Placenta

Placenta’s Role in Brain Development Linked to Child Cognition

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Summary: A new study reveals the oxygenation levels in the placenta during the last trimester of pregnancy are a key predictor of the development of the cerebral cortex and likely childhood cognition and behavior.

Utilizing magnetic resonance imaging (MRI) for a more accurate assessment of placental health, the study offers new insights into how the placenta mediates the impact of maternal health on fetal brain development.

This research not only underscores the placenta’s critical role in early neurodevelopment but also opens the door to potential early interventions and treatments for neurodevelopmental disorders.

Key Facts:

  1. MRI Over Ultrasound: MRI provides a more specific and precise imaging of placental growth and its impact on fetal brain development compared to traditional ultrasound.
  2. Impact on Cortical Growth: Healthy placental oxygenation levels in the third trimester are crucial for the development of the cerebral cortex, which plays a significant role in learning and memory.
  3. Potential for Early Intervention: The findings highlight the importance of monitoring placental health for early detection of potential cognitive and behavioral issues in children, pointing towards new directions for prenatal care and interventions.

Source: University of Western Ontario

A new study shows oxygenation levels in the placenta, formed during the last three months of fetal development, are an important predictor of cortical growth (development of the outermost layer of the brain or cerebral cortex) 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 fetal 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.

This shows a mom and baby.
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. Credit: Neuroscience NewsSubcortical 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.

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 fetal brain.”

The study, published today in the high impact journal JAMA Network Open, 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 fetus needs to grow and thrive is mostly delivered through the placenta so if there is anything wrong with the placenta, the fetus might not be receiving the nutrients or the levels of oxygenation it needs to thrive,” said Nichols.

Poor nutrition, smoking, cocaine use, chronic hypertension, anemia, and diabetes may result in fetal growth restriction and may cause problems for the development of the placenta. Fetal 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 fetal 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 fetal 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 gray 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 fetal 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.”

Abstract

T2* Mapping of Placental Oxygenation to Estimate Fetal Cortical and Subcortical Maturation

Placental dysfunction is associated with a decrease in nutrients and oxygen to the fetus; the gestational age at which this happens varies depending on severity but is an important factor in outcome as it relates to when and which brain structures are most at risk.

Evidence from Doppler ultrasonography of fetuses affected by severe placental dysfunction leading to intrauterine growth restriction (IUGR) suggests blood flow distribution occurs in a hierarchical manner. In IUGR, oxygenated blood is directed toward the brain, away from other fetal organs (except the fetal heart), a process referred to as brain sparing.

Further evidence suggests that subcortical regions critical for homeostasis receive more blood flow, at the cost of cortical regions involved in higher-order functions.

Although Doppler findings suggest that cortical regions show more variability to placental oxygenation changes, a Cochrane review found that the evidence was of moderate to low quality, indicating the need for more sensitive techniques to study how placental function affects the brain.

Recent work has demonstrated an association between a magnetic resonance imaging (MRI)–based measure of placental oxygenation, transverse relaxation time (T2*), and birth weight,2 suggesting that T2* may similarly estimate variations in fetal brain development.

To determine whether placental MRI-based methods could provide a biomarker of fetal brain development, we investigated the association between placental T2* and cortical and subcortical fetal brain volumes in typically developing fetuses scanned longitudinally in the third trimester. We hypothesized that in fetuses with reduced placental oxygenation, cortical brain regions would show reduced volumes relative to subcortical regions.

Lab-grown placenta organoids offer insights into pregnancy disorders

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Placental organoid (circle in the centre). Trophoblast cells are invading out of the organoid, mimicking placental cells invading the uterus in the early weeks of pregnancy.

Placental organoid (circle in the centre). Trophoblast cells are invading out of the organoid, mimicking placental cells invading the uterus in the early weeks of pregnancy.

Researchers have created “mini-placentas,” which serve as biological models of the initial phases of placental development. 

This laboratory-created artificial placental organoid has the potential to reveal key details about the early stages of pregnancy, which is often referred to as the “black box of human development.”

Researchers at the University of Cambridge created these mini-placentas, also known as trophoblast organoids. Trophoblast cells provide nourishment to the embryo and contribute significantly to the creation of the placenta.

