Placental Insufficiency Syndromes Research Articles

From Molecules to Imaging: Assessment of Placental Hypoxia Biomarkers in Placental Insufficiency Syndromes.

Placental hypoxia poses significant risks to both the developing fetus and the mother during pregnancy, underscoring the importance of early detection and monitoring. Effectively identifying placental hypoxia and evaluating the deterioration in placental function requires reliable biomarkers. Molecular biomarkers in placental tissue can only be determined post-delivery and while maternal blood biomarkers can be measured over time, they can merely serve as proxies for placental function. Therefore, there is an increasing demand for non-invasive imaging techniques capable of directly assessing the placental condition over time. Recent advancements in imaging technologies, including photoacoustic and magnetic resonance imaging, offer promising tools for detecting and monitoring placental hypoxia. Integrating molecular and imaging biomarkers may revolutionize the detection and monitoring of placental hypoxia, improving pregnancy outcomes and reducing long-term health complications. This review describes current research on molecular and imaging biomarkers of placental hypoxia both in human and animal studies and aims to explore the benefits of an integrated approach throughout gestation.

Nanomedicines: An approach to treat placental insufficiency and the current challenges.

Preeclampsia and fetal growth restriction are common pregnancy complications that significantly impact perinatal health and offspring development later in life. The origin of these complex syndromes overlap in placental insufficiency. Progress in developing treatments for maternal, placental or fetal health is mainly limited by the risk of maternal and fetal toxicity. Nanomedicines are a promising approach to safely treat pregnancy complications since they can regulate drug interaction with the placenta to enhance efficacy of the treatment while minimizing exposure of the fetus. This narrative review discusses the current developments and challenges of nanomedicines during pregnancy with a focus on preclinical models of placenta insufficiency syndromes. Firstly, we outline the safety requirements and potential therapeutic maternal and placental targets. Secondly, we review the prenatal therapeutic effects of the nanomedicines that have been tested in experimental models of placental insufficiency syndromes. The majority of liposomes and polymeric drug delivery system show promising results regarding the prevention of trans-placental passage nanomedicines in uncomplicated and complicated pregnancies. The others two studied classes, quantum dots and silicon nanoparticles, have been investigated to a limited extent in placental insufficiency syndromes. Characteristics of the nanoparticles such as charge, size, and timing of administration have been shown to influence the trans-placental passage. The few available preclinical therapeutic studies on placental insufficiency syndromes predominantly show beneficial effects of nanomedicines on both maternal and fetal health, but demonstrate contradicting results on placental health. Interpretation of results in this field is complicated by the fact that results are influenced by the choice of animal species and model, gestational age, placental maturity and integrity, and nanoparticle administration route. Nanomedicines form a promising therapeutic approach during (complicated) pregnancies mainly by reducing fetal toxicity and regulating drug interaction with the placenta. Different nanomedicines have been proven to effectively prevent trans-placental passage of encapsulated agents. This can be expected to dramatically reduce risks for fetal adverse effects. Furthermore, a number of these nanomedicines positively impacted maternal and fetal health in animal models for placental insufficiency. Demonstrating that effective drug concentrations can be reached in the target tissue. While these first animal studies are encouraging, more research is needed to better understand the influence of the pathophysiology of this multi-factorial disease before implementation in clinical practice can be considered. Therefore, extensive evaluation of safety and efficacy of these targeted nanoparticles is needed within multiple animal, in vitro, and/or ex vivo models. This may be complemented by diagnostic tools to assess the disease status to identify the best time to initiate treatment. Together these investigations should contribute to building confidence in the safety of nanomedicines for treating mother and child, as safety has, understandably, the highest priority in this sensitive patient groups.

Abstract 10533: Greater Left Ventricular Mass And Abnormal Diastolic Myocardial Function In Neonates Of Pre-eclamptic Pregnancies

