Category: Obstetrics & Gynaecology

Categories : Cardiovascular Disease Obstetrics & GynaecologyTags :

Infertility Treatment Associated with Double the Risk of Postpartum Cardiovascular Disease

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A study by Rutgers Health experts of more than 31 million hospital records shows that infertility treatment patients were twice as likely as those who conceived naturally to be hospitalised with heart disease in the year after delivery. The results were published in the Journal of Internal Medicine.

Compared to those who conceived naturally, patients who underwent infertility treatment 2.16 times as likely be hospitalised for hypertension.

“Postpartum checkups are necessary for all patients, but this study indicates they are particularly important for patients who undergo infertility treatment to achieve a conception,” said Rei Yamada, an obstetrics and gynaecology resident at Rutgers Robert Wood Johnson Medical School and lead author of the study.

The study authors say their results support standards of care that now call for an initial postpartum checkup three weeks after delivery, standards that some health systems have yet to adopt. Much of the elevated risk came in the first month after delivery, particularly for patients who developed dangerously high blood pressure.

“And these results aren’t the only ones to indicate that follow-up should occur early,” said Cande Ananth, chief of the Division of Epidemiology and Biostatistics in the Department of Obstetrics, Gynecology, and Reproductive Sciences at Rutgers Robert Wood Johnson Medical School and senior author of the study. “We have been involved in a series of studies over the past few years that have found serious risks of heart disease and stroke to various high-risk patient populations within those initial 30 days after delivery – risks that could be mitigated with earlier follow-up care.”

The study analysed the Nationwide Readmissions Database, which contains nationally representative data on about 31 million hospital discharges and readmissions per year. The database contains diagnosis codes, which let researchers find specific populations and identify reasons for readmission.

The researchers used data from more than 31 million patients who were discharged following delivery from 2010 to 2018, including 287 813 patients who had undergone any infertility treatment.

Although infertility treatment predicted a sharply elevated risk of heart disease, the study authors said the relative youth of infertility treatment patients kept their overall risk fairly low. Just 550 of every 100 000 women who received infertility treatment and 355 of every 100 000 who conceived naturally were hospitalized with cardiovascular disease in the year after delivery.

The cause of the elevated risk of heart disease associated with infertility treatment remains unclear. The increase in heart disease could stem from the infertility treatments themselves, the underlying medical issues that made patients infertile or some other cause.

“Looking forward, I’d like to see if different types of infertility treatment and, importantly, medications are associated with different risk levels,” said Yamada. “Our data gave no information about which patients had undergone which treatment. More detailed information might also provide insight into how infertility treatment impacts cardiovascular outcomes.”

Source: Rutgers University

Categories : Genetics Obstetrics & GynaecologyTags :

A Tiny Chromosomal Deletion is Linked to Spina Bifida

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A group of researchers at the University of California San Diego School of Medicine led an investigation that offers new insight into the causes of spina bifida, the most common structural disorder of the human nervous system.

The group’s work reveals the first link between spina bifida and a common chromosomal microdeletion in humans. The study demonstrates that individuals carrying this chromosomal deletion – present in one of 2500 live births – demonstrate a risk of spina bifida more than 10 times greater than the general public.

The study, published in Science, also underscores the potential role of folic acid (aka vitamin B-9) in reducing the risk of spina bifida.

Professor Joseph G. Gleeson at Rady Children’s Institute for Genomic Medicine, is the senior author of the study. He explained that spina bifida, also known as meningomyelocele, affects one in every 3000 newborns. Unfortunately, the causes are mostly unknown. A few mutations were reported but could only explain a tiny fraction of risk, Gleeson added.

To uncover the genetic causes of the disease, Gleeson’s UC lab joined with colleagues around the world to establish the Spina Bifida Sequencing Consortium in 2015. The consortium began focusing on a tiny deletion in chromosome 22. Chromosome microdeletions refer to a condition in which several genes in a chromosome are missing. The group’s target condition, known as 22q11.2del, has been implicated in a number of other disorders. They began looking for 22q11.2del in spinal bifida patients.

“All patients we recruited have the most severe form of spina bifida, and all underwent best-practice comprehensive genomic sequencing,” Gleeson said. “We identified 22q11.2del in 6 out of 715 patients. This may not seem a high percentage, but this is by far the most common single genetic variation that could contribute to spina bifida.”

