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Research Achievements

Research Achievements by the Placenta Clinic

SCREENING CAN CUT STILLBIRTH RISK

HYPOSPADIAS IN MALES WITH INTRAUTERINE GROWTH RESTRICTION DUE TO PLACENTAL INSUFFICIENCY: THE PLACENTAL ROLE IN THE EMBRYOGENESIS OF MALE EXTERNAL GENITALIA

MALE SEX BIAS IN SEVERE PLACENTAL INSUFFICIENCY

DISCOVERING A GENETIC BASIS FOR ELEVATED SFLT-1 RELEASE BY THE PLACENTA


    John Kingdom
 

John Kingdom

SCREENING CAN CUT STILLBIRTH RISK

Mount Sinai Hospital's Dr John Kingdom and Dr Rory Windrim have discovered that the size of a pregnant woman's placenta can determine whether her fetus is at a high risk of stillbirth when she is found to have a low level of PAPP-A in her blood at the 12 week first trimester screening test for Down's syndrome.

A low PAPP-A blood level typically puts the woman into the high risk group for Down's syndrome, causing anxiety until the results of an amniocentesis test are known; however, if the true underlying cause of the low PAPP-A (i.e. placental insufficiency) is not recognized in mid-pregnancy using ultrasound, then stillbirth could occur from lack of appropriate ultrasound monitoring.

The Placenta Clinic research discovered that if women with low PAPP-A are screened during pregnancy with a placental ultrasound, those with placental abnormalities can be monitored effectively and the risk of stillbirth can be significantly reduced by planning delivery while the developing baby is still healthy.

Leslie SMFM 2009 - Low PAPP-A

   
Leslie Proctor presenting her poster at the 2009 SMFM meeting  

 Published in the Sinai Scene, Mount Sinai's bi-weekly newsletter, September 2009. Read the full article.

You can read the abstract of the original article published in Ultrasound in Obstetrics & Gynecology (2009) by Leslie Proctor and Dr John Kingdom. This work was presented by Leslie Proctor at the 2009 Society for Maternal-Fetal Medicine (SMFM) meeting in San Diego, CA.

Leslie Proctor was the Placenta Clinic Research Fellow (2007-2009) and is now a medical student at the University of Toronto. 


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HYPOSPADIAS IN MALES WITH INTRAUTERINE GROWTH RESTRICTION DUE TO PLACENTAL INSUFFICIENCY: THE PLACENTAL ROLE IN THE EMBRYOGENESIS OF MALE EXTERNAL GENITALIA

Hypospadias is malformation of the male genitalia which occurs in approximately 0.3-0.4% of males.  The Placenta Clinic has seen a number of cases of this condition in association with intrauterine growth restriction (IUGR) with placental insufficiency. Dr Yoav Yinon, a fellow in Maternal-Fetal Medicine, chose to study the risk of hypospadias in male IUGR pregnancies in collaboration with Leslie Proctor and Dr John Kingdom. He identified over 40 cases of hypospadias in severe IUGR. The key points of his research findings are that:

  • the degree of hypospadias is correlated to the severity of intrauterine growth restriction (IUGR)

  • the IUGR is due to placental insufficiency

  • the IUGR is of the early-onset type as it is commonly found with low PAPP-A

  • a high proportion of affected pregnancies were conceived using assisted reproductive technologies, like IVF. 

The external male genitalia (penis, scrotum, testes) form early in the first trimester - around weeks 7-8. One reason why hypospadias may be occurring in male pregnancies destined to develop severe IUGR is that an early task of the placenta is to provide the male hormone testosterone to build up the external genitalia.   The implications of these findings, adopted in our Placenta Clinic, are that the sex of an IUGR fetus is medically-relevant. We therefore carefully assess the external genitalia using ultrasound in male IUGR fetuses. If hypospadias is suspected we will offer a discussion session with a pediatrician before birth.  If the baby's sex is in doubt using ultrasound, then amniocentesis may be indicated to distinguish a female developing baby from a male with severe hypospadias. The research has been accepted for publication in American Journal of Medical Genetics and will be published in 2010. See the abstract here.

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MALE SEX BIAS IN SEVERE PLACENTAL INSUFFICIENCY

Several placental complications of pregnancy (see Placental Insufficiency) are thought to have a male bias. In his classic textbook "Hypertensive Complications of Pregnancy", Leon Chesley noted in the 1950's that male offspring were more common if a woman had an eclamptic convulsion (a severe but fortunately very rare complication of pregnancy). Since then both stillbirth and early severe IUGR have been noted to be more common if the developing fetus is male.

