Twin pregnancy and the risk of preeclampsia: bigger placenta or relative ischemia?

doi:10.1016/j.ajog.2007.10.783

American Journal of Obstetrics and Gynecology

Volume 198, Issue 4, April 2008, Pages 428.e1-428.e6

https://doi.org/10.1016/j.ajog.2007.10.783 Get rights and content

Objective

Twin pregnancies are a risk factor for preeclampsia with a reported incidence of 2-3 times higher than singleton pregnancies. Soluble fms-like tyrosine kinase 1 (sFlt1), which is a circulating antiangiogenic molecule of placental origin, plays a central role in preeclampsia by antagonizing placental growth factor (PlGF) and vascular endothelial growth factor signaling in the maternal vasculature. Increased sFlt1 and the ratio sFlt1/free PlGF have been shown to antedate clinical signs in preeclampsia. Although the cause of the upregulated sFlt1 in preeclampsia still is not understood clearly, placental ischemia with accompanying hypoxia is thought to play an important role. We therefore hypothesized that the higher risk of preeclampsia in twin pregnancies results from high sFlt1 (or sFlt1/PlGF) and that the sFlt1 upregulation was due to either relative placental hypoxia and/or increased placental mass.

Study Design

Maternal serum samples and placentas from third-trimester twin and singleton pregnancies without preeclampsia were used. Serum samples were analyzed for levels of sFlt1 and free PlGF by enzyme-linked immunosorbent assay and reported as means (in nanograms per milliliter and picograms per milliliter, respectively). Placentas were weighed and examined for content of sFlt1 and PlGF messenger RNA (mRNA) by quantitative polymerase chain reaction and hypoxia inducible factor-1α (HIF-1α) protein by Western blot.

Results

Soluble Flt1 concentrations in twin pregnancy maternal serum were 2.2 times higher than those that were measured in singleton pregnancy maternal serum samples (30.98 ± 9.78 ng/mL vs 14.14 ± 9.35 ng/mL, respectively; P = .001). Free PlGF concentrations were not significantly different between twin and singleton maternal serum samples, but the mean sFlt1/PlGF ratio of twin pregnancy maternal serum samples was 2.2 times higher than the equivalent ratio in singleton pregnancy samples (197.58 ± 126.86 ng/mL vs 89.91 ± 70.63 ng/mL, respectively; P = .029). Quantitative polymerase chain reaction for sFlt1 and PlGF mRNA revealed no significant differences between the 2 study groups. Western blot analysis of placental samples for HIF-1α revealed a mean ratio HIF-1α/actin of 0.53 vs 0.87, for the twins vs singletons placental samples respectively (twins showed lower HIF-1α, not higher). The mean weights of twin and singleton placentas were 1246 vs 716 g, respectively (P < .001). Importantly, the placental weights correlated very well with the circulating sFlt1 levels (R² = .75).

Conclusion

In twin pregnancies, circulating sFlt1 levels and sFlt1/PlGF ratios were twice as high as those in singleton pregnancies. The increased serum sFlt1 levels in twin pregnancies were not accompanied by any changes in the levels of sFlt1 mRNA and HIF-1α protein in the twin placentas but were correlated with increased placental weight. These findings suggest that the increased risk of preeclampsia in twin pregnancies may be due to increased placental mass that leads to increased circulating levels of sFlt1.

Section snippets

Patients

Patients were recruited from a cohort of women in the third trimester of their pregnancy who delivered at the Beth Israel Deaconess Medical Center delivery room in the years 2002-2005. After informed consent was obtained, the placentas were collected and weighed, and fresh tissue samples were frozen in liquid nitrogen in either phosphate-based saline solution or RNA Later solution (Ambion Inc, Austin, TX). Serum samples were also obtained just before delivery (−12 hours to delivery). Obstetric

Results

The clinical parameters of singleton and twin pregnancies that were compared in the study are shown in Table 1. Gestational ages of the pregnancies that were examined were longer in the singleton cases, because twin pregnancies usually deliver prematurely (39.1 ± 1.4 weeks of gestation compared with 36.1 ± 3.0 weeks of gestation; P = .001).