He went on to say the group identified eight additional spina bifida patients who carried the deletion from a cohort of approximately 1500 individuals recruited because of the presence of the common 22q11.2 deletion, Gleeson said.

The researchers then narrowed the cause among the many genes in the 22q11.2 deletion to a single gene known as CRKL. Gleeson explained that there are nine other genes in this chromosomal region that could have been the cause. He said the team began a process of elimination, “knocking out” each of the mouse genes one-by-one, when they received a fortuitous email from Dolores Lamb from Weil Cornell College of Medicine. Lamb had noted some of the mice in their vivarium that were missing Crkl and showed spina bifida. (Study co-first author Keng Ioi Vong, PhD, explained that researchers use all capital letters to describe the gene in humans, and lower-case for mice.) Lamb’s group heard about the Gleeson lab project through the Spina Bifida Association.

“This finding really got us excited because it meant that CRKL disruption might be sufficient for spina bifida,” said Vong. “We removed the mouse Crkl gene ourselves and confirmed that some of the mice developed neural tube defects, including spina bifida.” Most of the other genes in 22q11.2 deletion were subsequently excluded, he added.

They next turned their attention to how folic acid may modulate CRKL-mediated spina bifida. Vong noted that prior studies in humans demonstrated that folic acid supplementation prior to conception reduces the incidence of spina bifida and other neural tube defects by up to 30-50 %, but the mechanisms are still a mystery.

“When we deprived the Crkl mutant female mice of folic acid in their chow, many more of their offspring had neural tube defects, and the severity increased dramatically,” Vong explained. “This suggests that folic acid taken by pregnant women may not only reduce the risk, but also the severity of neural tube defects in their offspring.”

“We hope our findings can help the research community to better understand causes of neural tube defects, especially the causes attributable to common genetic findings like 22q11.2 deletion,” Gleeson said. “We also hope our findings can contribute to healthy pregnancies, improved women’s health, and improved outcomes for children.”

Source: University of California – San Diego

Categories : Obstetrics & GynaecologyTags :

Genetic Defects – not Hypoxia – Behind 1 in 4 Cerebral Palsy Cases

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Photo by Christian Bowen on Unsplash

The world’s largest study of cerebral palsy (CP) genetics has discovered genetic defects are most likely responsible for more than a quarter of cases in Chinese children, rather than a lack of oxygen at birth as previously thought.

The study, published in Nature Medicine, used modern genomic sequencing and found mutations were significantly higher in CP cases with birth asphyxia, indicating a lack of oxygen could be secondary to the underlying genetic defect. The results are consistent with smaller studies globally.

More than 1500 Chinese children with CP were involved in this collaborative effort between the University of Adelaide and Fudan University Shanghai, Zhengzhou University, Zhengzhou and associates.

The Australian team was led by obstetrician and University of Adelaide’s Emeritus Professor Alastair MacLennan AO and human geneticist, Professor Jozef Gecz.

“24.5 percent of Chinese children in the study had rare genetic variations linked to cerebral palsy. This revelation mirrors our earlier findings in our Australian cerebral palsy cohort, where up to one third of cases have genetic causes,” said Professor Gecz, who is the University of Adelaide’s Head of Neurogenetics at the Adelaide Medical School and the Robinson Research Institute.

“Our research shows at least some babies who experience birth asphyxia and are diagnosed with CP may have improper brain development as a result of the underlying genetic variants rather than a lack of oxygen.

“Crucially, clinically actionable treatments were found in 8.5 percent of cases with a genetic cause. It is exciting to see how genetic pathways to cerebral palsy inform tailored treatments for these individuals.”

Cerebral palsy affects movement and posture and is the most common motor disability in children. The disorder is diagnosed in up to 2 per 1000 children globally and is sometimes in association with epilepsy, autism and intellectual difficulties. Symptoms often emerge during infancy and early childhood and can range from mild to severe.

The research team identified 81 genes with causation mutations in the children with CP. These genes are known to play important roles in neural and embryonic development and may affect the molecular pathways responsible for respiration.

Oxygen deprivation frequently claimed in medical litigation

“A lack of oxygen at birth is often claimed to be the cause of CP in medical litigation following a diagnosis and this has led to the presumption that the condition is preventable with better obstetrics or midwifery. This is simply not the case,” said Professor MacLennan, who has spent the past 30 years advocating that there is little scientific evidence to support the myth that cerebral palsy is due to trauma or lack of oxygen at birth.