 
Ally
    
Ally Murji with his award and John Kingdom
 

We have investigated this possibility using family tree analysis of women who attended the Placenta Clinic between 2002-2007. Across a range of complications (stillbirth, severe IUGR, severe preeclampsia, abruption) that resulted in delivery between 20-32 weeks, more than 74% were found to be male. Family tree analysis showed that this risk is extended to the male, but not female, siblings of an affected male fetus. The male bias is even stronger when a maternal risk factor like chronic hypertension (high blood pressure before becoming pregnant) is excluded.

 

There are two potential mechanisms. The first is genetic and may be on the X chromosome. Since a male fetus has only one X chromosome, if genes on this chromosome are defective, there is no back-up copy to work, compared to a female fetus that has an additional X chromosome (as it is XX, not XY).  A number of genes, and even a candidate region containing a cluster of genes, on the X chromosome are needed for normal placental function. We are presently studying the gene Dusp9 that is located on the X chromosome as a potential genetic link. The second cause has a similar effect but is called epigenetic, meaning that the DNA genetic code is intact and normal, but that the promoter region of the gene has been silenced - so it won't work. A common mechanism to silence a gene is by methylation. We are presently studying the phenomenon of gene methylation in normal and abnormal placental development.

This family tree and genetic analysis work was done by Dr. Ally Murji, MD, a senior Resident in Obstetrics & Gynaecology at the University of Toronto, working with Dr. Kingdom. Ally presented his work to the 2009 Society for Maternal-Fetal Medicine meeting held in San Diego, CA. He gave a superb talk and received the prestigious Resident Research award by the Society. Dr Murji is presently writing up his project for publication and hopes to undertake a Fellowship in Maternal-Fetal Medicine following completion of his Obstetrics & Gynecology Residency.

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DISCOVERING A GENETIC BASIS FOR ELEVATED SFLT-1 RELEASE BY THE PLACENTA

Severe early-onset preeclampsia is a placentally-mediated disease that gradually resolves after delivery. The pathology of the placenta is complex, and is reviewed in pre-eclampsia. The central maternal feature of the disease is elevated blood pressure caused mainly by "spasm" in the arteries, termed increased systemic vascular resistance (SVR).  In normal pregnancy, SVR falls to allow the healthy pregnant woman to lower her blood pressure, despite an increase in her blood volume and cardiac output.  Women destined to develop severe pre-eclampsia fail to lower their blood pressure in mid-pregnancy, have poor weight gain, concentrated blood (relatively high hemoglobin levels) and then develop protein in their urine. The high SVR is now considered to be caused by an antagonist of blood vessel relaxation, called sFlt-1. sFlt-1 is a soluble circulating receptor for vascular endothelial growth factor (VEGF), an important signal that maintains a healthy lining of blood vessels (the endothelium). The placenta destined to cause pre-eclampsia begins to release high levels of sFlt-1 several weeks before the disease of pre-eclampsia is recognized by the doctor, midwife or patient.  Testing for sFlt-1 in the blood is now on the horizon to identify women at high risk of pre-eclampsia.  Soon an "sFlt-1 test" may help in the diagnosis and management of elevated blood pressure in pregnancy.

Molecular biology researchers Dora Baczyk (MSc candidate) and Dr Sascha Drewlo, working with Dr. Kingdom, recently published in the Journal Cell Death and Differentiation.  They described how the transcription factor Glial Cell Missing-1 (GCM-1) is necessary to make the outer layer of the placenta - the syncytiotrophoblast (see Placenta 101).  You can read their abstract here.

GCM-1 levels are deficient in placentas of severely pre-eclamptic women. When GCM-1 levels are reduced in placental samples in the laboratory, our research team showed that this recapitulates many of the features that are found under the microscope in the severely pre-eclamptic placenta.

In March 2009, Sascha presented findings to the International Society for Gynecologic Investigation (SGI) meeting in Glasgow Scotland, demonstrating that when GCM-1 is reduced in developing placental villi at 12 weeks, this causes the placental villi to make sFlt-1 in large amounts. So, reducing GCM-1 produces both the microscopic features of severe pre-eclampsia and the elevation in sFlt-1. For this research, Sascha won a prestigious Wyeth President's achievement award - one of just 25 awards from over 1200 abstracts of scientific research submitted to the meeting. 

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