Introduction: Maternal pre-eclampsia (PEC) is a placental insufficiency syndrome with potential effects on neonatal cardiac function. Hypothesis: We tested the hypothesis that neonatal exposure to maternal PEC results in systolic and diastolic myocardial dysfunction on echocardiogram. Methods: Neonates exposed to maternal PEC (N=142) were matched 1:1 for gestational age and gender (N=142) with neonates concurrently enrolled in our center during the same study period (2009-2019). Echocardiograms performed in first 30 days of life were analyzed. Image analysis was done retrospectively and included LV and RV global peak longitudinal strain, mitral and tricuspid inflow and tissue Doppler, and LV mass indexed to body surface area. Analyses included two-sample t-test, Wilcoxon rank sum, chi-squared, and Bonferroni correction testing. Results: The average gestational age was 28 weeks, with slight male predominance of 54.9%. Birth weight was 885g in PEC group, compared to 1100g in the control (p=0.003). Median age at echocardiogram was 8 days for PEC and 6 days for control.In the PEC group, systolic function demonstrated decreased longitudinal 2-chamber average peak strain and higher mean LV mass. There was no difference in 4-chamber average peak strain, circumferential mid-LV average peak strain, or longitudinal RV 6-segment average strain. Mitral and tricuspid valve E-wave deceleration times were shorter in the PEC group. There were no differences in other markers of diastolic function, including E/A and E/e’ ratio. Conclusions: PEC neonates have increased RV and LV stiffness, indicated by reduced E-wave deceleration time of the mitral and tricuspid valves. This is suggestive of grade 2 diastolic dysfunction. LV mass was increased in the PEC group. We did not find compelling evidence of systolic dysfunction with strain analysis. In conclusion, maternal PEC exposure results in neonatal diastolic abnormalities that may have long term effects on cardiac function.

Galectin Family in Placental Insufficiency Syndromes

Galectin Family in Placental Insufficiency Syndromes

Maternal Obesity and Male Genital Anomalies: Potential Role of Placental Insufficiency and Metabolic Syndrome.

Maternal Obesity and Male Genital Anomalies: Potential Role of Placental Insufficiency and Metabolic Syndrome.

Enhancement of trophoblast differentiation and survival by low molecular weight heparin requires heparin-binding EGF-like growth factor.

Does low molecular weight heparin (LMWH) require heparin-binding epidermal growth factor (EGF)-like growth factor (HBEGF) signaling to induce extravillous trophoblast differentiation and decrease apoptosis during oxidative stress? LMWH increased HBEGF expression and secretion, and HBEGF signaling was required to stimulate trophoblast extravillous differentiation, increase invasion in vitro and reduce trophoblast apoptosis during oxidative stress. Abnormal trophoblast differentiation and survival contribute to placental insufficiency syndromes, including preeclampsia and intrauterine growth restriction. Preeclampsia often manifests as a pro-thrombotic state, with unsuccessful transformation of the spiral arteries that reduces oxygen supply and can produce placental infarction. LMWH improves placental function by increasing blood flow. Recent data suggest that the actions of LMWH transcend its anti-coagulative properties, but the molecular mechanism is unknown. There is evidence that LMWH alters the expression of human HBEGF in trophoblast cells, which regulates human trophoblast pathophysiology. HBEGF, itself, is capable of increasing trophoblast survival and invasiveness. First-trimester placental explants and the HTR-8/SVneo cell line, established using extravillous trophoblast outgrowths from first-trimester villous explants, were treated in vitro with LMWH to examine the effects on HBEGF signaling and trophoblast function under normal physiological and pathological conditions. A highly specific antagonist of HBEGF and other inhibitors of HBEGF downstream signaling were used to determine the relationship between LMWH treatment and HBEGF. Placental tissues (n = 5) were obtained with IRB approval and patient consent from first-trimester terminations. Placental explants and HTR-8/SVneo cells were cultured on plastic or Matrigel™ and treated with a therapeutic dose of LMWH (Enoxaparin; 10 IU/ml), with or without CRM197, pan Erb-B2 Receptor Tyrosine Kinase (ERBB) inhibitor, anti-ERBB1 or ERBB4 blocking antibodies, or pretreatment of cells with heparitinase I. Extravillous differentiation was assessed by immunocytochemistry to determine the relative levels of integrins α6β4 and α1β1. Trophoblast invasiveness was assessed in villous explants by measuring outgrowth from villous tips cultured on Matrigel, and by invasion assays with HTR-8/SVneo cells cultured on Matrigel-coated transwell insert. Placental explants and HTR-8/SVneo cells were exposed to oxidative stress in a hypoxia-reoxygenation (H-R) model, measuring cell death by TUNEL assay, caspase 3 cleavage, and BCL-2α expression. LMWH induced extravillous differentiation, according to trophoblast invasion assays and integrin (α6β4-α1β1) switching. Treatment with LMWH rescued cytotrophoblasts and HTR-8/SVneo cells from apoptosis during exposure to reoxygenation injury, based on TUNEL, caspase 3 cleavage and BCL-2α expression. Experiments using CRM197, ERBB1 and ERBB4 blocking antibodies, pan-ERBB inhibitor and removal of cell surface heparin demonstrated that the effects of LMWH on trophoblast invasion and survival were dependent upon HBEGF signaling. N/A. The primary limitation of this study was the use of only in vitro experiments. Patient demographics from elective terminations were not available. These data provide new insights into the non-coagulation-related aspects of perinatal LMWH treatment in the management of placental insufficiency disorders. This research was supported by grants from the National Institutes of Health (HD071408 and HL128628), the March of Dimes, and the W. K. Kellogg Foundation. There were no conflicts or competing interests.

