When Dr. Isabella Caniggia was two years old, her mother was diagnosed with gestational diabetes as well as pre-eclampsia, a life-threatening pregnancy complication in which a mother’s blood pressure elevates dangerously. Her sister Alessandra’s arrival into the world was bittersweet: She was born with cerebral palsy. Though Alessandra has never been able to walk or talk and requires specialized care, she has always been smart and happy, and an integral part of the Caniggia family.
“She’s a daily reminder to us of how precious life is,” says Dr. Caniggia, who, growing up as one of seven children — and a twin — in Siena, Italy, was devoted to her sister’s care.
It was their special bond that inspired Dr. Caniggia first to become a paediatrician and, ten years later, to improve outcomes for mothers and babies through research. Her focus: understanding and combating pre-eclampsia, which affects five to 10 per cent of pregnancies regardless of a woman’s socioeconomic status or racial background.
Never has this research been more urgent. The condition is on the rise due to a host of factors including increasing maternal age and higher rates of obesity, diabetes, and other health conditions among pregnant women. Worse, pre-eclampsia can negatively affect the health of moms and babies throughout their lives. Women who experience pre-eclampsia are at higher risk of developing cardiovascular disease, high blood pressure and metabolic syndrome earlier in life, while their newborns are at risk for cerebral palsy, blindness, deafness, and other conditions.
According to Dr. John Kingdom, the Rose Torno Chair in Obstetrics and Gynaecology and an associate member of the LTRI, reversing this trend requires a two-step approach. “First, we need to develop a highly precise, cost-effective screening test that can identify women who will develop pre-eclampsia early in their pregnancies,” says Dr. Kingdom. “And second, we need to develop an effective, patient-friendly treatment that can significantly reduce the risk of developing the disease in screen-positive women.”
Predicting risk for pre-eclampsia
“The placenta is the culprit in pre-eclampsia,” explains Dr. Caniggia, a senior investigator at the LTRI whose lab is working to identify molecular biomarkers or “signatures” that can predict early on in a woman’s pregnancy whether she will develop pre-eclampsia. Already, her work has helped define two unique signatures for early-onset and late-onset pre-eclampsia — helping to classify these diseases as distinct disorders disguised by similar clinical symptoms.
Dr. Caniggia’s research looks at factors produced by the placenta and released as “debris” into a mother’s blood stream during pregnancy. Those molecules carry signals that may promote inflammation or cause injury or death in the mother’s blood vessels, triggering a dangerous rise in blood pressure.
She is also studying sphingolipids, molecules that play a key role in cell signaling. She has found that the signature of sphingolipids in pre-eclampsia is very different from those in uterine growth restriction and gestational diabetes — other common and sometimes concurrent pregnancy complications — bringing her team a crucial step closer to developing a diagnostic test that can help doctors identify at-risk women who need to be monitored closely throughout pregnancy.
Dr. Kingdom is also looking to placental “debris” for clues about how the placenta influences changes within the mother’s body. Dr. Kingdom’s lab is studying a class of microparticles called exosomes, the smallest microparticles released into the mother’s bloodstream through the surface of the placenta. These tiny exosomes pass through the mother’s lungs, where they are absorbed by the cells that line the blood vessels (endothelial cells, which are responsible for relaxing the underlying blood vessels) and can interfere with the endothelial cells’ function, causing the mother’s blood pressure to rise and leading to damage to many organs, such as the liver, kidneys and brain. Dr. Kingdom’s research has benefited from the LTRI’s vast expertise in this area: Dr. Jeff Wrana, one of the LTRI’s pre-eminent cancer biologists, has been studying exosomes in cancer for years. Drawing on these resources, Dr. Kingdom’s team is analyzing the microRNA signals inside placental exosomes to identify which of the mother’s endothelial genes may be affected by these signals, causing high blood pressure and organ damage.
Finding new therapies in familiar places
Dr. Kingdom’s team is also breaking ground in developing new therapeutics for treating pre-eclampsia by repurposing heparin, an inexpensive blood thinning drug that reduces the risk of recurrent severe pre-eclampsia in women who have had it during a previous pregnancy.