Early phases of placental development

The team hopes that their model could potentially enhance experts’ understanding of pregnancy disorders, including pre-eclampsia, and could lay the groundwork for future therapeutic advancements

Pre-eclampsia, which affects around six out of every hundred first pregnancies, is a disorder characterized by elevated blood pressure when pregnant. It can pose serious health concerns to both the mother and the baby. 

“The study shows that it is possible to experiment on a developing human placenta, rather than merely observe specimens, in order to study major disorders of pregnancy,” mentioned the release. 

Furthermore, this small organoid might help researchers better understand how the placenta interacts with the womb’s inner lining (endometrium).

The interactions between the cells of the endometrium and the placenta play a crucial role in determining the success of a pregnancy. These interactions play a vital role in amplifying the maternal blood supply to the placenta, which is required for the proper growth and development of the fetus.

Insights into pregnancy disorders

Professor Ashley Moffett, from the Department of Pathology at the University of Cambridge, highlighted the importance of studying the first few weeks of placental development.

“Most of the major disorders of pregnancy – pre-eclampsia, stillbirth, growth restriction, for example – depend on failings in the way the placenta develops in the first few weeks. This is a process that is incredibly difficult to study – the period after implantation, when the placenta embeds itself into the endometrium,” Moffett explained.  

Moffett further added in the release: “Over the past few years, many scientists – including several at Cambridge – have developed embryo-like models to help us understand early pre-implantation development. But further development is impeded because we understand so little about the interactions between the placenta and the uterus.” 

These lab-grown placenta models have the potential to advance reproductive disease research and help discover future therapies for problems affecting early pregnancy.

The development and study of mini-placentas represent a significant step forward in the effort to enhance mother and fetal health throughout pregnancy.

The study was published in the journal Cell Stem Cell.

In Addition to Testosterone, Another Hormone Is Vital for Early Male Development

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A hormone called androsterone, produced in the placenta and other organs, plays a role in fetal development in the womb

Baby
While testosterone plays a significant role in fetal development, it is not the only hormone that influences masculinization. 

Often the first question parents are asked after the birth of their child is “congratulations, girl or boy?” For parents of one in 2,000 to 4,000 births, however, there is not an easy answer. This is when the baby has “ambiguous” genitalia, where it is not clear which sex they belong to. In baby boys, this was long thought to be caused by problems linked to testosterone—as were more common disorders such as undescended testicles and malformed penises, which respectively occur in 9 percent and 1 percent of births.

But now it is clear that the reality is slightly different. According to new research in which I am a co-author, another hormone known as androsterone—which originates in the placenta and fetal adrenal gland—is also vital to the process that turns fetuses in boys. These insights have the potential to make a big difference to how we treat sexual disorders in male babies in future—and are also relevant to the whole debate about male and female identity.

Even small children are aware that men and women usually look different. It is common knowledge that boys become men because the testes of the man produce the “male” hormone testosterone and, in turn, testosterone makes men masculine. We know this thanks to the French endocrinologist Alfred Jost’s groundbreaking studies in the early 1950s.

There are several times in boys’ lives in which bursts of testosterone play a key role in their development as males. The most well known is of course puberty, in which the testes start making much more testosterone. This makes boys hairier, grows their genitals and makes their voices break.

The other times are the “mini-puberty” that takes place at around three months after birth, which leads certain changes in the testes and brain; and when a boy is still a fetus in the womb, around three months into his mother’s pregnancy. While all these bursts of testosterone are probably very important in making a normal male, it is the one in the womb that affects whether the child will be a boy at all. What is now clear is that testosterone and the testes have been hogging the podium when in fact we need to share the honors around.

Testosterone and super-testosterone

Testosterone is part a family of male sex hormones called androgens. To get a normal male, testosterone needs to be turned into another androgen called dihyrotestosterone or DHT, a “super-testosterone” that is five times more potent than its cousin. This conversion is done in the tissue of what will become the penis, along with the other parts of the body that develop male characteristics. The consequences of the process are clear: boys who cannot turn testosterone into DHT are born looking female and only become more obviously male at puberty.

These include the Guevedoces in the Dominican Republic, who, due to a genetic mutation, lack the enzymes to make the DHT conversion. Studying these extraordinary children in the early 1970s led the American researcher Julianne Imperato-McGinley to develop the drug finasteride to treat prostate cancer.