Head growth in fetuses with isolated congenital heart defects: lack of influence of aortic arch flow and ascending aorta oxygen saturation

Congenital heart defects (CHDs) are reported to be associated with a smaller fetal head circumference (HC) and neurodevelopmental delay. Recent studies suggest that altered intrauterine brain hemodynamics may explain these findings. Our objectives were to evaluate the pattern of head growth in a large cohort of fetuses with various types of CHD, analyze these patterns according to the type of CHD and estimate the effect of cerebral hemodynamics with advancing gestation in the second and third trimesters. Singleton fetuses with an isolated CHD were selected from three fetal medicine units (n = 436). Cases with placental insufficiency or genetic syndromes were excluded. CHD types were clustered according to the flow and oxygen saturation in the aorta. Z-scores of biometric data were constructed using growth charts of a normal population. HC at different gestational ages was evaluated and univariate and multivariate mixed regression analyses were performed to examine the patterns of prenatal HC growth. Fetuses with severe and less severe types of CHD demonstrated statistically significant HC growth restriction with increasing gestational age (slope of -0.017/day); however, there was no statistically significant effect of fetal hemodynamics on HC growth. Fetuses with CHD but normal brain oxygenation and normal aortic flow showed a significant decrease in HC growth (slope of -0.024/day). Only fetuses with isolated tetralogy of Fallot demonstrated a smaller HC z-score at 20 weeks of gestation (-0.67 (95% CI, -1.16 to -0.18)). Despite the decline in head growth in fetuses with a prenatally detected isolated CHD, HC values were within the normal range, raising the question of its clinical significance. Furthermore, in contrast to other studies, this large cohort did not establish a significant correlation between aortic flow or oxygen saturation and HC growth. Factors other than altered fetal cerebral hemodynamics may contribute to HC growth restriction with increasing gestational age, such as (epi)genetic or placental factors. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

TCDD induces the hypoxia-inducible factor (HIF)-1α regulatory pathway in human trophoblastic JAR cells.

The exposure to dioxin can compromise pregnancy outcomes and increase the risk of preterm births. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) has been demonstrated to induce placental hypoxia at the end of pregnancy in a rat model, and hypoxia has been suggested to be the cause of abnormal trophoblast differentiation and placental insufficiency syndromes. In this study, we demonstrate that the non-hypoxic stimulation of human trophoblastic cells by TCDD strongly increased hypoxia inducible factor-1 alpha (HIF-1α) stabilization. TCDD exposure induced the generation of reactive oxygen species (ROS) and nitric oxide. TCDD-induced HIF-1α stabilization and Akt phosphorylation was inhibited by pretreatment with wortmannin (a phosphatidylinositol 3-kinase (PI3K) inhibitor) or N-acetylcysteine (a ROS scavenger). The augmented HIF-1α stabilization by TCDD occurred via the ROS-dependent activation of the PI3K/Akt pathway. Additionally, a significant increase in invasion and metallomatrix protease-9 activity was found in TCDD-treated cells. The gene expression of vascular endothelial growth factor and placental growth factor was induced upon TCDD stimulation, whereas the protein levels of peroxisome proliferator-activated receptor γ (PPARγ), PPARγ coactivator-1α, mitochondrial transcription factor, and uncoupling protein 2 were decreased. Our results indicate that an activated HIF-1α pathway, elicited oxidative stress, and induced metabolic stress contribute to TCDD-induced trophoblastic toxicity. These findings may provide molecular insight into the TCDD-induced impairment of trophoblast function and placental development.