Professor MacLennan said frequent litigation has been associated with a high increase in “defensive” caesarean delivery and high insurance premiums for obstetricians.

“These results highlight the need for early genetic testing in children with cerebral palsy, especially those with risk factors like birth asphyxia, to ensure they receive the right medical care and treatment.

“All children with cerebral palsy merit modern genetic screening as early and customised interventions really can make a difference and improve their long-term outcomes,” he said.

Ongoing genetic research is also investigating other types of contributing genetic variation to the cause of CP and, as a result, the researchers expect that the overall genetic diagnosis rate is likely to increase.

Source: University of Adelaide

Categories : Injury & Trauma Obstetrics & GynaecologyTags :

Menstrual Cycle Phases Linked to Increased Injury Risk for Female Athletes

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Photo by Ashley Williams

Football players in England’s top-tier WSL were six times more likely to experience a muscle injury in the days leading up to their period compared to when they were on their period, according to a new study published in Medicine & Science in Sports & Exercise.

This the first prospective longitudinal study monitoring menstrual cycles alongside injuries in female footballers. The findings suggest there could be increased injury risk windows at particular times in the cycle.

Despite being a relatively small sample size, the data demonstrates the need to consider the menstrual cycle in elite sports, to reduce injury risk and to support the wellbeing of athletes.

Menstrual cycle symptoms are common and around two thirds of elite athletes feel that these can have negative impacts on their performance. There has been little previous research tracking injuries alongside the menstrual cycle in female sport, despite much speculation and anecdotal evidence suggesting that there may be some key times for increased injury risk. Given the increased professionalism, interest, growth, and investment in women’s sport, the authors say further research in this area is needed.

In this study, researchers at UCL and the University of Bath recorded time-loss injuries and menstrual cycle data for elite female football players across three seasons. All of the players were based at one Women’s Super League (WSL) club, the top tier of women’s football in England. During the study they tracked 593 cycles across 13 390 days, in which time 26 players experienced 74 injuries.

The authors divided each cycle into four main phases in their study. Each phase comes with assumed hormonal changes that have the potential to influence different aspects of a woman’s health and wellbeing.

Ally Barlow, first author of the study from the University of Bath and a physiotherapist at the WSL club, said: “We have been tracking player’s menstrual cycles for a number of seasons to observe trends in terms of symptoms and cycle characteristics. We were interested to learn more about the potential association between injury risk across the menstrual cycle. This study set out to collect specific scientific data so that we could learn more about the menstrual cycle and player’s injury risk.”

Analysis of the data found that players were six times more likely in the pre-menstrual phase (oestrogen and progesterone decrease to bring about the onset of menstruation) and five times more likely in the early-mid luteal phase (after ovulation when both oestrogen and progesterone are assumed to increase and remain high) to experience a muscle injury, compared to when they were in the menstrual phase.

Dr Georgie Bruinvels, senior author of the study from UCL Surgery & Interventional Science and the Institute of Sport, Exercise & Health (ISEH), said: “While these results must be viewed with caution, this data highlights a need to investigate this area further. Given the growth of women’s sport it’s an exciting time to be working in female physiology, but there are a number of known challenges when conducting research with female athletes, in part explaining why there is such a significant sex data gap.

“Conducting large-scale research is complex but must be prioritised to best support female athletes, and we hope studies like this will pave the way for this. Every woman has their own unique physiology, so it’s crucial to support and empower them in the right ways. If future research demonstrates that there are risk windows for certain injury types, we should be proactive in mitigating these risks to enable female athletes to exercise and compete on any given day.”

The authors emphasise that further data collected in a standardised manner is needed before the sports science community can start to look for biological explanations for this increased injury risk.

Dr Jo Blodgett, an author of the study from UCL Surgery & Interventional Science and the Institute of Sport, Exercise & Health (ISEH), said: “Though our sample size for this research was relatively small, we observed clear links between cycle phase and injury prevalence, and the size of the association – six times higher in the premenstrual phase and five times higher in the early-mid luteal phase for muscular injuries – was quite large.

