Women who suffer severe complications during their first pregnancy or delivery are less inclined to have more babies, according to a study published in JAMA by researchers at Karolinska Institutet. For Sweden, given its recent steady decline in birth rate, the researchers propose monitoring in antenatal care to address the problem.
“The clinical monitoring of these women is essential, and they need individualised advice on possible future pregnancies,” says the study’s first author Eleni Tsamantioti, doctoral student at the Department of Medicine in Solna, Karolinska Institutet.
Reduced fertility
Birth rates and fertility have both been in steady decline in Sweden over the past years. In this new population-based study, the researchers have studied the association between severe maternal morbidity in first-time mothers and the likelihood of their having a second baby. The study comprised over a million women in Sweden who had their first baby between 1999 and 2021.
“We found that the likelihood of having more children was much lower in women who had experienced severe complications during their first pregnancy, delivery or postnatal period,” says the study’s last author Neda Razaz, associate professor at the same department. “Such events can often have a physical and mental impact on women for a long time to come.”
All in all, 3.5% of the first-time mothers in the study suffered serious complications and were 12% less likely to have a second baby. Most impacted were women who had experienced cardiac complications, a ruptured uterus or severe mental health problems, who were 50% less likely to have another birth than women who had not experienced such complications.
Monitoring in antenatal care
Women who needed respiratory care or who suffered a cerebrovascular accident like stroke or intracranial haemorrhage were 40% less likely to have a second baby. Acute kidney failure, severe preeclampsia and blood clotting were also associated with a lower probability of a second pregnancy. The researchers also compared the women with any sisters they had to control for familial factors.
“The reasons are hard to speculate on and may result from multiple factors, such as decreased desire for more children, trauma, infertility related to psychiatric medications, or lack of health counselling,” says Tsamantioti. “Proper support and monitoring by antenatal care staff is therefore essential for women who have suffered serious health problems during pregnancy or delivery.”
A world-first study has found low-dose aspirin may treat flu-induced blood vessel inflammation, creating better blood flow to the placenta during pregnancy. Animal studies examined whether the treatment for preeclampsia could be applied to flu infections – and the results, published in Frontiers in Immunology, were very promising.
Lead researcher and RMIT Post-Doctoral Research Fellow, Dr Stella Liong, said that flu infections during pregnancy can resemble preeclampsia, a pregnancy complication that causes inflammation to the aorta and blood vessels. Low-dose aspirin is commonly taken to prevent preeclampsia, as it stops the body from creating chemicals that cause inflammation.
“When the vascular system is inflamed, it leads to poor blood flow and affects the aorta’s function,” she said. “This is especially a problem during pregnancy where good blood flow to the placenta is crucial to the development of the foetus.”
The research, led by RMIT University in collaboration with Trinity College Dublin, Ireland Professor John O’Leary and University of South Australia Professor Doug Brooks, found foetuses and placenta from mice with influenza A were smaller than those from uninfected mice.
Markers of low blood oxygenation and poor blood vessel development were also evident in the foetuses. The mice treated daily with low-dose aspirin had less inflammation and improved foetal development and offspring survival.
While the research was still awaiting human clinical trials, Liong said low-dose aspirin was already recognised as safe to take during pregnancy. The research team however recommended pregnant people seek medical advice before taking new medications.
Brooks said influenza A infections during pregnancy was a big concern as every pregnancy overlaps with part of a flu season.
“There are long term implications for both the mother and the foetus, and aspirin might provide a simple solution for preventing this influenza associated pathology,” Brooks said.
Why flu infection is dangerous during pregnancy
O’Leary said the research findings had huge implications for pregnancy and seasonal influenza virus infections for pregnant people.
“This study shines a light, for the first time, on the role of vascular inflammation associated with influenza virus and the potential dramatic effect of the disease-modifying drug aspirin, in low dosage, in pregnant women with co-morbid influenza,” O’Leary said.