Hypoxia and Trophoblast Differentiation: A Key Role for PPARγ

Tissue oxygen tension regulates differentiation of multiple types of stem cells. In the placenta, hypoxia has been associated with abnormal trophoblast differentiation and placental insufficiency syndromes of preeclampsia (PE) and intrauterine growth restriction (IUGR). Peroxisome proliferator-activated receptor-γ (PPARγ) is a ligand-activated transcription factor involved in many cellular processes, including differentiation. We have previously shown that PPARγ-null trophoblast stem (TS) cells show a defect in differentiation to labyrinthine trophoblast, instead differentiating preferentially to trophoblast giant cells (TGC). Since PPARγ is known to be regulated by hypoxia in adipose tissue, we hypothesized that there may be a link between oxygen tension, PPARγ expression, and trophoblast differentiation. We found that hypoxia reduced PPARγ expression by a mechanism independent of both hypoxia-inducible factor (HIF) and histone deacetylases (HDACs). In addition, PPARγ partially rescued hypoxia-induced inhibition of labyrinthine differentiation in wild-type TS cells but was not required for hypoxia-induced inhibition of TGC differentiation. Finally, we show that induction of labyrinthine trophoblast differentiation by HDAC inhibitor treatment is independent of both PPARγ and Gcm1. We propose a model with two pathways for labyrinthine trophoblast differentiation of TS cells, one of which is dependent on PPARγ and inhibited by hypoxia. Since hypoxia is associated with PE and IUGR, we propose that PPARγ may at least partially mediate hypoxia-induced placental insufficiency and as such may be a promising therapeutic target for these disorders.

Heme oxygenase-1 in placental development and pathology

Pregnancy is accompanied by several adaptations in the mother, such as increased blood volume, higher cardiac output and reduced peripheral vascular resistance. Inability to accomplish these changes places both her and her pregnancy at risk of major placental complications such severe pre-eclampsia (sPE) or severe intra-uterine growth restriction (sIUGR). sPE is characterized by wide-spread maternal vascular dysfunction expressed as increased systemic vascular resistance; this state is accompanied by elevated levels of anti-angiogenic factors and lower production of vasodilatory gases. One of the key molecules implicated in sPE pathogenesis is heme oxygenase-1 (HO-1), a rate-limiting enzyme that breaks down heme into carbon monoxide (CO), biliverdin and free iron. CO and bilirubin (a downstream product of biliverdin processing) account for the angiogenic, vasodilatory and anti-oxidant properties of HO-1. These collective actions of the heme breakdown metabolites generated by HO-1 offer protection against cytotoxicity, inflammation, hypoxia and other forms of cellular stress that are central to the pathogenesis of sPE. Placental HO-1 expression and exhaled CO levels are both lower in women with sPE, consistent with a pathogenic role of HO-1. In vitro experiments demonstrate that induction of HO-1 downregulates secretion of the anti-angiogenic factor soluble fms-like tyrosine kinase-1 (sFLT-1) and increases CO production. Advancing our understanding of regulatory pathways promoting placental HO-1 expression may offer new pharmacological tools to reduce maternal and perinatal morbidity in severe placental insufficiency syndromes, especially in women at greatest risk of developing sPE.

Revisiting the housekeeping genes of human placental development and insufficiency syndromes

Gene expression analysis using semi-quantitative RT-PCR is a common tool in placental research. However the comparison of steady-state gene transcription between different clinical groups is dependent upon comparison of target mRNA data with mRNA obtained from so-called housekeeping (HK) genes whose steady-state transcription does not differ significantly between the groups. In this communication, we evaluated the performance of candidate HK genes across nine clinical groups commonly used in placental research. We used the GeNorm method to evaluate qRT-PCR data to determine the performance of candidate HKs.

Predictive value of hyperhomocysteinemia in pregnant women with chronic hypertension

Objective. To investigate homocysteine ​​levels in pregnant women with chronic hypertension in different terms of pregnancy, and to evaluate the prognostic significance of hyperhomocysteinemia in the development of preeclampsia, placental insufficiency syndrome and fetal growth retardation. Design and methods. It is a cohort prospective study. Pregnant women were divided into 2 groups: group 1 was formed by women with chronic hypertension (n = 80), group 2 consisted of 40 women without hypertension. Results. Pregnant women with chronic hypertension had higher homocysteine ​​levels throughout the pregnancy compared to those without hypertension. Homocysteine ​​level was higher in pregnancy complicated by preeclampsia, placental insufficiency and fetal growth retardation syndrome. Conclusion. Homocysteine ​​levels above 5,8 mmol/l in the III trimester of pregnancy may be used as a prognostic risk factor for preeclampsia development.