Circulating soluble Flt1 concentrations in twin pregnancy were 2.2 times as high as in those measured in singleton pregnancy maternal serum samples (30.98 ±

Comment

These results throw light on the pathophysiologic condition of preeclampsia and a hypothesis for the increased propensity of women with multigestational pregnancies to experience this disease. It is well-established that the risk of preeclampsia is greater in twin rather than in singleton pregnancies⁶ and is even greater in triplets.⁸ An increase in the circulating levels of sFlt1 in the maternal serum is characteristic of preeclampsia and is thought to play a major role in the pathogenesis of

Acknowledgements

We thank Guang Hu for his assistance with the quantitative PCR experiments.

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To assess the predictive accuracy of the sFlt-1/PlGF ratio cut-off 38 in addition to the standard-of-care spot urine protein/creatinine ratio (PCr) for multiple pregnancies in women with suspected pre-eclampsia.
Post-hoc analysis of a prospective cohort study.
Primary outcome was the occurrence of pre-eclampsia in one and four weeks after presentation with suspected pre-eclampsia. Test characteristics with 95% confidence intervals (CI) were calculated on pre-eclampsia development in one and four weeks.
Twenty-three multiple pregnancies with suspected pre-eclampsia between 20 and 37 weeks gestation were included for analysis. Women who eventually developed pre-eclampsia had a significantly higher PCr (34.0 vs. 16.5, p = 0.015), sFlt-1 (17033 vs. 5270 pg/ml, p = 0.047) and sFlt-1/PlGF ratio (99 vs. 25, p = 0.033) at baseline. Furthermore, PCr ≥ 30 and sFlt-1/PlGF ratio > 38 was respectively seen in 1/16 (6.3 %) and 3/16 (18.8 %) of the women who did not develop pre-eclampsia. For predicting pre-eclampsia within one week the sFlt-1/PlGF ratio sensitivity was 75.0 % [95 % CI 19.4–99.4] and the negative predictive value 93.8 % [73.0–98.8], while no pre-eclampsia developed when PCr was < 30. Consequently, the combination of these tests did not lead to an improvement in test characteristics, with non-significant differences in positive predictive value (50.0 % [29.5–70.5] versus 80.0 % [37.3–96.4]) compared to PCr alone for pre-eclampsia development in one week.
In addition to standard-of-care spot urine PCr measurements, this study has not been able to demonstrate that the sFlt-1/PlGF ratio cut-off 38 is of added value in the prediction of pre-eclampsia in multiple pregnancy.
Trial registration: Netherlands Trial Register (NL8308).
Maternal hemodynamic evaluation in monochorionic twin pregnancy complicated by twin-to-twin transfusion syndrome treated with fetoscopic laser surgery
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Maternal cardiovascular adaptations are amplified in twin pregnancies to support the metabolic request of the feto-placental unit. Few studies have evaluated the maternal hemodynamics changes after routine use of laser surgery in the treatment of twin-twin transfusion syndrome.
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A prospective observational study from 2020 to 2022, included monochorionic twin pregnancies complicated with twin-twin transfusion syndrome undergoing laser surgery between 16 and 26 weeks of gestation. To assess placental function and perfusion, uterine artery pulsatility index, hemoglobin, hematocrit, and soluble fms-like tyrosine kinase-1/placental growth factor ratio sampling prelaser and 24 hours postlaser were measured. Echocardiography by a single cardiologist evaluated maternal hemodynamics at presurgery, 24 hours, and 1 week postlaser. Those data were crosswise compared with cardiovascular indices of uncomplicated monochorionic pregnancies recruited at the same gestational age using nonparametric tests. Moreover, we fitted random-intercept linear regression models to investigate maternal hemodynamic changes according to the amount of amniotic fluid drained during laser surgery.
Forty-two twin-twin transfusion syndrome pregnancies with a median gestational age of 19.1 (17.4–20.9) weeks and 15 uncomplicated monochorionic pregnancies at the same gestational age were enrolled. Overall survival rate after laser was 72% with delivery at a median gestational age of 31.5 (27–34) weeks.
Significant changes in blood chemistry and placental function were observed in the twin-twin transfusion syndrome group, along with alterations in arterial pressure, heart rate, cardiac output, and ventricular strain, eventually aligning with the uncomplicated group's values by 1 week postlaser. The amount of amniodrainage, with a 1000 ml cut-off, did not significantly impact hemodynamic parameters.
Lastly, we detected a percentage of laser surgery complications in agreement with international literature and we did not record any maternal procedure-related problems.
Our analysis highlighted that maternal cardiovascular status in monochorionic twin pregnancy complicated by twin-twin transfusion syndrome was more dynamic and; 1 week after fetoscopic laser ablation of placental anastomosis completed by amniodrainage, maternal hemodynamic parameters restored to values similar to uncomplicated monochorionic twin pregnancies.
Correlation between placental weight and angiogenic markers sFlt-1 and PlGF in women with preeclampsia and fetal growth restriction
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The angiogenic factors sFlt-1 (soluble fms-like tyrosine kinase) and PlGF (Placental Growth Factor) play a key role in the pathophysiology, prediction and diagnosis of preeclampsia-associated pregnancy disorders. However, the correlation between maternal serum levels and the placental weight, especially in hypertensive pregnancy disorders is still unclear.