While there weren’t many studies of the impacts of flu infections during pregnancy, project lead and RMIT Professor Stavros Selemidis said it was clear that pregnancy changed how the body responded to the virus.
Liong and Selemidis’ earlier breakthrough research found the flu virus during pregnancy could trigger a damaging hyperactive immune response, causing the virus to spread around the body from the lungs through the blood vessels.
“We used to think the flu virus just stayed in the lungs, but during pregnancy it escapes from the lungs to the rest of the body,” Selemidis said.
“This infection could set you up for cardiovascular disease later in life, but also set up cardiovascular disease in the offspring later in life.”
While vaccination was still the considered the best way to prevent flu infection during pregnancy, Selemidis pointed out vaccination rates were generally low in the pregnant population.
“Low vaccination rates aside, the flu shot may not generate the perfect immune response, especially if someone is pregnant or has an underlying medical condition,” he said.
“That’s why it’s useful to have a potential back up in low-dose aspirin to help prevent vascular dysfunction during pregnancy and improve foetal development.”
A world-first study in animals has found low-dose aspirin may treat flu-induced blood vessel inflammation, creating better blood flow to the placenta during pregnancy. The study, published in Frontiers in Immunology, showed that treatment for preeclampsia could be applied to flu infections – and the results, according to the research team, were very promising.
Lead researcher and RMIT Post-Doctoral Research Fellow, Dr Stella Liong, said flu infections during pregnancy can resemble preeclampsia, a pregnancy complication that causes inflammation to the aorta and blood vessels.
Low-dose aspirin is commonly taken to prevent preeclampsia, as it stops the body from creating chemicals that cause inflammation.
“When the vascular system is inflamed, it leads to poor blood flow and affects the aorta’s function,” she said.
“This is especially a problem during pregnancy where good blood flow to the placenta is crucial to the development of the foetus.”
The research, led by RMIT University in collaboration with Trinity College Dublin, Ireland Professor John O’Leary and University of South Australia Professor Doug Brooks, found foetuses and placenta from mice with influenza A were smaller than those from uninfected mice.
Markers of low oxygen to the blood and poor blood vessel development were also evident in the foetuses.
However, mice treated daily with low-dose aspirin had less inflammation and improved foetal development and offspring survival.
While the research was still awaiting human clinical trials, Liong said low-dose aspirin was already recognised as safe to take during pregnancy.
However, the research team recommended pregnant people seek medical advice before taking new medications.
Brooks said influenza A infections during pregnancy was a big concern as every pregnancy overlaps with part of a flu season.
“There are long term implications for both the mother and the foetus, and aspirin might provide a simple solution for preventing this influenza associated pathology,” Brooks said.
Some individuals with anti-Ro/SSA antibodies (anti–Sjögren’s-syndrome–related antigen A autoantibodies, also called anti-Ro antibodies) have autoimmune diseases such as lupus or Sjögren’s syndrome, but many have no symptoms. A clinical trial published in Arthritis & Rheumatology found that high levels of these antibodies in pregnant women are associated with foetal atrioventricular block (AVB), which occurs when inflammation and subsequent scarring prevent electric signals from the heart’s atria from reaching the ventricles. The disease is associated with life-long pacing and can be fatal.
In the trial, called Surveillance ToPrevent AV Block Likely to Occur Quickly (STOP BLOQ), the incidence of AVB increased with higher levels of anti-Ro/SSA antibodies, reaching 7.7% for those in the top quartile, which increased to 27.3% in those with a previous child who had AVB, although participant numbers in that category were small. Antibody titres did not change over time. The trial also revealed that home-based foetal heart rate monitoring reliably detected conduction abnormalities, which may reduce the need for serial echocardiograms.
“Examining the levels of anti-Ro/SSA antibodies is an important advance since for women with low titres, monitoring is probably not necessary and for those with high titres the increased risk supports surveillance,” said corresponding author Jill Buyon, MD, of NYU Langone Health. She added that this study also indicated that titres of antibodies do not change and that additional factors besides antibodies contribute to risk.
