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Study reveals how assisted reproduction affects placenta and child’s growth

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Approximately one in six couples trying to have a child experiences infertility. Each year, over five percent of children in Finland are born with the help of Assisted Reproductive Technology (ART), and to date, over ten million children worldwide have been conceived using these techniques.

Although ART-conceived children are generally healthy, a slightly increased risk of growth disturbances as well as cardiovascular, metabolic, and neurodevelopmental disorders has been observed. The underlying causes of the risks, and whether they result from the ART procedures or parental subfertility, are unknown.

To understand the molecular mechanisms behind ART-associated risks, researchers have examined newborns and placentas from 80 ART and 77 spontaneous pregnancies. When the placentas were compared, they considered different ART methods as well as the children´s sex for the first time.

The placenta has proven to be an extremely fascinating organ which connects the mother and the foetus, mediates environmental effects on the foetus and influences foetal development.

“The placenta offers a unique window into the very early developmental stages, which are otherwise difficult to study in human”, says associate professor Nina Kaminen-Ahola, the leader of the study in the University of Helsinki.

Frozen embryo transfer resembles natural pregnancy

Genome-wide placental gene function and DNA methylation, the most well-known epigenetic mark involved in gene regulation, were examined. Also, potential connections between the observed changes and the placental weight as well as newborns’ weight and height were studied.

One of the most interesting findings concerned the two commonly used ART methods, fresh and frozen embryo transfer. In the fresh embryo transfer, the IVF-fertilised embryo is transferred directly from the culture dish into the uterus, while in the frozen embryo transfer the embryo is frozen for a varying period before the transfer.

Several studies have discovered that placentas and children from fresh embryo transfer are smaller on average compared to those from frozen embryo transfer. This was also the case in the current study. Particularly, it was seen that the observed changes related to metabolism and growth were specific only to placentas from fresh embryo transfers.

“Almost all placentas from frozen embryo transfers had been transferred into the uterus during the mother’s natural cycle, rather than during an artificial hormone surge as in the case with fresh embryo transfers. Consequently, the onset of pregnancy in these cases resemble more spontaneous pregnancies,” explains Pauliina Auvinen, the doctoral researcher on the project.

Altered gene is linked to obesity and diabetes

In addition, the researchers identified altered function of a gene called DLK1. The expression of this gene was reduced in both ART placentas and in placentas from pregnancies of subfertile couples who had applied for fertilization treatment but who got pregnant spontaneously.

The DLK1 gene regulates metabolism and has been associated previously with obesity and type 2 diabetes. Additionally, it can have a role in maternal physiological adaptations to pregnancy.

According to a previous mouse study, Dlk1 is essential for proper maternal fasting response during pregnancy, enabling the switch to using fat for energy resource and thereby securing foetal growth. Silencing of Dlk1 was also associated with the offspring’s lower birth weight.

Kaminen-Ahola says that the silencing of DLK1 gene has also been linked to low birth weight in humans.

“The role of this gene in subfertility and the increasing metabolic disorders such as obesity and type 2 diabetes,” needs to be further clarified.

More research needed

Despite the significant new results, more samples need to be collected to better understand the effects of the different fertility treatment methods, subfertility, and sex on the children´s development and health. In addition, understanding the long-term impact of ART requires long-term monitoring of the children.

“Based on the results, it will be possible to improve ART treatments and understand the causes of sub- and infertility. We are continuously collecting more samples, and we warmly thank all the families for participating in the epiART study,” said Kaminen-Ahola.

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UK reviews surrogacy firm over rejected insurance claims

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The UK government is reviewing a surrogacy firm after complaints that medical insurance claims involving surrogates in Mexico were rejected.

The Department of Health and Social Care (DHSC) is considering whether UK-based provider My Surrogacy Journey should remain listed on gov.uk as one of four domestic surrogacy agencies available to intended parents.

The review follows allegations concerning its Mexican sister company, where surrogates are based.

Health minister Diana Johnson said: “The department is looking into the allegations about My Surrogacy Journey.

“As part of that assessment, the department will consider whether it is appropriate for that company to remain on the gov.uk list of agencies.”

Emails sent by My Surrogacy Journey chief executive Michael Johnson-Ellis and seen by the Guardian suggest multiple surrogate women in Mexico had their insurance claims rejected.

The emails also suggest 300 couples using the company were moved to a new insurance provider because of the increased risk of claims being rejected.

