

PURPOSE OF REVIEW: This review examines the variation in clinical practice with regards to ultrasound estimation of fetal weight, as well as calculation of fetal weight centiles. RECENT FINDINGS: Placental dysfunction is associated with fetal smallness from intrauterine malnutrition as well as fetal disability and even stillbirth from hypoxemia. Although estimating fetal weight can be done accurately, the issue of which fetal weight centile chart should be used continues to be a contentious topic. The arguments against local fetal growth charts based on national borders and customization for variables known to be associated with disease are substantial. As for other human diseases such as hypertension and diabetes, there is a rationale for the use of an international fetal growth reference standard. Irrespective of the choice of fetal growth reference standard, a significant limitation of small for gestational age (SGA) detection programs to prevent stillbirth is that the majority of stillborn infants at term were not SGA at the time of demise. SUMMARY: Placental dysfunction can present with SGA from malnutrition and/or stillbirth from hypoxemia depending on the gestational age of onset. Emerging data show that at term, fetal Doppler arterial redistribution is associated more strongly with perinatal death than fetal size. Properly conducted trials of the role for maternal characteristics, fetal size, placental biomarkers, and Doppler assessing fetal well-being are required urgently.

Cardiac structure and function in normal pregnancy.

PURPOSE OF REVIEW: To review the published data on maternal cardiac adaptation to pregnancy. RECENT FINDINGS: Normal pregnancy is characterized by significant changes in the cardiovascular system. Studies on systemic arterial system and heart remodelling in pregnancy provide somewhat uniform results. In normal pregnancy, left ventricle mass, cardiac output and arterial compliance increase, whereas total vascular resistance decreases. In contrast, findings on left ventricular systolic and diastolic chamber and myocardial function are conflicting. SUMMARY: The major limitation of earlier studies on left ventricular systolic function is the use of ejection-phase indices that are dependent on loading conditions. Even when tissue Doppler velocity and deformation indices were measured, studies interpreted diastolic indices in isolation, rather than using validated diagnostic algorithms which account for the interdependency of cardiac events. Furthermore, the strong age-dependency of diastolic function indices was not accounted for in the majority of assessments and none of the studies diagnose or grade diastolic dysfunction. Future studies should aim to use appropriate control individuals, age-adjusted cutoff of cardiac diastolic indices and extended tissue Doppler velocity and deformation indices to provide objective information about chamber and myocardial function.

Screening for pre-eclampsia by using changes in uterine artery Doppler indices with advancing gestation.

OBJECTIVE: The aim of the study was to assess the relationship of changes in uterine artery (UtA) Doppler pulsatility indices (PI) between first and second trimesters and the subsequent development of pre-eclampsia. METHODS: A retrospective study of singleton pregnancies undergoing both first and second trimesters UtA Doppler screening between 2002 and 2009 was conducted. Multiples of median of UtA Doppler PI were used for developing indices describing UtA changes between the two trimesters. Receiver-operating characteristics curves (ROC) were calculated for multiple comparisons. RESULTS: Three thousand five hundred sixty women had UtA Doppler screening in the first and second trimesters. Eleven women were excluded because of termination of pregnancy before 24 weeks. Out of the 3549 women recruited, 126 developed Pre-eclampsia (PE; 22 early PE delivered <34 weeks and 41 preterm PE delivered <37 weeks). The best index for predicting pre-eclampsia was the difference between the mean second trimester and mean first trimester UtA PI (areas under the ROC for early PE and preterm PE of 0.851 and 0.786, respectively). CONCLUSION: Changes of UtA resistance between the first and second trimesters can be calculated as the difference between UtA PI at these gestations. The data of this study demonstrate that the difference in mean PI is the best index in predicting early PE and preterm PE.

Maternal cardiac function in preeclampsia.