“To better understand the variability in injury risk across the cycle we need more players and teams to continually track injury incidence, menstrual cycle and symptoms in a standardised manner. At the elite level, injuries to your squad can mean the difference between winning and losing, the difference between being crowned champions and runners-up. But perhaps more importantly, it means pain and suffering for players that could perhaps be avoided with better player-centred support.”

Source: University College London

Categories : Obstetrics & Gynaecology Pain ManagementTags :

A Third of Women Experience Migraines Associated with Menstruation

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Of the nearly 20 million women who participated in a U.S. national health survey, one-third reported migraines during menstruation. The analysis was conducted by researchers at Georgetown University Medical Center and Pfizer, Inc., which makes a migraine medication.

Because of the underuse of medications to help treat or prevent menstrual migraines, investigators wanted to understand how common menstrual migraines were and which groups of women could most benefit from potential therapies. The study, presented April 16, at the American Academy of Neurology 2024 Annual Meeting in Denver, also revealed the most common medications taken by those women seeking to prevent menstrual migraines.

“The first step in helping a woman with menstrual migraine is making a diagnosis; the second part is prescribing a treatment; and the third part is finding treatments patients are satisfied with and remain on to reduce disability and improve quality of life,” says the study author, Jessica Ailani, MD, professor of clinical neurology at Georgetown University School of Medicine.

The researchers used the 2021 U.S. National Health and Wellness Survey to analyse responses from women who reported their current migraine treatments, frequency and disabilities via the Migraine Disability Assessment Test (MIDAS), a five-question survey. A migraine headache can cause severe throbbing pain or a pulsing sensation, usually on one side of the head. It’s often accompanied by nausea, vomiting, and extreme sensitivity to light and sound.

“Discrepancies in the incidence of who gets migraine attacks associated with menses is likely due to premenopausal women having more regular menstrual cycles and thus more menstrual-related migraines,” says Ailani, also director of the MedStar Georgetown Headache Center at Medstar Georgetown University Hospital. “Additionally, as women move into their 40’s and become peri-menopausal, there tends to be a greater shift through the month in hormone levels also leading to frequent migraine attacks.”

The survey found that for all women during their menstrual periods, migraine attacks occurred as frequently as 4.5 times and that monthly only migraine headaches lasted 8.4 days, on average; 56.2 % of women had moderate-to-severe migraine-specific disabilities that ranked highest on the MIDAS scale.

When looking at treatments women in the survey used to help control their migraine symptoms, 42.4% used over-the-counter medications while 48.6% used prescription medications. Of the 63.9 % of women who used migraine treatments for acute symptoms, the most commonly used were triptans, a class of drugs developed in the 1990s to quiet overactive nerves associated with migraines and cluster headaches.

Sara’s story

Sara, a 38 year old mother of two, says her migraines are predictably and consistently worse during her period.

“It definitely disrupts my ability to go about my normal activities including at work,” Sara says. “I’m pretty lucky that I’m generally responsive to prescription medication, but I often still have to lie down for an hour or so while the medicine kicks in.”

Sara is being treated preventatively for migraines with Botox. She says over the past couple of months, she’s had a couple of migraines outside of when she gets her period, but that the headaches are definitely worse during menstruation.

“While I had my last period, I had a migraine every day for a week,” Sara says. “It’s starkly different [during menstruation].”

Prevention possibilities

Non-steroidal anti-inflammatory drugs (NSAIDs) are sometimes used as preventive medications for women with regular menstrual periods. In this study, 21.1% of women reported use of any migraine prevention medications or therapies.

“Preventive treatments are used less frequently than acute treatment for migraine,” Alaini said. “In my opinion, this is because preventive therapy is a long-term commitment by both a woman and her clinician to improving the disease process. Migraine is a life-long brain disease without a cure, and the goal of preventive therapy is to reduce disease burden and improve quality of life. Unfortunately, newer disease-specific treatments are costly, so generic older treatments are often used and come with greater side effects.”

Next steps

The researcher’s next steps involve looking at larger databases to see if they can mimic findings on a global scale. They want to determine if women with menstrual-related migraine are frequently turning to non-migraine treatments as was seen in around 53% of their current study group.

“As a headache specialist in the U.S., I know I can do better for women in my clinic, but what can be done for the millions of women who don’t get into a headache clinic? That is our true next step,” says Ailani. “If you have migraines related to your menstrual cycle, discuss this with your gynaecologist or neurologist. There are treatments that can help and if the first treatment tried does not work, do not give up.”