“That home monitoring can rapidly and accurately identify early foetal conduction disease is a major step forward that may significantly decrease the need for echocardiograms and hopefully facilitate reversibility,” added senior author and research professor Bettina Cuneo MD, of the University of Arizona-Tucson College of Medicine.
Researchers report in Nature Communications that they have made ground-breaking progress towards identifying the root cause and potential therapy for preeclampsia. They identified a toxic protein, cis P-tau, in the blood and placenta of preeclampsia patients. This protein is also linked to the development of memory loss after brain injury or Alzheimer’s.
The pregnancy complication affects up to 8% of pregnancies globally and is the leading cause of maternal and foetal mortality due to premature delivery, complications with the placenta and lack of oxygen. It also disproportionately affects women of certain races.
According to the study, led by Drs Kun Ping Lu and Xiao Zhen Zhou at the University of Western Ontario, and Drs Surendra Sharma and Sukanta Jash at Brown University, cis P-tau is a central circulating driver of preeclampsia.
“The root cause of preeclampsia has (so far) remained unknown, and without a known cause there has been no cure. Preterm delivery is the only life-saving measure,” said Lu, professor of biochemistry and oncology at Schulich School of Medicine & Dentistry.
“Our study identifies cis P-tau as a crucial culprit and biomarker for preeclampsia. It can be used for early diagnosis of the complication and is a crucial therapeutic target,” said Sharma.
In 2016, Sharma, a leading preeclampsia researcher, and his team had identified that preeclampsia and diseases like Alzheimer’s had similar root causes related to protein issues. This research builds on that finding.
Until now, cis P-tau was mainly associated with neurological disorders like Alzheimer’s disease, traumatic brain injuries (TBI) and stroke. This association was discovered by Lu and Zhou in 2015 as a result of their decades of research on the role of tau protein in cancer and Alzheimer’s.
An antibody developed by Zhou in 2012 to target only the toxic protein while leaving its healthy counterpart unscathed is currently undergoing clinical trials in human patients suffering from TBI and Alzheimer’s Disease. The antibody has shown promising results in animal models and human cell cultures in treating the brain conditions.
The researchers were curious whether the same antibody could work as a potential treatment for preeclampsia. Upon testing the antibody in mouse models they found astonishing results.
“In this study, we found the cis P-tau antibody efficiently depleted the toxic protein in the blood and placenta, and corrected all features associated with preeclampsia in mice. Clinical features of preeclampsia, like elevated blood pressure, excessive protein in urine and foetal growth restriction, among others, were eliminated and pregnancy was normal,” said Sharma.
Sharma and his team at Brown have been working on developing an assay for early detection of preeclampsia and therapies to treat the condition. He believes the findings of this study have brought them closer to their goal.
Preeclampsia, genetics and the brain
Recent research has also thrown light on preeclampsia’s long-term impacts and possible links to brain health.
“Research has shown that women of certain races have genes that could possibly lead to higher than average blood pressure levels, eventually creating conditions for preeclampsia during pregnancy. However, it’s also true that in many low socio-economic countries there’s no registry to record PE cases. So, its link to other environmental factors is still unclear,” said Sharma.
“Preeclampsia presents immediate dangers to both the mother and foetus, but its long-term effects are less understood and still unfolding,” said Sharma. “Research has suggested a heightened risk of dementia later in life for both mothers who have experienced preeclampsia and their children.” However, the causal link between preeclampsia and dementia is not known.
The researchers say this new study has pinpointed a potential underlying cause of the complex relationship between preeclampsia and brain health.
“Our study adds another layer to this complexity. For the first time, we’ve identified significant levels of cis P-tau outside the brain in the placenta and blood of preeclampsia patients. This suggests a deeper connection between preeclampsia and brain-related issues,” said Jash, the lead author of the study.
As researchers delve deeper, how our bodies respond to stress is also emerging as a potential factor in the onset of preeclampsia.