Retrospectively, we analyzed data from a real-world cohort of patients with preeclampsia (PE), intrauterine growth restriction (IUGR), PE + IUGR and controls giving birth within 14 days from inclusion. Herein, correlational analyses were calculated between placental weight, maternal serum levels of sFlt-1, PlGF and the respective sFlt-1/PlGF-ratios.
This study included n = 328 patients (n = 134 with PE, n = 40 with IUGR and n = 25 showed PE + IUGR) and n = 129 controls. The gestational age-adjusted placental weight was significantly decreased in patients with PE ± IUGR, but not in PE alone, when comparing to controls. Correlation between PlGF and the placental weight was significantly positive and increasing with severity of disease (controls 0.134, p = 0.131, PE 0.419, p < 0.01, IUGR 0.517, p < 0.01, PE + IUGR r = 0.723, p < 0.01). Furthermore, an inverse correlation between the sFlt-1/PlGF-ratio and the placental weight was found. The sFlt-1/PlGF-ratio per gram placental weight was highest in patients with PE + IUGR and lowest in controls (0.6 (IQR 0.4–1.8) vs. 0.05 (IQR 0.02–0.15)).
A correlation between the serum levels of sFlt-1 and PlGF and the placental weight is present in PE-associated pregnancy disorders.
This mirrors the model of an angiogenic continuum in the placenta where the serum sFlt-1 to PlGF ratio increases with severity of the disease.
Cardiovascular mortality risk a decade after twin and singleton pregnancies complicated by hypertensive disorders of pregnancy
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To describe the cardiovascular mortality (CVM) risk in women after twin versus singleton pregnancies complicated by hypertensive disorders of pregnancy (HDP).
Retrospective cohort study of nulliparous women with a twin or singleton pregnancy who delivered in the Netherlands between 1995 and 2015. We used data of the Perinatal Registry of the Netherlands and data of the National Death Registry to determine baseline data, the occurrence of HDP and CVM. In the two main analyses we compared twin pregnancies complicated by HDP to 1) singleton pregnancies complicated by HDP and 2) uncomplicated twin pregnancies (i.e. without HDP) of women who delivered within a hospital setting.
CVM risk using cox-proportional hazard models, adjusted for maternal age (aHR).
1,243,231 nulliparous women were included, of which 30,623 (2.5%) had a twin and 1,212,608 (97.5%) had a singleton pregnancy. A total of 9,853 (32.2%) twin pregnancies were complicated by HDP, versus 249,141 (20.6%) singleton pregnancies (p < 0.0001). Within the HDP twin cohort, 14/73 (19.2%) maternal deaths were due to cardiovascular causes, versus 335/1,788 (18.7%) in the HDP singleton cohort and 10/117 (8.6%) in the uncomplicated twin cohort. The corresponding aHR was 2.85 (95% CI 1.26–6.41; p = 0.01) for the HDP twin versus the uncomplicated twin cohort, and 1.05 (95% CI 0.62–1.80; p = 0.85) for the HDP twin versus the HDP singleton cohort.
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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.
Imbalances in circulating angiogenic factors in the pathophysiology of preeclampsia and related disorders
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Preeclampsia is a devastating medical complication of pregnancy that can lead to significant maternal and fetal morbidity and mortality. It is currently believed that there is abnormal placentation in as early as the first trimester in women destined to develop preeclampsia. Although the etiology of the abnormal placentation is being debated, numerous epidemiologic and experimental studies suggest that imbalances in circulating angiogenic factors released from the placenta are responsible for the maternal signs and symptoms of preeclampsia. In particular, circulating levels of soluble fms-like tyrosine kinase 1, an antiangiogenic factor, are markedly increased in women with preeclampsia, whereas free levels of its ligand, placental, growth factor are markedly diminished. Alterations in these angiogenic factors precede the onset of clinical signs of preeclampsia and correlate with disease severity. Recently, the availability of automated assays for the measurement of angiogenic biomarkers in the plasma, serum, and urine has helped investigators worldwide to demonstrate a key role for these factors in the clinical diagnosis and prediction of preeclampsia. Numerous studies have reported that circulating angiogenic biomarkers have a very high negative predictive value to rule out clinical disease among women with suspected preeclampsia. These blood-based biomarkers have provided a valuable tool to clinicians to accelerate the time to clinical diagnosis and minimize maternal adverse outcomes in women with preeclampsia. Angiogenic biomarkers have also been useful to elucidate the pathogenesis of related disorders of abnormal placentation such as intrauterine growth restriction, intrauterine fetal death, twin-to-twin transfusion syndrome, and fetal hydrops. In summary, the discovery and characterization of angiogenic proteins of placental origin have provided clinicians a noninvasive blood-based tool to monitor placental function and health and for early detection of disorders of placentation. Uncovering the mechanisms of altered angiogenic factors in preeclampsia and related disorders of placentation may provide insights into novel preventive and therapeutic options.