Placental size and the prediction of severe early‐onset intrauterine growth restriction in women with low pregnancy‐associated plasma protein‐A

Screening studies for trisomy 21 demonstrate that low maternal serum pregnancy-associated plasma protein-A (PAPP-A) at 11-13 weeks' gestation is associated with stillbirth, intrauterine growth restriction (IUGR) and pre-eclampsia in chromosomally normal fetuses. However, the strength of these associations is too weak to justify screening for these placental insufficiency syndromes. Our objective was to evaluate placental size and uterine artery (UtA) Doppler imaging as second-stage screening tests for women with low PAPP-A. We prospectively studied 90 normal singleton pregnancies with first-trimester PAPP-A </= 0.30 multiples of the median. Maternal serum alpha-fetoprotein (AFP) at 15-18 weeks' gestation, and second-trimester placental size and UtA Doppler indices were assessed as predictors of pregnancy outcome. The risks of IUGR, preterm delivery before 32 weeks' gestation and stillbirth were significantly associated with small placental size (relative risk (RR), 3.96; 95% CI, 2.21-5.98; RR, 3.96; 95% CI, 2.21-5.98; and RR, 6.44, 95% CI, 2.74-14.54, respectively) and elevated AFP (RR, 3.67; 95% CI, 1.78-7.71; RR, 2.48; 95% CI, 1.23-4.94; and RR, 5.14; 95% CI, 1.66-16.85, respectively), but not with abnormal UtA Doppler indices. The combination of elevated AFP and small placental size further increased the risk of IUGR (RR, 4.88; 95% CI, 2.88-5.31), delivery before 32 weeks' gestation (RR, 4.25; 95% CI, 2.38-4.98) and stillbirth (RR, 7.44; 95% CI, 3.04-3.75). Small placental size and elevated AFP, but not UtA Doppler indices, identify women with low PAPP-A at high risk of IUGR, extreme preterm delivery and stillbirth. These additional screening tests may directly improve perinatal outcomes in women with low PAPP-A.

Glial cell missing-1 transcription factor is required for the differentiation of the human trophoblast

Mammalian placentation is a highly regulated process and is dependent on the proper development of specific trophoblast cell lineages. The two major types of trophoblast, villous and extravillous, show mitotic arrest during differentiation. In mice, the transcription factor, glial cell missing-1 (Gcm1), blocks mitosis and is required for syncytiotrophoblast formation and morphogenesis of the labyrinth, the murine equivalent of the villous placenta. The human homolog GCM1 has an analogous expression pattern, but its function is presently unknown. We studied GCM1 function in the human-derived BeWo choriocarcinoma cell line and in first trimester human placental villous and extravillous explants. The GCM1 expression was either inhibited by siRNA and antisense oligonucleotides methods or upregulated by forskolin treatment. Inhibition of GCM1 resulted in an increased rate of proliferation, but prevented de novo syncytiotrophoblast formation in syncytially denuded floating villous explants. GCM1 inhibition prevented extravillous differentiation along the invasive pathway in extravillous explants on matrigel. By contrast, forskolin-induced expression of GCM1 reduced the rate of proliferation and increased the rate of syncytialization in the floating villous explant model. Our studies show that GCM1 has a distinct role in the maintenance, development and turnover of the human trophoblast. Alterations in GCM1 expression or regulation may explain several aspects of two divergent severe placental insufficiency syndromes, namely preeclampsia and intrauterine growth restriction, which cause extreme preterm birth.