PURPOSE OF REVIEW: Acute cardiovascular complications affect 6% of severe preeclampsia and epidemiological studies demonstrate a strong association between preeclampsia and subsequent cardiovascular morbidity and mortality. This data suggests that not only can preeclampsia acutely impair cardiac function, but also it has the potential to provoke myocardial ischaemia and affect long-term cardiovascular health. This review highlights the recent insights on cardiovascular impairment in preeclampsia and postpartum. RECENT FINDINGS: Recent studies on preeclampsia have used newer echocardiographic indices that are more sensitive at detecting asymptomatic myocardial damage, better correlated to invasive indices of myocardial function and are predictive for subsequent cardiovascular morbidity. Current findings indicate an unexpectedly high prevalence of cardiac impairment in preeclampsia and postpartum. These findings have important implications for the long-term cardiovascular health of women whose pregnancies were complicated by preeclampsia. SUMMARY: Preeclampsia is associated with stage B heart failure (asymptomatic left ventricular dysfunction/hypertrophy), a high prevalence of essential hypertension and an increased cardiovascular risk status within few years postpartum. These findings are more prevalent with early onset/preterm preeclampsia. These cardiovascular findings are consistent with epidemiological studies showing a 'dose-dependent' relationship between preeclampsia and long-term cardiovascular morbidity and mortality. There is increasing evidence supporting the concept that a history of early onset/preterm preeclampsia should be taken into account to identify women at high cardiovascular risk even in the absence of other concomitant risk factors.

Stillbirth at term: Does size really matter?

Placental dysfunction has a deleterious influence on fetal size and is associated with higher rates of perinatal morbidity and mortality. This association underpins the strategy of fetal size evaluation as a mechanism to identify placental dysfunction and prevent stillbirth. The optimal method of routine detection of small for gestational age (SGA) remains to be clarified with choices between estimation of symphyseal-fundal height versus routine third-trimester ultrasound, various formulae for fetal weight estimation by ultrasound, and the variable use of national, customized, or international fetal growth references. In addition to these controversies, the strategy for detecting SGA is further undermined by data demonstrating that the relationship between fetal size and adverse outcome weakens significantly with advancing gestation such that near term, the majority of stillbirths and adverse perinatal outcomes occur in normally sized fetuses. The use of maternal serum biochemical and Doppler parameters near term appears to be superior to fetal size in the identification of fetuses compromised by placental dysfunction and at increased risk of damage or demise. Multiparameter models and predictive algorithms using maternal risk factors, and biochemical and Doppler parameters have been developed, but need to be prospectively validated to demonstrate their effectiveness.

Hypertensive Disorders of Pregnancy and Future Cardiovascular Health.

Hypertensive disorders of pregnancy (HDP) occur in almost 10% of gestations. These women are known to have higher cardiovascular morbidity and mortality later in life in comparison with parous controls who had normotensive pregnancies. Several studies have demonstrated that women with preeclampsia present in a state of segmental impaired myocardial function, biventricular chamber dysfunction, adverse biventricular remodeling, and hypertrophy, a compromised hemodynamic state and indirect echocardiographic signs of localized myocardial ischemia and fibrosis. These cardiac functional and geometric changes are known to have strong predictive value for cardiovascular disease in non-pregnant subjects. A "dose effect" response seems to regulate this relationship with severe HDP, early-onset HDP, coexistence of fetal growth disorders, and recurrence of HDP resulting in poorer cardiovascular measures. The mechanism underlying the relationship between HDP in younger women and cardiovascular disease later in life is unclear but could be explained by sharing of pre-pregnancy cardiovascular risk factors or due to a direct impact of HDP on the maternal cardiovascular system conferring a state of increased susceptibility to future metabolic or hemodynamic insults. If so, the prevention of HDP itself would become all the more urgent. Shortly after delivery, women who experienced HDP express an increased risk of classic cardiovascular risk factors such as essential hypertension, renal disease, abnormal lipid profile, and diabetes with higher frequency than controls. Within one or two decades after delivery, this group of women are more likely to experience premature cardiovascular events, such as symptomatic heart failure, myocardial ischemia, and cerebral vascular disease. Although there is general agreement that women who suffered from HDP should undertake early screening for cardiovascular risk factors in order to allow for appropriate prevention, the exact timing and modality of screening has not been standardized yet. Our findings suggest that prevention should start as early as possible after delivery by making the women aware of their increased cardiovascular risk and encouraging weight control, stop smoking, healthy diet, and daily exercise which are well-established and cost-effective prevention strategies.

Adverse intrapartum outcome in pregnancies complicated by small for gestational age and late fetal growth restriction undergoing induction of labor with Dinoprostone, Misoprostol or mechanical methods: A systematic review and meta-analysis.