“Although genetics play a role, factors like stress could be an important piece of the puzzle. Understanding how stress and other environmental factors intersect with biological markers like cis P-tau may offer a more complete picture,” said Jash, assistant professor of molecular biology, cell biology and biochemistry (research) and paediatrics (research) at Brown.
A stress-response enzyme called Pin1
In 1996 and 1997, Lu and Zhou made the ground-breaking discovery of Pin1, which turns out to be a stress-response enzyme. This is a specific protein in the cells that becomes active or changes its behaviour in response to stressors, such as environmental challenges, toxins or physiological changes.
“Pin1 plays a pivotal role in keeping proteins, including the tau protein, in the functional shape during stress. When Pin1 becomes inactivated, it leads to the formation of a toxic, misshapen, variant of tau — cis P-tau,” said Zhou, associate professor, pathology and laboratory medicine at Schulich Medicine & Dentistry.
Interestingly, Pin1 is a key player in cancer signalling networks, turning on numerous cancer-causing proteins and turning off many cancer-suppressing ones. Found in high levels in most human cancers, it’s particularly active in cancer stem cells, which are thought to be central to starting and spreading tumours and are hard to target with existing treatments.
“Essentially, when Pin1 is activated, it can lead to cancer. On the other hand, when there’s a decrease or deactivation in Pin1, it results in the formation of the toxic protein cis P-tau, which leads to memory loss in Alzheimer’s and after TBI or stroke. Now, we’ve uncovered its connection to preeclampsia as well,” said Zhou.
“The results have far-reaching implications. This could revolutionise how we understand and treat a range of conditions, from pregnancy-related issues to brain disorders,” said Lu.
Heparin, commonly prescribed to pregnant women with an inheritable blood clotting condition and a history of recurrent miscarriage does not help to reduce their miscarriage risk, new research has found. The UK-led international study was published in The Lancet.
Researchers are now advising doctors to stop offering the anticoagulant heparin to women and birthing people with inherited thrombophilia, an inherited condition which increase clotting risk.
Despite the lack of evidence and guidance, doctors often prescribe heparin to women with recurrent miscarriage and inherited thrombophilia. It’s costly for health services, and inconvenient for women who must inject the drug daily and are more likely to experience bruising as a result.
The results show that a daily injection of heparin does not improve the chance of a live birth for women who have previously had two or more miscarriages and confirmed inherited thrombophilia, when compared to standard care.
Led by Professor Siobhan Quenby at the University of Warwick, the ALIFE2 trial recruited women from 40 hospitals in Europe and the US.
326 women with inherited thrombophilia and recurrent miscarriage were split into 2 groups; 164 received heparin across the course of their pregnancy, starting from as soon as possible after a positive pregnancy test and ending at the start of labour. 162 were not offered the medication.
All women received standard obstetrician-led care and all women were encouraged to take folic acid.
The rate of live births for each group was roughly the same: 116 women (71.6%) treated with heparin had a baby born alive after 24 weeks’ pregnancy. 112 women (70.9%) in the standard care group had a baby born alive after 24 weeks’ pregnancy.
The risk of other pregnancy complications, including miscarriage, babies with low birth weight, placental abruption, premature birth or pre-eclampsia, was about the same for both groups.
As expected, bruising easily was reported by 73 (45%) of women in the group taking heparin (mostly around injection-sites) and only 16 (10%) in the standard care group.
Professor Siobhan Quenby says, “Based on these findings, we don’t recommend the use of Low Molecular Weight Heparin for women with recurrent pregnancy loss and confirmed inherited thrombophilia.”
“We also suggest that screening for inherited thrombophilia in women with recurrent pregnancy loss is not needed. Patients and doctors will always value knowing about any factor which could be associated with recurrent miscarriage, but the association between inherited thrombophilia and recurrent miscarriage isn’t proven: a recent review of research showed that thrombophilia is as common in the general population as it is in women with recurrent miscarriage.”
