A study found birth rates among middle-aged women in Northern European increased thanks to assisted reproductive technologies.
The study examined the total population of women aged 40–49 years between 2008–2018 in Denmark, Norway, and Sweden, birth rates increased in Denmark and Sweden, and births resulting from assisted reproductive technology doubled in all three countries. The findings were published in Acta Obstetricia et Gynecologica Scandinavica.
The study found that use of hormonal contraception increased among women aged 40–44 years in Denmark from 24% to 31%, in Sweden from 27% to 30%, and in Norway from 22% to 24%. Additionally, birth rates among women 40–44 years increased from 9.5 to 12 per 1000 women in Denmark and from 11.7 to 14.3 per 1,00 in Sweden, while they remained stable in Norway at approximately 11 per 1000 women.
In women aged 40–49 years, there was a doubling of assisted conceptions in Denmark from 0.71 to 1.71 per 1000 women; in Sweden from 0.43 to 0.81 per 1000; and in Norway from 0.25 to 0.53 per 1000. The study also found that Sweden had the highest induced abortion rate (7.7 to 8.1 per 1000 women) in women aged 40–49 years during the study period.
“This study confirms the trend of postponing childbirth observed for most of Europe and demonstrates the important role of assisted reproductive technology on birth rates in this age group,” said lead author Ingela Lindh, MD, of Sahlgrenska University Hospital. “The study provides valuable information to improve women’s knowledge about their fertility.”
In an analysis published in Reproductive Medicine and Biology, researchers found evidence that thyroid conditions in women could negatively impact egg reserves in their ovaries.
Hypothyroidism is a disease that is prevalent in women, even in those of reproductive age. Thyroid hormones are involved in the control of the menstrual cycle. Oocytes express cell surface receptors for thyroid hormones that affect the actions of follicle-stimulating hormone and luteinising hormone through steroid biosynthesis. As such, thyroid dysfunction disturbs menstrual regularity and ovulation. However, the effects of low thyroid hormone levels (hypothyroidism) and thyroid autoimmune diseases on the functioning of a woman’s ovaries are not fully understood. This analysis aimed to investigate whether hypothyroidism and/or thyroid autoimmunity affect the ovarian reserve, evaluated using levels of anti-Mullerian hormone (AMH).
The researchers found nine relevant trials, and their findings indicated that hypothyroidism and thyroid autoimmunity can negatively impact a woman’s ovarian reserve, or the total number of healthy immature eggs in the ovaries.
“Our age-stratified analysis demonstrated that thyroid autoimmunity and hypothyroidism possibly have different impacts on the ovarian reserve. It provides an important clue in determining how these conditions affect the development of ovarian follicles,” said senior author Akira Iwase, MD, PhD, of the Gunma University Graduate School of Medicine, in Japan.
While cannabis use may impact some autism-linked genes in men’s sperm, briefly quitting cannabis over time may significantly lower many of those effects, according to a new study.
This study, published online in Environmental Epigenetics, followed several other studies at Duke University that linked cannabis use to epigenetic changes (alteration of expression without changing genes) present in sperm, including genes in early development.
This new study aimed to find out if cannabis abstinence could reduce such epigenetic changes. The results showed marijuana users who stopped using cannabis for 77 days produced sperm lacking most of the significant changes found when the men were actively using cannabis. Study author Susan Murphy, PhD, associate professor in the Department of Obstetrics & Gynecology at Duke University School of Medicine, said the results may suggest that marijuana abstinence could result in washout of sperm with the drug’s epigenetic effects. More research is needed for lingering epigenetic effects after abstinence, but there are immediate implications for some.
“Stopping cannabis use for as long as possible – at least for a 74-day period before trying to conceive – would be a good idea,” she said. “If someone is really serious about that, I would say to stop cannabis use for as long as possible prior to conception – meaning multiple spermatogenic cycles.”
“Is it going to fix everything? Probably not,” Prof Murphy said. “We know there are other epigenetic changes that emerged in the ‘after’ sample that we don’t understand yet – and some of those changes are troubling, like an enrichment of other genes related to autism. But it does appear that the things that were the most severely affected in the ‘before’ sample seem to be mitigated by the abstinence period in the ‘after’ samples.”
The study took a baseline sperm sample from marijuana users and non-marijuana users, then followed both groups as the marijuana-using group abstained from cannabis for 77 days – a period spanning the average time it takes for a sperm to mature, which is 74 days. Researchers collected a second sample from both groups after the 77-day period.