Historical Perspectives

This month’s contribution by Dr. Battaglia draws attention to the importance of both birthweight and gestational age in determining neonatal morbidity and mortality. It is hard to imagine the language of neonatology without the terms SGA, AGA, and LGA (small, appropriate, and large for gestational age), but prior to 1967 it was unusual to combine birthweight with gestational age. As Dr. Battaglia points out, small babies were considered to have been born prematurely. It is also interesting to note the mortality statistics in that era. The figures in the original article from Colorado subsequently were revised in a chart that detailed birthweight/gestational age categories by 250 g/1 week groups. (1) 1. ↵ Lubchenco LO, Searle DJ, Brazie JF. Neonatal mortality rate: relationship to birth weight and gestational age. J Pediatr. 1972;81:814–822 [OpenUrl][1][CrossRef][2][PubMed][3][Web of Science][4] # Classification by Birthweight and Gestational Age {#article-title-2} Small for gestational age (SGA), a term that has become widely used and occasionally misused, originated in the 1960s. At that time, neonatal intensive care units (ICUs) were called “premature nurseries” because it was assumed that all babies admitted to those units were preterm infants. Consideration of the small baby born at term or even postterm had led to the use of the term “placental insufficiency syndrome,” but scant attention had been paid to the heterogeneous population that was cared for in “premature nurseries” at that time. Some years earlier, my colleagues and I at Johns Hopkins, Dr Hellegers and Dr Frazier, had published an article examining the outcome of teenage pregnancies. (1) That study alerted us to the fact that clinical problems could be missed with specific study restrictions. For example, if teenage pregnancies included 16- to 19-year-old women, the perinatal mortality rate was not increased compared with women ages 20 to 29 years. Pregnancies in the 16- to 19-year-old group were far more frequent than in girls younger than 15 years of age and masked the high perinatal mortality rate of the latter group. This prompted us … [1]: {openurl}?query=rft.jtitle%253DThe%2BJournal%2Bof%2Bpediatrics%26rft.stitle%253DJ%2BPediatr%26rft.aulast%253DLubchenco%26rft.auinit1%253DL.%2BO.%26rft.volume%253D81%26rft.issue%253D4%26rft.spage%253D814%26rft.epage%253D822%26rft.atitle%253DNeonatal%2Bmortality%2Brate%253A%2Brelationship%2Bto%2Bbirth%2Bweight%2Band%2Bgestational%2Bage.%26rft_id%253Dinfo%253Adoi%252F10.1016%252FS0022-3476%252872%252980114-8%26rft_id%253Dinfo%253Apmid%252F5074362%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [2]: /lookup/external-ref?access_num=10.1016/S0022-3476(72)80114-8&link_type=DOI [3]: /lookup/external-ref?access_num=5074362&link_type=MED&atom=%2Fneoreviews%2F4%2F4%2Fe91.atom [4]: /lookup/external-ref?access_num=A1972N589700027&link_type=ISI

The fetal origins hypothesis: placental insufficiency and inheritance versus maternal malnutrition in well-nourished populations.

The 'Fetal origins hypothesis' states that individuals born small because of malnutrition are predisposed to adult diseases. Fetal malnutrition has two main causes, poor maternal nutrition and placental insufficiency. A distinction between these causes is important because it is likely that maternal nutrition has been sufficient in the majority of populations in which the fetal origins hypothesis has been tested. Thus, placental insufficiency is a more reasonable cause of reduced fetal growth in adequately nourished populations. Placental insufficiency is mainly due to inadequate vascular adaptation at the uteroplacental interface ('poor placentation'). Among women with placental insufficiency syndromes such as pre-eclampsia and 'idiopathic' intrauterine growth retardation, there is an increased prevalence of risk factors for cardiovascular diseases. Maternal cardiovascular risk factors may therefore increase the risk of adult diseases in the offspring both through direct inheritance and by interfering with uteroplacental vascular adaptation. The latter may result in placental insufficiency and fetal growth retardation that by itself could cause adult disease (as the Fetal origins hypothesis states). Alternatively, the association between low birth weight for gestational and adult disease could be an epiphenomenon, leaving inheritance as the main explanation for the fetal origins hypothesis, in adequately nourished populations.

Esx1 is an X-chromosome-imprinted regulator of placental development and fetal growth.

In marsupials and mice, the paternally derived X chromosome is preferentially inactivated in the placental tissues of female embryos. We show here that the X-linked homeobox gene Esx1 (refs 5,6), whose expression is restricted to extraembryonic tissues, is a chromosomally imprinted regulator of placental morphogenesis and trophoblast differentiation. Heterozygous female mice that inherited a mutant Esx1 allele from their father developed normally. Heterozygous females that inherited the Esx1 mutation from their mother, however, were born 20% smaller than normal and are identical in phenotype to hemizygous mutant males and homozygous mutant females. Although Esx1 mutant embryos were initially comparable in size with controls at 13.5 days post coitum (dpc), their placentas were significantly larger. Defects in the morphogenesis of the labyrinthine layer were observed as early as 11.5 dpc. Subsequently, vascularization abnormalities developed at the maternal-fetal interface, causing fetal growth retardation. These results identify Esx1 as the first essential X-chromosome-imprinted regulator of placental development that influences fetal growth, and may aid our understanding human placental insufficiency syndromes.