“Many women with recurrent miscarriage around the world are tested for inherited thrombophilia and are treated with heparin daily. Research now shows that this screening is not needed, the treatment isn’t effective, and it is giving false hope to many by continuing to offer it as a potential preventive treatment.”
Twenty-eight percent of women who participated in the trial lost their badly wanted pregnancies, and these unexplained losses will be the focus of further study, as our researchers continue to search for answers and treatment to prevent early pregnancy loss.
With growing legalisation and recreational use of cannabis comes a change in attitudes. Research has shown that dispensaries often recommend cannabis for the easing of pregnancy symptoms, especially morning sickness.
Growing evidence links cannabinoid consumption during pregnancy with poor child outcomes, though the exact effects on the developing foetus remain unclear. In a study published in Frontiers in Pediatrics, researchers in the US have now examined how timing of cannabis exposure during pregnancy impacts foetal development.
“We show that even when marijuana use occurred only in the first trimester of pregnancy, birth weight was significant reduced, by more than 150g on average,” said senior author Dr Beth Bailey, professor and director of population health research at Central Michigan University. “If that use continued into the second trimester, newborn head circumference was significantly decreased as well.”
Continued exposure results in largest deficiencies
“These findings are important as newborn size is one of the strongest predictors of later child health and development,” added study first author Dr Phoebe Dodge.
Recent work, including the research by Dodge et al., has shown significant effects of cannabis use on newborn size. “Size deficits were largest among newborns exposed to marijuana throughout gestation,” Bailey explained. The babies born after continued in-utero exposure were nearly 200g lighter, and their head circumference was nearly 1cm less than that of babies who had not been exposed. Pregnancy cannabis use did not significantly predict newborn length in this study.
The effects the scientists observed have also shed light on patterns of use. Their study showed that occasional use, such as for first trimester morning sickness, may reduce fetal growth in the same way as continued use throughout pregnancy. The same is true for other use in early stages, including cases when someone uses cannabis not knowing they are pregnant.
Quitting before pregnancy is best recommendation
The authors pointed out that in their study they did not have information about how much or how often participants used cannabis. Their results were based on whether people did or did not use it at certain times in pregnancy. Therefore, the study could not establish if there was a connection between heavy use and more pronounced outcomes in newborn growth.
More studies are needed to determine whether timing or amount of use is most important when it comes to effects on newborn size, they wrote.
“The best recommendation is that women should be advised to quit marijuana use prior to becoming pregnant,” Dodge said. However, quitting as soon as possible after getting pregnant is the second-best option to avoid long term adverse health and developmental outcomes. “There are some benefits of quitting among those who begin pregnancy using marijuana,” she continued.
A serious neonatal health threat, preterm labour has long mystified researchers – and how does the uterus normally stay dormant, letting it stretch and expand during the 40 weeks it takes a foetus to grow? New research published in The Journal of Physiology suggests that a protein called Piezo1 keeps the uterus relaxed throughout gestation.
Preterm birth is a major cause of neonatal mortality and morbidity. The identification of Piezo1 in the uterus, and its role to maintain relaxation of uterus through stretch-activation during pregnancy, paves the way for drugs and therapies to be developed that could one day treat or delay preterm labour.
The muscular outer layer of the uterus is peculiar because it is the only muscle that it is not regulated by nerves and it must remain dormant for the 40 weeks despite significant expansion and stretch as the foetus develops into a baby. The researchers from University of Nevada USA studied tissue samples of the smooth muscle of the uterus to explore the mechanistic pathways to better understand the dynamics controlling the uterus, how pregnancy is maintained and what maintains quiescence until labour.
Stretching the uterus tissue, to mimic what happens during pregnancy, activates Piezo1 channels. This drives the flow of calcium molecules generating a signalling cascade that activates the enzyme nitric oxide synthase to produce the molecule nitric oxide. This Piezo1 cascade promotes and maintains the dormant state of the uterus.