For years, this story was considered complete—masculinization was due to testosterone and the conversion of testosterone to DHT. Then an Australian zoologist named Marilyn Renfree, in an elegant series of studies in the 2000s, published the first evidence that things may not be that simple. She was actually studying wallabies, since the young in the pouch were easily accessible for experimental purposes and they mimic much of the period of pregnancy in humans and other mammals with placentas. Renfree found that the genitals of the young male wallabies made DHT even without testosterone from their testes. The only reliable conclusion was that they were converting other androgens to DHT.

It became clear that there are two ways to make a “male signal” in a wallaby fetus, both of which are necessary to normal sexual development. The first is by testosterone from the testes. The second is through different androgens that can also be made by other organs in the human, including the fetus’s adrenal glands, liver and the placenta. These other processes came to be known as the “backdoor” pathway.

But was the same thing true in humans? It was later shown that it was, by studying male human newborns who were not properly masculinized; they had undescended testes and ambiguous genitals, despite having testes that made testosterone. It turned out they were unable to make the backdoor androgens because they had mutations in the genes of enzymes that were key to the process of the conversion into DHT.

As further evidence that both types of male signal are essential to normal development of human male fetuses, it was also discovered that fetuses whose placentas are not working properly are around twice as likely to be born with undescended testes or with malformed penises—especially if they are also born abnormally small (for their gestational age).

What we have shown

In our research, which also involved the University of Glasgow and French and Swedish collaborators, we have been able to explain why. We measured the levels of different male sex hormones in the blood of male and female fetuses, and were surprised to find that only two androgens were higher in males than females: testosterone and androsterone. The relevance to the placenta is that it is up to 6,000 times heavier than the fetus and it makes large amounts of a hormone called progesterone, which it can convert into androsterone—as can the fetal liver and adrenal glands. The human fetuses’ testes have no ability to make this conversion.

Fetus Development
Fetal development.

We then also showed that the testosterone and androsterone were converted into DHT in male target tissues like the penis. And not only are both androgens required to masculinize the fetus, there can be abnormalities where levels are lower than normal: for example, a good index of the degree of masculinization is the distance between the anus and genitals, and this is shorter than usual in newborns with malformed penises.

People affected by disorders of sexual development, including malformed penises, can have a very difficult time and face delicate surgery, hormone therapy and other treatments. Every new piece of information into how masculinization happens raises the prospect of improving when and how these disorders are detected and treated in future. Early enough diagnosis of reduced placental function related to androgen production in early pregnancy might enable treatment before penis formation is complete, avoiding the need for corrective surgery later in life.

A final take-home message from our study is that while testosterone and androsterone are indeed higher on average in male than female fetuses, the difference is quite small. There is also considerable overlap between the lowest levels in boys and the highest levels in girls. Those in society who are adamant that the only choice for people is a binary choice of man or woman are not basing their views on biological reality. Treasured beliefs about the supremacy of testosterone and the testes in making a man are also obviously flawed.

4 Research-Backed Supplements to Boost Your Hair, Skin, and Nails

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fish oilCollagen. Biotin. Shark cartilage. Frankincense. Even… placenta? Every day, patients in my dermatology practice ask about supplements claiming to restore or improve the skin, hair, or nails. But do they, really?

Unlike medicines, which are regulated by the Food & Drug Administration, over-the-counter supplements are subject to little oversight. There is no guarantee that their claims or ingredients are backed by science (or that the ingredients on the label are actually even in the tablet) – making the supplement aisle the wild west of every pharmacy. While no vitamin or supplement should ever be taken without consulting a physician first, there are a few that are backed by scientific research showing that they may have a positive effect on our strands, skin, or nails. Here are some of them.

For skin cancer prevention: Vitamin B3, also called nicotinamide, has been shown to lower the risk of nonmelanoma skin cancers (such as basal cell carcinoma or squamous cell carcinoma) and precancerous growths (called actinic keratoses). In a 2015 New England Journal of Medicine study of more than 600 patients with a history of skin cancer, 500mg of B3 taken twice daily led to a 23% drop in new cancerous growths over 1 year. Sun protection remains the most important way to lower skin cancer risk – but those stats aren’t too shabby, for a vitamin.