Source: Georgetown University Medical Center

Categories : Ageing Obstetrics & GynaecologyTags :

Pregnancy may Add Months to a Woman’s Biological Age

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Pregnancy may carry a cost, according to a new study involving 1735 young people in the Philippines, and shows that women who reported having been pregnant looked biologically older than women who had never been pregnant, and women who had been pregnant more often looked biologically older than those who reported fewer pregnancies.

Notably, the number of pregnancies fathered was not associated with biological aging among same-aged cohort men, which implies that it is something about pregnancy or breastfeeding specifically that accelerates biological aging. The findings are published in the Proceedings of National Academy of Sciences.
 
This study, from the Columbia University Mailman School of Public Health, builds on epidemiological findings that high fertility can have negative side effects on women’s health and longevity. What was unknown, however, was whether the costs of reproduction were present earlier in life, before disease and age-related decline start to become apparent. Until now, one of the challenges has been quantifying biological aging among the young. This challenge was overcome by using a collection of new tools that use DNA methylation (DNAm) to study different facets of cellular aging, health, and mortality risk. These tools, called ‘epigenetic clocks’ allow researchers to study aging earlier in life, filling a key gap in the study of biological aging.
 
“Epigenetic clocks have revolutionised how we study biological aging across the lifecourse and open up new opportunities to study how and when long-term health costs of reproduction and other life events take hold”, said Calen Ryan, PhD, associate research scientist in the Columbia Aging Center, and lead author.
 
“Our findings suggest that pregnancy speeds up biological aging, and that these effects are apparent in young, high-fertility women,” said Ryan. “Our results are also the first to follow the same women through time, linking changes in each woman’s pregnancy number to changes in her biological age.”
 
The relationship between pregnancy history and biological age persisted even after taking into account various other factors tied to biological aging, such as socioeconomic status, smoking, and genetic variation, but were not present among men from the same sample. This finding, noted Ryan, points to some aspect of bearing children – rather than sociocultural factors associated with early fertility or sexual activity – as a driver of biological aging.
 
Despite the striking nature of the findings, Ryan encourages readers to remember the context: “Many of the reported pregnancies in our baseline measure occurred during late adolescence, when women are still growing. We expect this kind of pregnancy to be particularly challenging for a growing mother, especially if her access to healthcare, resources, or other forms of support is limited.”
 
Ryan also acknowledged that there is more work to do, “We still have a lot to learn about the role of pregnancy and other aspects of reproduction in the aging process. We also do not know the extent to which accelerated epigenetic aging in these particular individuals will manifest as poor health or mortality decades later in life.”
 
Ryan said that our current understanding of epigenetic clocks and how they predict health and mortality comes largely from North America and Europe, but that the aging process can take slightly different forms in the Philippines and other places around the world.

“Ultimately I think our findings highlight the potential long-term impacts of pregnancy on women’s health, and the importance of taking care of new parents, especially young mothers.”

Source: Columbia University’s Mailman School of Public Health

Categories : Mental Health Obstetrics & GynaecologyTags :

Positive Associations between Premenstrual Disorders and Perinatal Depression

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Researchers utilise data from Swedish nationwide registers of over 900 000 women

Photo by Sydney Sims on Unsplash

Women affected by premenstrual disorders have a higher risk of perinatal depression compared with those who do not, according to research published March 28th in the open access journal PLOS Medicine. The relationship works both ways: those with perinatal depression are also more likely to develop premenstrual disorders after pregnancy and childbirth. This study suggests that a common mechanism might contribute to the two conditions.

Menstruating women experience cyclical hormone fluctuations through puberty, menstrual cycle, pregnancy and menopause. Some women have difficult to manage symptoms of low mood and depression during these fluctuations. Between a fifth and a third of women are reportedly affected by premenstrual disorders and 11% of mothers suffer perinatal depression – depressive symptoms during pregnancy and up to 12 months after delivery.

Qian Yang and colleagues at the Karolinska Institutet, Sweden and University of Iceland used the Swedish nationwide registers from 2001 to 2018 and identified 84 949 women with perinatal depression and 849 482 unaffected women. The researchers matched the women on age and calendar year, and further controlled for demographic factors, smoking, BMI, parity and history of psychiatric disorders. Among women with perinatal depression, almost 3% had premenstrual disorders before pregnancy compared with 0.6% of matched unaffected women. Women with perinatal depression were also twice as likely to report premenstrual disorders when the menstruation resumed after childbirth, compared to those unaffected by perinatal depression.