Piezo1 controls the uterus by working in a dose-dependent manner, where channel activity is stimulated by the chemical Yoda1 and inhibited by a chemical called Dooku1 (Star Wars fans will no doubt recognise the inspiration behind these two names). When Piezo1 is upregulated, the uterus remains in a relaxed state. However, in preterm tissue, the expression of Piezo1 is significantly downregulated, ‘switching off’ the dormant signalling to the muscle, so the uterus contracts and initiates labour.
Professor Iain Buxton at the Myometrial Research Group at the University of Nevada said: “Pregnancy is the most impressive example of a human muscle enduring mechanical stress for a prolonged period. Finding Piezo1 in the muscular layer of the uterus means the uterus is controlled locally and is coordinated by a stretch-activated mechanism rather than hormonal influence from the ovaries or the placenta, which has been the assumption.
“It is troubling that there are still no drugs available to stop preterm labour. Thanks to the Nobel Prize winning discovery of Piezo proteins, which are responsible for how the body responds to mechanical force, and our investigation we are now closer to developing a treatment. Piezo1 and its relaxation mechanism provide a target for us which we could potentially activate with drugs. We need to test this with further studies and we hope to carry out clinical trials in the future.”
Contraction and relaxation were assessed in tissue samples compared for the following gestational periods: non-pregnant, term non-labouring, term labouring, preterm non-labouring and preterm labouring. The presence of Piezo1 channels was discovered using molecular tools while pregnant tissues contracting in a muscle bath were stimulated with Piezo1 channel activator and inhibitor to characterize the regulation of quiescence.
More research is needed to understand just how all the molecular signals and steps involved in the Piezo1 channel regulate uterus relaxation, and to identify other chemicals that may be involved.
COVID vaccination during pregnancy is not associated with a higher risk of pregnancy complications, according to a large scale Swedish and Norwegian study published in the journal JAMA.
The study, which comprised almost 160 000 pregnancies, found there to be no increase in the risk of preterm birth, growth retardation, low Apgar scores at birth or the need for neonatal care after vaccination against COVID during pregnancy.
“The results are reassuring and can hopefully make pregnant individuals more willing to get vaccinated,” said co-first author Anne Örtqvist Rosin, researcher at the Department of Medicine, Karolinska Institutet.
Studies have shown that, compared to non-pregnant peers, pregnant women are at risk of serious COVID requiring intensive care with a higher risk of death. Preterm births are also more likely in pregnant women with severe COVID. COVID vaccines have been available in Sweden and Norway since January 2021, and in May 2021 Sweden recommended all pregnant individuals to have a COVID jab, followed in August by Norway.
“We’re still seeing that vaccination rates are lower than in the rest of the population, so it’s likely that there’s some concern about how the vaccines affect the pregnant individual and the foetus,” explained Dr Örtqvist Rosin. “When the vaccines were produced, pregnant women were not included in the large clinical studies, and until now there have been no population-based data about any risk there might be to them.”
The researchers linked Sweden’s Pregnancy Register and Norway’s Medical Birth Register to each country’s vaccination register to obtain data on if and when pregnant individuals were vaccinated and with which vaccine. The study included a total of 157 521 individuals who gave birth between January 2021 and January 2022, of whom 18% had been vaccinated. It was found that vaccinated individuals were at no higher risk than unvaccinated of developing one of the studied complications.
The majority of the pregnant individuals included in the study were vaccinated after week 12 in accordance with current recommendations, and 95% received an mRNA vaccine. This should be factored in when interpreting the results, which were similar for the different mRNA vaccines regardless of whether one or two doses were given. Vaccination during the third trimester and vaccination with the Moderna vaccine was associated with a slightly lower risk of needing neonatal care.
A possible benefit of vaccination during pregnancy is that the antibodies generated pass through the placenta, conferring a certain degree of protection against COVID to the newborn baby.
“We’re now planning to study how long this protection lasts, and if SARS-CoV-2 infection or vaccination during pregnancy has any other lasting effects on the child’s health,” said joint last author Professor Olof Stephansson at the Karolinska Institutet .