Commercial surrogacy is banned in the UK, where only altruistic arrangements are permitted.

My Surrogacy Journey operates a not-for-profit UK branch alongside for-profit sister companies in Mexico and the US. All three companies have the same owners and chief executives.

The reported insurance issues relate to surrogacy arrangements in Mexico.

One couple told the Guardian they paid tens of thousands of pounds to cover medical costs after their surrogate had a hysterectomy during childbirth and an insurance claim was refused.

The Guardian said it understood that at least five sets of parents said they had to cover medical costs after insurance claims were rejected.

In an email to the couple whose surrogate underwent a hysterectomy, Johnson-Ellis wrote: “We have already told you that the insurance companies have been declining some of the claims and we are actively working with the broker to get this issue resolved but you should also consider that they may not be paid out and there is nothing we are able to do to change this …

“We appreciate this is not an insignificant sum but this genuinely is out of our control.”

Johnson-Ellis also said the company had switched insurance providers, writing: “We’re also managing this for 300 other journeys, which is a complex position to be in.”

Lawyers acting for My Surrogacy Journey said the company did not comment on individual cases, but that existing insurance policies were in place and claims continued to be accepted and processed.

They said the company understood that a small number of claims had been rejected and was supporting people seeking to resolve those claims with an insurer.

Under the surrogacy arrangements, intended parents are understood to be contractually required to cover medical costs not paid by an insurer.

The couple said they had been recommended the company’s Mexico option. Its website advertises that intended parents using the route can have a baby in “under 18 months”.

They said they were told the UK route could take up to five years and that the US option was much more expensive.

Lawyers for My Surrogacy Journey said prospective parents are given information about typical timelines, costs, legal frameworks and practical considerations, and that the 18-month timeframe is indicative only.

The couple said their surrogate developed placenta accreta, a serious condition in which the placenta attaches to the wall of the uterus.

Emails from Johnson-Ellis acknowledged that the insurance provider investigated the birth after the surrogate experienced health complications.

The parents are considering legal action, while the Guardian said it understood at least four other couples were reviewing their options.

Phil Brickell, MP for Bolton West, raised concerns in parliament about a separate couple who had used My Surrogacy Journey.

He said: “Two of my constituents recently travelled to Mexico, where their children were born by surrogacy.

“Those births were facilitated by a company called My Surrogacy Journey, which is listed on gov.uk.

“While in Mexico, they had repeated traumatic experiences with the company relating to issues including insurance for their children, accusations of bullying towards staff and repeated efforts to silence any constructive criticism.

“I understand that other members of this house have received similar complaints.”

Brickell called for My Surrogacy Journey to be removed from gov.uk pending a review by the Human Fertilisation and Embryology Authority.

Lawyers acting for My Surrogacy Journey said the company was communicating with DHSC and was confident any issues could be resolved.

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Fertility

Spain football federation partnership to offer players egg-freezing and fertility treatment

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Spain’s football federation will offer national team players egg-freezing and fertility treatment through a clinic partnership running until 2029.

The agreement with the Tambre clinic in Madrid will give Spain’s World Cup winners more options to pursue motherhood when they feel the time is right.

The Royal Spanish Football Federation (RFEF) said the agreement covers all national team players, including the futsal team, as well as Primera Division referees and assistants and all other federation employees.

It is the latest policy introduced by the RFEF as it seeks to lead the way in work-life balance and maternity protection.

The federation has also introduced measures allowing players to travel with their children during major tournaments. The scheme was extended to the men’s team during their successful World Cup campaign in North America this past summer.

RFEF president Rafael Louzán said: “If Spain and its national teams are the best in the world on the pitch, they must also be the best in matters such as work-life balance.

“This is a new, comprehensive and pioneering benefit that extends to all federation employees. Today is a great day for the entire Spanish football family.”

The agreement followed a direct request from players after discussions with national team captains, including London City Lionesses midfielder Alexia Putellas.

Putellas told Spanish outlet El País: “As a group of captains, we had a concern — because experiencing a World Cup is vital for a player — regarding the difficulty of reconciling that with the desire to become a mother.”

“It’s a desire I didn’t originally have but developed some time ago.

“Thanks to the incredible work done by the federation, an agreement has been reached with a clinic allowing us to freeze our eggs while we are still active players, for as long as we wish.

“For me, this is a huge step forward; the federation understands that you are serving your country in a way that runs counter to your biological clock — that you can’t simply pause your career to become a mother because you need your body to do your job.”