The research sheds light on the association between the two conditions and supports a theory that they may share underlying biological mechanisms and/or risk factors. Understanding this association could help healthcare providers to better target support to women most likely to be affected.

The authors add, “This study reveals a strong bidirectional relationship between perinatal depression and premenstrual disorders, using data from over 900 000 pregnancies. The findings suggest that both disorders may exist on a continuum, and emphasise the importance of recognising these susceptibilities in clinical practice.”

Provided by PLOS

Categories : Metabolic Disorders Obstetrics & GynaecologyTags :

Metformin for Gestational Diabetes may Negatively Impact Offspring

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With the rise in gestational diabetes and metabolic disorders during pregnancy, metformin is also being prescribed more frequently. Although it is known that the oral antidiabetic agent can cross the placental barrier, the impacts on the brain development of the child are largely unknown. Now, researchers have been able to demonstrate in a mouse model that although metformin has positive effects in pregnant animals, it does not in the offspring. The researchers, from German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE), published their findings in Molecular Metabolism.

Around one in six pregnant women worldwide are affected by gestational diabetes. According to the Robert Koch Institute, 63 000 women in Germany were affected by the disease in 2021, and the trend is increasing. Excessively high blood sugar levels during pregnancy are associated with negative consequences for mother and child. It increases the risk of affected women developing type 2 diabetes later on and their children have a higher risk of developing metabolic disorders and being overweight.

Long-term effect of metformin on offspring is unclear

The placenta-crossing oral antidiabetic agent metformin has been gaining importance as an alternative to insulin administration when lifestyle changes fail to treat gestational diabetes. But there are currently only a few studies on the long-term effects of metformin on the health of offspring. It is known that metformin has an impact on the AMPK signaling pathway, which regulates the networking of nerve cells during brain development.

The interdisciplinary team of DIfE researchers led by Junior Research Group Leader Dr Rachel Lippert therefore grappled with two central questions:

Firstly, is metformin treatment only beneficial for the mother or also the child?

Secondly, does metformin treatment lead to long-term negative physiological changes in the offspring, especially in connection with the development of neuronal circuits in the hypothalamus, a critical region in the regulation of energy homeostasis?

Mouse models shed some light

To answer the key questions, the researchers used two mouse models with high-fat or control diets to represent the main causes of gestational diabetes, ie, severe obesity of the mother before pregnancy and excessive weight gain during pregnancy. The antidiabetic treatment of female mice and their offspring took place during the lactation period as this corresponds to the third trimester of a human pregnancy in terms of brain development.

The mice were treated with insulin, metformin, or a placebo, with dosage based on standard human treatments. The research team collected data on the body weight of the mice, analysed various metabolic parameters and hormones, and examined molecular signaling pathways in the hypothalamus.

Maternal metabolic state is crucial

“As a result of antidiabetic treatment in the early postnatal period, we were able to identify alterations in the weight gain and hormonal status of the offspring, which were critically dependent on the metabolic state of the mother,” explains Lippert. Furthermore, sex-specific changes in hypothalamic AMPK signalling in response to metformin exposure were also observed. Together with the metformin-induced shift in the examined hormone levels, the results indicate that the maternal metabolic state must be taken into account before starting the treatment of gestational diabetes.

Focusing on prevention

According to Rachel Lippert, treatment of gestational diabetes in future could entail developing a medication that is available for all and does not cross the placenta. “Given the increasing prevalence, education about gestational diabetes and preventive measures are of vital importance. If we can find a way to manage lifestyle and diet more proactively, we are in a better position to exploit the potential of gestational diabetes treatment,” says Lippert.

Source: Deutsches Zentrum fuer Diabetesforschung DZD

Categories : Obstetrics & GynaecologyTags :

Artificial Intelligence Probes Link between Smoking in Pregnancy and Behavioural Disorders in Newborns

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Although several studies have linked smoking during pregnancy with neurodevelopmental disorders, the results of behavioural experiments in mice prenatally exposed to nicotine have been inconsistent. In a recent study, scientists from Japan developed a deep learning-based framework to automatically observe and classify mice behaviour in such experiments, producing more accurate and unbiased results. In their results, published recently in Cells, they show that prenatal exposure to nicotine could increase the risk of autism spectrum- and attention deficit/hyperactivity disorders in newborns.