During baseline tests, the marijuana-consuming group produced sperm with changes in line with previous studies, which showed altered epigenetic information, including changes in genes linked to early development and neurodevelopmental disorders. With a 77-day abstinence period, this same group was able to produce sperm that had far less altered epigenetic information at the same genes.
The post-abstinence sample was also much more in line with the samples produced by the non-cannabis-using control group.
Prof Murphy says further research is needed to see if the remaining epigenetic changes observed in the sperm of cannabis consumers, when they abstain, carry over into development after fertilisation.
“We don’t know yet whether the alterations that we’re seeing are at genes that have a stable characteristic,” she said, “or if they are in genes that get reprogrammed and really are going to be of no consequence to the child.”
In any case, Prof Murphy says this work is not about legalisation, rather about giving people the power to make informed decisions for themselves.
“I think that we deserve to know what the biological consequences are so that if you are planning to have a child, or even for your own health, you can make an informed decision about whether you want to use it and when, and that’s not really an option right now because we don’t know what it does,” Prof Murphy said.
For the first time, mice have been born from gametes that have been created entirely from stem cells, marking the beginning of a revolutionary new reproductive option.
The experiment is the brainchild of Dr Katsuhiko Hayashi of Kyushu University, who has led the pursuit of making gametes outside of a living body. If adapted for humans, these wild reproductive pursuits are bound to shake up our entire conception of the beginning of life, similar to the way “test-tube” babies did when in vitro fertilisation (IVF) was first introduced.
Dr Hayashi dreams of even bigger possibilities; since stem cells can be rapidly created from skin or other cells, they are an endless source of raw material to make sperm and egg cells. These gametes, if fully functional, can merge into a zygote inside a test tube, be transplanted into a surrogate, and birth a new generation without ever seeing testes or ovaries.
Though still far off for humans, in vitro gametogenesis, or IVG, has great potential. Researchers can use these lab-grown models to better understand how reproductive cells form and mature. For couples struggling to conceive, or people who’ve lost reproductive function due to diseases like cancer, IVG would offer a new route towards pregnancy. Same-sex couples could also potentially conceive children with their own genetic makeup. There are many possibilities, and a wide range of ethical problems.
The basis of the technology uses induced pluripotent stem cells (iPSCs), which can be nudged in any direction, including sperm and egg. Back in 2011, Dr Hayashi showed that by bathing stem cells in a particular chemical soup, his team was able to produce sperm cell precursors, with the capacity to turn into functional sperm.
In 2016, the team achieved the same with eggs in mice, mimicking the entire process of how ovaries make eggs – which were used to produce healthy pups. However, eggs made in a test tube couldn’t develop naturally outside the ovary. Fresh ovarian tissue from mice was needed, creating an obvious challenge for fertility treatments in humans.
In the current study, the team focused on the support cells that normally encapsulate a developing egg. These support cells thrive inside the ovary, secreting hormones and nutrients that help support the metabolic needs of an egg – a crucial step, which includes forming ovarian follicles for the eggs to mature in.
These ovary-supporting cells can also be made from stem cells if the right chemical keys are used, and so after five years Dr Hayashi figured out those keys. Many of them sport fanciful names like ‘sonic hedgehog‘ (SHH), but most of these proteins belong to the morphogen family, in that they can morph the physical structure and identity of a tissue.
After dousing stem cells with this soup, the cells differentiated into foetal ovary supporting cells, with a gene expression profile closely mimicking that of their natural counterparts.
Next, the researchers added precursor immature egg cells, also made from stem cells. Together, the cells coalesced into tiny ovarian follicles, with support cells forming a bubble wrapping the developing egg. The eggs were then fertilised with sperm, transplanted into surrogate mouse mothers, and after normal pregnancies, resulted in about a dozen healthy pups. Those mice eventually gave birth to babies of their own.
The artificial ovary produces mature eggs less effectively than its natural counterpart, suggesting there’s still much to be learned about this stage of reproduction.
Application of this technology to assisted reproduction in humans is still decades away: human reproductive cells take far longer to mature than those in mice, and likely require different supporting nutrients for the sperm, egg, and surrounding tissue.
The team is now testing their chemical soup in marmosets, to be followed by primates.
Currently no laws or ethical frameworks deal with IVG, since the technology is so new.