The announcement follows Chelsea becoming the first Women’s Super League club to offer similar fertility treatment options to its players.

The move has also drawn criticism.

Spanish triple jumper Ana Peleteiro-Compaoré Brión said on Instagram: “The problem obviously isn’t freezing eggs.

“The problem is: why does the institution these women work for have an interest in financing them to delay their motherhood?

“And here there’s a problem that for me changes absolutely everything.

“Is this measure intended to make it easier for women to be mothers or is it intended to make it easier for them not to be while they’re playing?”

Spain are the current world champions in both the women’s and men’s games.

The women will attempt to defend their title at the 2027 World Cup in Brazil next summer.

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Fertility

Paracetamol use may impact future fertility, studies suggest

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Paracetamol use in pregnancy was not linked to autism or ADHD, while separate research found reproductive differences in girls exposed before birth.

One study analysed health records from more than 120,000 children and found no increased risk of autism following prenatal paracetamol exposure.

A separate analysis of nearly 100,000 children also found no increased risk of ADHD among those born to mothers who used the painkiller during pregnancy.

Researchers from the Hong Kong Hospital Authority examined electronic health records covering pregnancies between January 2001 and December 2023.

The autism analysis included 124,333 children, who were nine years old on average and split almost evenly between males and females. There were 3,445 autism diagnoses, representing 2.8 per cent of the group.

The ADHD analysis involved 97,285 children, who were seven years old on average and also split evenly between males and females. There were 5,168 ADHD diagnoses, representing 5.3 per cent.

Women prescribed paracetamol during pregnancy were more likely to be older and have pre-existing conditions including psychiatric disorders, as well as reasons for taking the drug such as infection, fever or chronic pain.

No association was found between prenatal paracetamol exposure and either autism or ADHD.

The findings did not differ according to the trimester in which paracetamol was taken or whether use was intermittent or daily. Advanced maternal age, defined as pregnancy in women over 35, did not alter the findings.

The researchers wrote: “Paracetamol remains a safe and essential analgesic [pain reliever] and antipyretic [fever reducer] during pregnancy, whereas alternatives, such as NSAIDs and opioids carry well-documented risks.

“Unwarranted reluctance to use paracetamol could lead to undertreatment of pain and fever, or the use of more harmful alternatives, both posing risks to the pregnancy and developing fetus.”

The authors said women should assess paracetamol use with guidance from their doctor.

A separate study involving 685 pregnant women without pre-existing conditions and 302 infant daughters found associations between prenatal paracetamol exposure and differences in reproductive organs and hormone levels.

Researchers from Copenhagen University Hospital enrolled the women during their first trimester and assessed them during the first trimester, third trimester and again when their babies were three months old.

At around three months, infants experience a temporary rise in reproductive hormones sometimes called mini-puberty.

Pregnant participants completed questionnaires every two weeks about their use of pain medicines including paracetamol. Infant girls underwent ultrasound scans of their reproductive organs and blood tests to measure hormone levels.

Researchers also examined a separate group of 1,210 girls followed from infancy to adolescence whose mothers reported paracetamol use during the third trimester.

Three-month-old girls exposed to paracetamol before birth had an average 40 per cent smaller ovarian volume, 13 per cent smaller uterine volume and 23 per cent fewer ovarian follicles.

Girls exposed during the first trimester also had lower levels of Anti-Müllerian hormone, a marker of ovarian function.

Among the older girls, those exposed before birth were more likely to have smaller uteruses at puberty and smaller ovaries during their teenage years.

Dr Margit Bistrup Fischer, lead study author and postdoctoral researcher in the Department of Growth and Reproduction at Rigshospitalet hospital in Denmark, said: “Animal studies have demonstrated that impaired formation of ovarian follicles can lead to reduced fertility and earlier reproductive aging.

“Whether the differences observed in our study have implications for fertility and age at menopause in humans remains unknown and will require long-term follow-up of the girls in our cohort.”

She cautioned that women who had used paracetamol during pregnancy “should not be alarmed by our findings”, as the study found associations rather than direct causation and outcomes for individual women and children are unclear.

“Importantly, our study does not evaluate whether [acetaminophen] causes reproductive problems, nor does it provide evidence that prenatal exposure affects future fertility or age at menopause,” she said.

“Although we observed similar associations in an independent cohort, long-term follow-up is needed to determine whether these early-life differences have any clinical significance later in life.”

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