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: Dr Karumanchi is listed as a coinventor or provisional patents filed by the Beth Israel Deaconess Medical Center and a consultant to Abbott Diagnostics, Beckmann Coulter, and Johnson & Johnson.

: This study was supported in part by National Institutes of Health grants DK 065997 and HL 079594 and seed funds from the Beth Israel Deaconess Medical Center Ob/Gyn Foundation (S.A.K.).

: Cite this article as: Bdolah Y, Lam C, Rajakumar A, et al. Twin pregnancy and the risk of preeclampsia: bigger placenta or relative ischemia? Am J Obstet Gynecol 2008;198:428.e1-428.e6.

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ResearchBasic science: ObstetricsTwin pregnancy and the risk of preeclampsia: bigger placenta or relative ischemia?

Objective

Study Design

Results

Conclusion

Section snippets

Patients

Results

Comment

Acknowledgements

Obstet Gynecol

Eur J Obstet Gynecol Reprod Biol

Am J Obstet Gynecol

J Biol Chem

Placenta

Semin Nephrol

A case-control study of 1253 twin pregnancies from a 1982-1987 perinatal data base

Obstet Gynecol

Preeclampsia in twin pregnancy: severity and pathogenesis

Aust N Z J Obstet Gynaecol

Comparison of risk factors for preeclampsia and gestational hypertension in a population-based cohort study

Am J Epidemiol

Preeclampsia in twin pregnancies: incidence and outcome

Hypertens Pregnancy

The origins and outcomes of triplet and quadruplet pregnancies in Nova Scotia: 1980 to 2001

Am J Perinatol

Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia

J Clin Invest

Overexpression of the soluble vascular endothelial growth factor receptor in preeclamptic patients: pathophysiological consequences

J Clin Endocrinol Metab

Elevated serum soluble vascular endothelial growth factor receptor 1 (sVEGFR-1) levels in women with preeclampsia

J Clin Endocrinol Metab

Evidence supporting a role for blockade of the vascular endothelial growth factor system in the pathophysiology of preeclampsia: Young Investigator Award

Am J Obstet Gynecol

Research
Basic science: Obstetrics
Twin pregnancy and the risk of preeclampsia: bigger placenta or relative ischemia?