Monitoring daily insulin needs--an important follow-up parameter in late pregnancy in diabetic mothers?

Pregnancy is a state of natural insulin resistance, which is due to placental production of human placental lactogen (HPL), an insulin antagonising hormone, leading to a remarkable increase of insulin requirement in pregnant diabetics in the 2nd and 3rd trimester. Aim of the prospective study was the quantification of daily insulin requirement during the last 28 days before delivery in pregnant women suffering from insulin-dependent diabetes mellitus (n = 20) with and without evidence of "placental insufficiency syndrome" employing peripheral rheography as indirect parameter for placental haemoperfusion. All diabetic women included controlled carbohydrate metabolism by means of a functional insulin therapy (FIT; HbA1c in normal range < 5.8%), a multiple injection regime with frequent blood glucose self-control at least from the 2nd trimester of pregnancy. According to the results of peripheral rheography in the 34th gestational week, an impedanceplethysmographic method for quantifying peripheral haemoperfusion, patients were subdivided in a group with (B: n = 8) and without (A: n = 12) indirect evidence of placental dysfunction. Groups did not differ in maternal age, duration of diabetes, maternal weight and week of delivery (A: 39.08 +/- 1.44; B: 39.12 +/- 1.46). Mean weight of neonates was lower in group B (3319 +/- 619 g) compared to group A (3613 +/- 437 g). During a comparable state of near-normoglycaemia in both groups, 7 out of 8 women in group B, but only 1 out of 12 women in group A displayed a significant decrease in daily insulin requirement from day -28 to day -3 before delivery (linear regression; p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

A Prostacyclin Analogue Crosses the in Vitro Perfused Human Placenta and Improves Transfer in Some Pathologic States

Placental blood flow is reduced in pregnancies complicated by hypertension, intrauterine growth retardation, maternal smoking, or diabetes. Umbilical-placental production of the potent vasodilator prostacyclin is also reduced in these pathologic states and this deficiency may contribute to an associated increase in the incidence of low infant birthweight by affecting a reduction in placental nutrient transfer. We have studied the effects of the prostacyclin analogue carbacyclin on diffusional transfer in the human placenta perfused in vitro. We have found that carbacyclin crosses the human placenta and can significantly increase diffusional transfer in placenta from pregnancies complicated by hypertension or maternal smoking and in the normal term placenta in which prostacyclin production has first been reduced through the administration of ibuprofen. Carbacyclin had no effect, however, in untreated placenta from normal pregnancies or in placenta from diabetic pregnancies. These results suggest that the prostacyclin-deficient perfused placenta may serve as a model for several placental insufficiency syndromes and that the possibility that prostacyclin analogues may improve deficient nutrient transfer in some pathologic pregnancies warrants further investigation.

Placental toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice

1-Methyl-4-phenyl-,1,2,3,6-tetrahydropyridine (MPTP) is a well-known model substance for inducing in humans and monkeys as a severe extrapyramidal syndrome similar to Parkinson's disease. The neurotoxic action of MPTP can be exerted not only in adult animals but also during fetal development by diaplacental passage. Here we show that, during the gestation period of mice, the placenta is another important target organ of MPTP cytotoxicity. Pregnant NMRI mice on gestation day 15 received a single intraperitoneal dose of 20, 40, or 60 mg/kg MPTP. Developmental parameters of the fetuses and the placentas were determined on gestation day 18. Placental weight was consistently reduced in all experimental groups. Histology showed conspicuous alterations of the labyrinth layer; at 20 mg/kg MPTP there was already a significant reduction of the trabecular diameters and from 40 mg/kg onwards, severe necrosis of the syncytial trophoblast cells. In addition, there were nectoric alterations of the cells of the visceral yolk sac. The toxic effects are confined to the placenta at the doses used in the present experiments, leading at just 60 mg/kg to a marked placental insufficiency syndrome.