For brittle nails: Biotin (also called vitamin H or B7) was shown to increase nail plate thickness by 25% in patients with brittle nails, while reducing splitting and improving nail smoothness, according to studies from the Journal of the American Academy of Dermatology (JAAD) and Cutis. The optimal dose isn’t known, but dermatologists have suggested 2.5mg daily for those with delicate nails. Just be sure to let your doctor know if you take biotin, and consider holding off on the vitamin prior to any bloodwork: In 2017, the FDA issued a warning that it can interfere with certain lab tests, including some measuring cardiovascular and thyroid levels.

For thinning hair: As a dermatologist, I never used to recommend dietary supplements for patients with sparse or shedding hair, unless there was a specific nutritional or medical issue to correct. Now I sometimes do for patients with male or female pattern hair loss – the gradual thinning many of us are prone to later in life. Small, randomized, double-blind, placebo-controlled studies of men and women with thinning hair, published in the Journal of Cosmetic Dermatology and Dermatology Research and Practice, showed a significant increase in hair density with reduced shedding over 3 to 6 months on a marine supplement called Viviscal. And the plant-based Nutrafol led to an increased number of hairs, with increased thickness, volume and growth rate in women over 3 to 6 months, according to a May 2018 study from the Journal of Drugs in Dermatology. This supplement contains ingredients said to reduce inflammation, antioxidants to help guard against cell-damage, and saw palmetto, which may inhibit hormonal factors that can contribute to hair thinning.

For psoriasis: Fish oil supplements may help to alleviate rashes in those suffering from psoriasis – a chronic condition of scaly, pink skin that often affects the elbows, knees, scalp, and other areas. A 2014 meta-analysis published in JAAD showed a moderate benefit in psoriasis – reduced area of rash, and improved thickness and redness of psoriasis – after supplementing with omega-3 polyunsaturated fatty acids from fish oils (eicosapentanoic acid, EPA, and docosahexanoic acid, DHA). The study authors suggested doses of 0.45 to 13.5 grams of EPA and up to 9 grams of DHA daily – and explained that the supplements are expected to be most helpful when used along with established psoriasis medications.

For whatever ails you: If there’s a supplement you believe in, it might just work – due to the powerful placebo effect. Decades of research have shown that the expectation of results is sometimes enough to actually see results. That’s one reason I don’t discourage vitamins that have a decent safety profile, if a patient truly believes in them.

But before starting any supplement, be sure to talk to your doctor to find out if it’s right for you and whether it’s safe to take with other medicines.

The Womb Makes It Easy Being A Girl: How The Placenta Protects Girls More Than Boys

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In the battle of the sexes, a new study suggests that girls have a natural advantage over boys. Researchers have found that the answer to why women carrying baby girls statistically have easier pregnancies than those carrying baby boys lies in the placenta.

shutterstock_133423679

In the study published in Molecular Human Reproduction,  it was found that genes produced by the placenta are different in males and females. “We found that with female babies, there is much higher expression of genes involved in placental development, the maintenance of pregnancy, and maternal immune tolerance,” said study co-author Sam Buckberry, a graduate student at Adelaide, as reported by HealthDay. It is known that pregnancies are more likely to have bad outcomes if the baby is a boy. This is partly due to the fact that boys grow faster from the moment of conception, and this puts them at a higher risk to lacking nutrition. This is modelled by the observation that the number of boy births fell in contrast to the number of girls during the famine in Holland during WWII.

“We’ve known for some time that girls are clearly winning in the battle for survival,” said Claire Roberts, lead author of the study, according to HealthDay. This study’s results can explain why female babies are less likely to have a preterm birth, still birth, neonatal death, or macrosomia — a baby that weighs more than 8 lbs., 13 ounces at birth. This production of different genes in the placenta can also explain other gender differences that exist throughout life. “Male babies generally grow faster and bigger than females. This occurs in both the animal and human worlds, but until now we haven’t really understood how or why,” Roberts added.

Our genes help to determine whether our bodies will develop as female or male. Most humans are born with 46 chromosomes in 23 pairs. Men have one X chromosome and one Y, while women have two copies of the X chromosome. The biological difference between men and women is a result of sex determination and differentiation. Determination, which happens at conception, controls whether an embryo will develop into a male or female. Differentiation is the actual development of the given sex.

Results from this study could possibly help scientists develop gender-specific treatment options for pregnant women, the researchers said.