His lab is investigating the non-blood thinning properties of heparin to learn how the drug helps prevent the disease, and is studying modified forms of heparin that do not thin the blood but otherwise are the same to test the hypothesis that heparin’s benefits in pre-eclampsia are not caused by its blood thinning effects. This is a crucial step in using heparin more widely to treat pre-eclampsia, says Dr. Kingdom, because it’s not ideal for pregnant women to take blood-thinning drugs, since it can make delivery or Caesarian sections more challenging and prevent the safe use of epidurals for pain relief in labour.
The goal is to give a subset of women who — with a new, precise screening test — are identified as likely to develop severe pre-eclampsia an “optimized” version of heparin that can help restore vascular function and lower blood pressure, preventing the onset of the disease, reducing the need for pre-term delivery, and improving the health of both mother and baby in the near and long term, without the negative effects of blood thinning drugs.
Moreover, such a breakthrough would help control healthcare costs across the entire system.
“Every baby that doesn’t require neonatal interventions or spend time in the NICU translates to a massive healthcare savings,” says Dr. Kingdom. “Not just in terms of immediate treatment, but also long-term developmental needs and other costs.”
Solving the problem of pre-term birth
Currently the only way to treat pre-eclampsia is to remove the placenta — and thus deliver the baby prematurely, a solution that strains a pre-term baby’s developing organs, especially its lungs.
“In just over 40 weeks, a single cell becomes a baby,” says Dr. Stephen Lye, the Mount Sinai Hospital Auxiliary Chair in Women’s and Infants’ Health Research and a senior investigator at the LTRI. “It’s a pretty short space of time, and the baby needs all of it.”
Pre-eclampsia is just one of several causes of pre-term birth, a complex condition that affects approximately eight per cent of all deliveries in Canada. Sometimes, as in pre-eclampsia, the baby must be delivered early for the mother’s or baby’s sake. But in 40 to 50 per cent of pre-term births, doctors don’t know what triggers uterine contractions to begin early.
Dr. Lye’s lab is working to change that, and to ultimately prevent babies being born pre-term unless required for the health of the mother or baby. His team recently discovered that the white blood cells found in a mother’s blood stream play a critical role in the timing of labour. Toward the end of pregnancy, in both full- and pre-term births, the uterus releases chemicals into the mother’s blood that activate these white blood cells and prompt them to migrate through the blood stream and into the uterus, where they produce inflammatory chemicals that promote uterine contractions, initiating labour.
The easy accessibility of white blood cells — they can be monitored through routine blood testing — has helped put his team on the road to developing a non-invasive test that can identify women that are at risk of giving birth pre-term many months before they do. Dr. Lye is also collaborating with colleagues in the U.S. to test drug candidates that could prevent the activation of the white blood cells and ultimately delay early onset of labour.
“After much investigation we’ve identified a clear target,” says Dr. Lye. “I’m really optimistic that a new strategy to prevent pre-term birth is close.”
A platform for future discovery: Ontario Birth Study
Supporting this and other research in women’s and infants’ health at Mount Sinai is the Ontario Birth Study (OBS), a major initiative developed by Dr. Lye and Dr. Alan Bocking, a renowned developmental biologist and an associate member of the LTRI, to provide the infrastructure researchers need to understand pregnancy complications and the role that the in utero environment and early childhood play in health and disease.
“The Ontario Birth Study gives us the opportunity to monitor many aspects of pregnancy very closely in a large population of women,” says Dr. Bocking.
In the two years since the study launched, more than 1,000 women — all Mount Sinai patients — have been recruited to participate; now that the infrastructure is in place, Dr. Bocking says the goal is to recruit 1,200 women each year, indefinitely. Participants fill out questionnaires about their health and lifestyle, and allow for a bit more blood, urine or other samples to be collected during routine checkups, providing researchers with a wealth of information about pregnancy.
“I think this study is going to reveal things about pregnancy that we’ve never known,” says Dr. Lye. “What could be better than to understand the health of our own patients? The knowledge we derive from that is directly applied back to the care of the next patient coming into our clinic.”
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