The fact that smoking is a risk factor for several diseases, including cancer, stroke, and diabetes, has been known for approximately half a century. However, over the past few decades, scientists have brought to light many of the detrimental effects of smoking during pregnancy, linking this habit to high infant mortality, failed delivery, and low body weight at birth. In addition, recent studies suggest that prenatal nicotine exposure (PNE) may be related to neurodevelopmental disorders, such as attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD).

For a long time now, scientists have used animal models (like rodents) to understand how PNE leads to neurodevelopmental disorders. By carefully analysing the behaviour of rodents, they can infer whether PNE is causing neurological changes and the brain regions affected by it; this can later be confirmed through histological analyses.

Unfortunately, thus far, studies on behavioural changes induced by PNE in mice have shown varied results, some of which are contradictory. Although there could be multiple reasons behind these discrepancies, human error and bias are prime suspects. In general, the assessment of complex animal behaviours, especially social interactions, relies on the efforts of human observers, which introduces a baseline level of subjectivity that is hard to dispel. But what if we can leverage artificial intelligence (AI) to produce more accurate and unbiased results from observations of PNE mice behaviour?

In this study , researchers from the Department of Molecular and Cellular Physiology at the Shinshu University School of Medicine, including graduate student Mengyun Zhou, Assistant Professor Takuma Mori, and Professor Katsuhiko Tabuchi, developed and trained a deep learning-based system to automatically analyse footage from behavioural experiments on mice. They used this tool to explore the behavioural changes induced by PNE in mice without observer biases, seeking to shed light on the link between nicotine and neurodevelopmental disorders.

The proposed AI-based framework relied on a combination of two well-established open-source toolkits, namely DeepLabCut and Simple Behavioral Analysis (SimBA). “AI tools can label the body parts of animals in a markerless video footage and precisely estimate their poses using supervised machine learning,” explains Prof Tabuchi. “Since animal behaviours are defined as a specific arrangement of body parts over a short period of time, deep-learning toolkits like SimBA can use the pose estimations obtained with DeepLabCut to classify different types of animal behaviours.”

After reaching an optimal training protocol for their framework using manually labelled data, the researchers conducted several experiments using PNE and control mice, looking for indicators of ADHD- and ASD-like behaviours. First, they carried out cliff avoidance reaction tests, which are used to test impulsivity. In these tests, they placed the subject mouse on top of a slightly elevated platform and took note, both manually and with the AI system, of how long the mouse waited before jumping down the platform. The test results suggested that PNE mice are more impulsive, a behavioural feature of ADHD in humans.

They also tested the working memory of mice using a Y-shaped maze and counted the number of times each mouse spontaneously switched from one arm of the maze to another. “We observed a decrease in the spontaneous alteration in PNE mice, suggesting that their working memory was altered, which is another behavioural feature of ADHD,” comments Mengyun Zhou. “These results suggest prenatal exposure to nicotine may cause ADHD in mice, which is consistent with clinical reports in humans.”

Finally, the researchers conducted open-field and social-interaction experiments, which represented the main challenge for their AI-based system. In these experiments, the researchers observed either one or two mice behaving freely in a large enclosure and looked for indicators of anxiety and social behaviours, such as grooming and following. Interestingly, PNE mice exhibited social behavioural deficits and increased anxiety which are features of ASD. Subsequent histological analysis of hippocampal brain tissue confirmed decreased neurogenesis, a hallmark of ASD. Thus, it appears that smoking may not only increase the risk of ADHD, but also ASD.

Worth noting, the results obtained using the AI-based system were highly reliable, as Prof Tabuchi highlights: “We validated the accuracy of our behavioural analysis framework by drawing a careful comparison between the results generated by the model and behaviour assessments made by multiple human annotators, which is considered the gold standard.” These analyses cement the potential of the proposed approach and showcase its capabilities for many types of behavioural studies.

With any luck, further efforts will pave the way to a solid understanding of mechanisms behind neurodevelopmental disorders like ASD and ADHD, ultimately leading to better diagnostic tools and therapeutic methods.