OBJECTIVE: To investigate the outcome of pregnancies with small baby, including both small for gestational age (SGA) and late fetal growth restriction (FGR) fetuses, undergoing induction of labor (IOL) with Dinoprostone, Misoprostol or mechanical methods. STUDY DESIGN: Medline, Embase and Cochrane databases were searched. Inclusion criteria were non-anomalous singleton pregnancies complicated by the presence of a small fetus, defined as a fetus with estimated fetal weight (EFW) or abdominal circumference (AC) <10th centile undergoing IOL from 34 weeks of gestation with vaginal Dinoprostone, vaginal misoprostol, or mechanical methods (including either Foley or Cook balloon catheters). The primary outcome was a composite measure of adverse intrapartum outcome. Secondary outcomes were the individual components of the primary outcome, perinatal mortality and morbidity. All the explored outcomes were reported in three different sub-groups of pregnancies complicated by a small fetus including: all small fetuses (defined as those with an EFW and/or AC <10th centile irrespective of fetal Doppler status), late FGR fetuses (defined as those with EFW and/or AC <3rd centile or AC/EFW <10th centile associated with abnormal cerebroplacental Dopplers) and SGA fetuses (defined as those with EFW and/or AC <10th but >3rd centile with normal cerebroplacental Dopplers). Quality assessment of each included study was performed using the Risk of Bias in Non-randomized Studies-of Interventions tool (ROBINS-I), while the GRADE methodology was used to assess the quality of the body of retrieved evidence. Meta-analyses of proportions and individual data random-effect logistic regression were used to analyze the data. RESULTS: 12 studies (1711 pregnancies) were included. In the overall population of small fetuses, composite adverse intra-partum outcome occurred in 21.2 % (95 % CI 10.0-34.9) of pregnancies induced with Dinoprostone, 18.0 % (95 % CI 6.9-32.5) of those with Misoprostol and 11.6 % (95 % CI 5.5-19.3) of those undergoing IOL with mechanical methods. Cesarean section (CS) for non-reassuring fetal status (NRFS) was required in 18.1 % (95 % CI 9.9-28.3) of pregnancies induced with Dinoprostone, 9.4 % (95 % CI 1.4-22.0) of those with Misoprostol and 8.1 % (95 % CI 5.0-11.6) of those undergoing mechanical induction. Likewise, uterine tachysystole, was recorded on CTG in 13.8 % (95 % CI 6.9-22.3) of cases induced with Dinoprostone, 7.5 % (95 % CI 2.1-15.4) of those with Misoprostol and 3.8 % (95 % CI 0-4.4) of those induced with mechanical methods. Composite adverse perinatal outcome following delivery complicated 2.9 % (95 % CI 0.5-6.7) newborns after IOL with Dinoprostone, 0.6 % (95 % CI 0-2.5) with Misoprostol and 0.7 % (95 % CI 0-7.1) with mechanical methods. In pregnancies complicated by late FGR, adverse intrapartum outcome occurred in 25.3 % (95 % CI 18.8-32.5) of women undergoing IOL with Dinoprostone, compared to 7.4 % (95 % CI 3.9-11.7) of those with mechanical methods, while CS for NRFS was performed in 23.8 % (95 % CI 17.3-30.9) and 6.2 % (95 % CI 2.8-10.5) of the cases, respectively. Finally, in SGA fetuses, composite adverse intrapartum outcome complicated 8.4 % (95 % CI 4.6-13.0) of pregnancies induced with Dinoprostone, 18.6 % (95 % CI 13.1-25.2) of those with Misoprostol and 8.7 (95 % CI 2.5-17.5) of those undergoing mechanical IOL, while CS for NRF was performed in 8.4 % (95 % CI 4.6-13.0) of women induced with Dinoprostone, 18.6 % (95 % CI 13.1-25.2) of those with Misoprostol and 8.7 % (95 % CI 2.5-17.5) of those undergoing mechanical induction. Overall, the quality of the included studies was low and was downgraded due to considerable clinical and statistical heterogeneity. CONCLUSIONS: There is limited evidence on the optimal type of IOL in pregnancies with small fetuses. Mechanical methods seem to be associated with a lower occurrence of adverse intrapartum outcomes, but a direct comparison between different techniques could not be performed.

Fetal facial profile in Pallister-Killian syndrome.