Source: Shinshu University

Categories : Obstetrics & GynaecologyTags :

New Study Links Placental Oxygen Levels to Foetal Brain Development

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A new study published in JAMA Network Open shows oxygenation levels in the placenta, formed during the last three months of foetal development, are an important predictor of cortical growth and is likely a predictor of childhood cognition and behaviour.

“Many factors can disrupt healthy brain development in utero, and this study demonstrates the placenta is a crucial mediator between maternal health and foetal brain health,” said Emma Duerden, Canada Research Chair in Neuroscience & Learning Disorders at Western University, Lawson Health Research Institute scientist and senior author of the study.

The connection between placental health and childhood cognition was demonstrated in previous research using ultrasound, but for this study, Duerden, research scientist Emily Nichols and an interdisciplinary team of Western and Lawson researchers used magnetic resonance imaging (MRI), a far superior and more holistic imaging technique. This novel approach to imaging placental growth allows researchers to study neurodevelopmental disorders very early on in life, which could lead to the development of therapies and treatments.

“While ultrasound provides some measure of placental function, it is imprecise and prone to error, so MRI is just a bit more specific and precise,” said Nichols, lead author of the study. “You wouldn’t use MRI necessarily to diagnose placental growth restriction, you would use ultrasound, but MRI gives us a much better way to understand the mechanisms of the placenta and how placental function is affecting the foetal brain.”

The study was led by Duerden and Nichols and co-authored by researchers from the Faculty of Education, Schulich School of Medicine & Dentistry, Western Engineering and Lawson Health Research Institute.

The placenta, an organ that develops in the uterus during pregnancy, is the main conduit for oxygenation and nutrients to a fetus, and a vital endocrine organ during pregnancy.

“Anything a foetus needs to grow and thrive is mostly delivered through the placenta so if there is anything wrong with the placenta, the foetus might not be receiving the nutrients or the levels of oxygenation it needs to thrive,” said Nichols.

Poor nutrition, smoking, cocaine use, chronic hypertension, anaemia, and diabetes may result in foetal growth restriction and may cause problems for the development of the placenta. Foetal growth restriction is relatively common and happens in about six per cent of all pregnancies and globally impacts 30 million pregnancies each year.

“There can be many issues related to the healthy development of the placenta,” said Duerden. “If it does not develop properly, the foetal brain may not get enough oxygen and nutrients, which may affect childhood cognition and behaviour.”

Impact, affect and change

The study revealed that a healthy placenta in the third trimester particularly impacts the cortex and the prefrontal cortex, regions of the child’s brain that are important for learning and memory.

“An unhealthy placenta can place babies at risk for later life learning difficulties, or even something more serious, like a neurodevelopmental disorder,” said Duerden. “This research can open a lot of doors as we still don’t really understand everything there is to know about the placenta. We are just scratching the surface.”

The study, funded by grants from Brain Canada, The Children’s Health Research Institute, Canadian Institutes of Health Research, BrainsCAN and the Molly Towell Perinatal Research Foundation, is also an important first step in biomarking the impact of oxygenation levels in the placenta and considering changes for expectant mothers to deal with less-than-ideal placental conditions.

While oxygenation in the placenta in the third trimester predicts foetal cortical growth (development of the outermost layer of the brain – the cerebral cortex), results of the study indicate it may not affect subcortical maturation, or the deep grey and white matter structures of the brain.

Subcortical structures in the brain, responsible for children’s temperament or motor functions such as the amygdala and basal ganglia, may be more vulnerable to factors affecting the placenta in the second trimester.

“We now have a better understanding of how the placenta affects the cortex. With this basic knowledge, we now have an idea of how these two things are related and we can identify or benchmark healthy levels that lead to brain cortical growth,” said Nichols. “The subcortical regions of the brain appear to be unaffected by placental growth, at least in the healthy samples from our study.”

Duerden, Nichols, and the team scanned pregnant women twice (during their third trimester) for the study at Western’s Translational Imaging Research Facility.

“This is one of the few datasets in the world where there are two scans collected in utero during the third trimester. There are not many groups in the world doing foetal MRI, so it is a super-rich data set that allows us to look at growth over time,” said Duerden. “Western is probably one of the few places where we can do the research because we have the expertise and the facilities to do it.”

Source: University of Western Ontario