Pallister-Killian syndrome (PKS) is a sporadic chromosomal anomaly, caused by a tissue-specific mosaic distribution of an additional isochromosome 12p. About 60 cases of prenatal diagnosis of PKS have been reported. Only 1 case of PKS is described on the basis of prenatal screening, presenting increased nuchal translucency. An abnormal fetal facial profile is described prenatally as sonographic evidence of PKS. We report a case of prenatal diagnosis in a fetus undergoing second-level scan due to positive triple screen with ultrasound features of PKS.

Maternal Cardiovascular Function in Normal Pregnancy: Evidence of Maladaptation to Chronic Volume Overload.

The aim of this study was to investigate cardiac functional status in pregnancy using a comprehensive approach taking into account the simultaneous changes in loading and geometry, as well as maternal age and anthropometric indices. This was a prospective cross-sectional study of 559 nulliparous pregnant women assessed at 4 time points during pregnancy and at 1 year postpartum. All women underwent conventional echocardiography and tissue Doppler velocities and strain rate analysis at multiple cardiac sites. Mean arterial pressure and total vascular resistance index significantly decreased (both P<0.001) during the first 2 trimesters of pregnancy and increased thereafter. Stroke volume index and cardiac index showed the opposite trend compared with mean arterial pressure and total vascular resistance index (both P<0.05). Myocardial and ventricular function were significantly enhanced in the first 2 trimesters but progressively declined thereafter. By the end of pregnancy, significant chamber diastolic dysfunction and impaired myocardial relaxation was evident in 17.9% and 28.4% of women, respectively, whereas myocardial contractility was preserved. There was full recovery of cardiac function at 1 year postpartum. Cardiovascular changes during pregnancy are thought to represent a physiological adaptation to volume overload. The findings of a drop in stroke volume index, impaired myocardial relaxation with diastolic dysfunction, and a tendency toward eccentric remodeling in a significant proportion of cases at term are suggestive of cardiovascular maladaptation to the volume-overloaded state in some apparently normal pregnancies. These unexpected cardiovascular findings have important implications for the management of both normal and pathological pregnancy states.

Maternal cardiovascular impairment in pregnancies complicated by severe fetal growth restriction.

Fetal growth restriction and preeclampsia are both conditions of placental etiology and associated to increased risk for the long-term development of cardiovascular disease in the mother. At presentation, preeclampsia is associated with maternal global diastolic dysfunction, which is determined, at least in part, by increased afterload and myocardial stiffness. The aim of this study is to test the hypothesis that women with normotensive fetal growth-restricted pregnancies also exhibit global diastolic dysfunction. This was a prospective case-control study conducted over a 3-year period involving 29 preterm fetal growth-restricted pregnancies, 25 preeclamptic with fetal growth restriction pregnancies, and 58 matched control pregnancies. Women were assessed by conventional echocardiography and tissue Doppler imaging at diagnosis of the complication and followed-up at 12 weeks postpartum. Fetal growth-restricted pregnancies are characterized by a lower cardiac index and higher total vascular resistance index than expected for gestation. Compared with controls, fetal growth-restricted pregnancy was associated with significantly increased prevalence (P<0.001) of asymptomatic left ventricular diastolic dysfunction (28% versus 4%) and widespread impaired myocardial relaxation (59% versus 21%). Unlike preeclampsia, cardiac geometry and intrinsic myocardial contractility were preserved in fetal growth-restricted pregnancy. Fetal growth-restricted pregnancies are characterized by a low output, high resistance circulatory state, as well as a higher prevalence of asymptomatic global diastolic dysfunction and poor cardiac reserve. These findings may explain the increased long-term cardiovascular risk in these women who have had fetal growth-restricted pregnancies. Further studies are needed to clarify the postnatal natural history of cardiac dysfunction in these women.

Severe myocardial impairment and chamber dysfunction in preterm preeclampsia.

OBJECTIVE: The long-term cardiovascular risk of preeclampsia is known to be significantly higher in women requiring preterm delivery before 37 weeks compared with those delivered at term. The aim of this study is to assess and compare maternal cardiac function and geometry in acute preterm and term preeclampsia. METHODS: This is a prospective case-control study of 27 preterm and 50 term preeclampsia and 104 matched controls assessed by conventional echocardiography and tissue Doppler imaging. RESULTS: Preeclampsia is associated with biventricular diastolic dysfunction, altered geometry, and widespread myocardial impairment. However, only preterm but not term preeclampsia is characterized by biventricular systolic dysfunction (26% vs. 4%; p < 0.05) and severe left ventricular hypertrophy (19% vs. 2%; p < 0.05). CONCLUSIONS: Women with preterm preeclampsia have a more severe cardiac impairment than those with term preeclampsia. This finding may explain the increased long-term cardiovascular risk associated with preterm preeclampsia. The cardiac assessment of women with preterm preeclampsia may be of relevance in identifying women at higher risk of developing cardiovascular morbidity and mortality in later life.

Preeclampsia is associated with persistent postpartum cardiovascular impairment.

Preeclampsia is associated with asymptomatic global left ventricular abnormal function and geometry during the acute phase of the disorder. These subclinical abnormalities in cardiac findings are known to be important in cardiovascular risk stratification for nonpregnant patients. Furthermore, epidemiological studies have also demonstrated a relationship between preeclampsia and cardiac morbidity and mortality later in life. The aim of this study was to evaluate the postpartum natural history and clinical significance of asymptomatic left ventricular impairment known to occur with acute preeclampsia. This was a prospective longitudinal case-control study of 64 subjects with preeclampsia and 78 matched controls. There were 3 time point assessments, pregnancy and 1 and 2 years postpartum. The assessments included a medical and family history, blood pressure profile, echocardiography, and 12-lead ECG. At 1 year postpartum, asymptomatic left ventricular moderate-severe dysfunction/hypertrophy was significantly higher in preterm preeclampsia (56%) compared with term preeclampsia (14%) or matched controls (8%; P values <0.001). The risk of developing essential hypertension within 2 years was significantly higher in both preterm preeclamptic women and those with persistent left ventricular moderate-severe abnormal function/geometry. The cardiovascular implications of preeclampsia do not end with the birth of the infant and placenta. The majority of preterm preeclamptic women have stage B asymptomatic heart failure postpartum, and 40% develop essential hypertension within 1 to 2 years after pregnancy. Women with a history of preterm preeclampsia may benefit from formal cardiovascular risk assessment in the 1 to 2 years after delivery to identify those who would benefit from targeted therapeutic intervention.

Maternal cardiac dysfunction and remodeling in women with preeclampsia at term.

Preeclampsia is a disease associated with significant cardiovascular morbidity during pregnancy and in later life. This study was designed to evaluate cardiac function and remodeling in preeclampsia occurring at term. This was a prospective case-control study of 50 term preeclampsia and 50 normal pregnancies assessed by echocardiography and tissue Doppler analysis. Global diastolic dysfunction was observed more frequently in preeclampsia versus control pregnancies (40% versus 14%, P = 0.007). Increased cardiac work and left ventricular mass indices suggest that left ventricular remodeling was an adaptive response to maintain myocardial contractility with preeclampsia at term. Approximately 20% of patients with preeclampsia at term have more evident myocardial damage. Diastolic dysfunction usually precedes systolic dysfunction in the evolution of ischemic or hypertensive cardiac diseases and is of prognostic value in the prediction of long-term cardiovascular morbidity. The study findings also have significant implications for the acute medical management of preeclampsia.

Raised maternal serum cystatin C: an early pregnancy marker for preeclampsia.

The balance between trophoblast cathepsin and decidual cystatin C expression is pivotal in physiological trophoblast development. Defective trophoblast invasion is characteristic of preeclampsia and may involve derangement of the cathepsin/cystatin C balance. We conducted a prospective nested case-control study of healthy women with singleton pregnancies in the first trimester of pregnancy. Maternal serum cystatin C concentrations in those subsequently developing preeclampsia (n = 30) were compared to controls with normal outcome (n = 90). The median cystatin C concentration in early pregnancy was significantly higher (P = .0001) in those who subsequently developed preeclampsia (median 0.65 mg/L) when compared to normal pregnancy (median 0.57 mg/L). Of the 30 women developing preeclampsia, 14 (47%) had cystatin C above the 80th centile (0.67 mg/L) for the controls. Maternal serum cystatin C concentrations in early pregnancy may be of value in identifying women at high risk of developing preeclampsia.