Dr Hayashi is taking it step by step, and welcoming public discourse before even considering any clinical use. The first step, he said, is verifying the quality of the stem-cell derived eggs, adding, “That could take a long, long time.”
Researchers have discovered that albumin (Alb), one of the most abundant proteins in the body, activates a proton channel (hHv1), also widespread in the body, giving sperm the ability to penetrate and fertilise an egg, and also allowing white blood cells to produce inflammatory mediators to fight infection.
The study explored the physiological connection between Alb and human voltage-gated proton channels (hHv1), which are both essential to cell biology in health and diseases. Researchers also demonstrated the mechanism by which Alb binds directly to hHv1 to activate the channel. This research explains how sperm are triggered to fertilise, and neutrophils are stimulated to release mediators in the innate immune response, describing a new role for Alb in physiology that will operate in the many tissues expressing hHv1.
“We found that the interaction of Alb and hHv1 activates sperm when they leave semen and enter the female reproductive tract because Alb is low in semen and high in the reproductive tract. We now understand why albumin supplementation improves IVF,” explained first author Ruiming Zhao, PhD, from the Department of Physiology & Biophysics at UCI School of Medicine. “We also found the same Alb/hHv1 interaction allows the white blood cells called neutrophils to produce and secrete the inflammatory mediators that kill bacteria and fight infection. However, it’s important to note that the inflammatory response itself can lead to disease.”
Alb’s stimulating role in the physiology of sperm and neutrophils via hHv1 pointed to its having other enhancing or deleterious roles in the other tissues, including the central nervous system, heart and lungs, and influencing cancers of the breast and gastrointestinal tract.
“It is exciting to discover that a common protein has the power to activate the proton channel. This finding suggests new strategies to block or enhance fertility, and to augment or suppress the innate immune response and inflammation,” said senior author Steve A. N. Goldstein, MD, PhD, vice chancellor of Health Affairs at UCI.
hHv1 is involved in many biological processes in addition to the capacitation of sperm and the innate immune responses included in the study. The channels have notable roles in proliferation of cancer cells, tissue damage during ischaemic stroke, and hypertensive kidney injury. Because Alb’s presence and involvement varies, the potentiation of hHv1 by Alb can be either beneficial or detrimental in different diseases or conditions.
“We have modeled the structural basis for binding of Alb to the channel that leads to activation and changes in cellular function, and we are now conducting in vivo studies of viral and bacterial infections. Our next steps include studies of the effects of inhibitors of the Alb-hHv1 interaction on infection, inflammation and fertility,” said Goldstein.
Journal information: Ruiming Zhao et al, Direct activation of the proton channel by albumin leads to human sperm capacitation and sustained release of inflammatory mediators by neutrophils, Nature Communications (2021). DOI: 10.1038/s41467-021-24145-1
The first comprehensive global survey of twinning has reported an enormous increase in the number of twin births around the world, but appears to be plateauing.
One main reason for the increase is that, due to IVF and other fertility services being more readily available, the number of non-identical twin births is increasing. This is due to practices such as hormone stimulation releasing multiple ova, as well as the now discouraged practice of releasing multiple embryos into the womb in IVF. A systematic review also found that with IVF, letting embryos mature before implantation is also linked to increased odds of monozygotic twins. as well as women becoming pregnant later in life – age increases the likelihood of having natural, non-identical twins, peaking at age 35 to 39.
However, instead of continuing to climb, there are signs that twin births have reached a maximum.
“The trends are really quite striking,” said Christiaan Monden, a professor of sociology and demography at Oxford University. “Over the past 40 to 50 years we’ve seen a strong increase in twinning rates in rich, developed countries, and that has led to more twins in both a relative and an absolute sense than we’ve seen ever before.”
The researchers analysed twinning rates from 2010 to 2015 in 165 countries, which covered 99% of the world’s population. In 112 of those countries, they examined further birth records for 1980 to 1985.
Although Africa is still the leading continent for twin births, other regions are catching up. The researchers found that, since the 1980s, twinning rates have risen from 9 to 12 per 1000 births, with the greatest rise in more developed regions such as America (71%), Europe (60%) and Asia (32%).
In the UK, twinning rates rose about 62% but are thought to have fallen since the launch of a campaign to reduce multiple births in 2007.
Raj Mathur, the chair of the British Fertility Society and a consultant gynaecologist at St Mary’s Hospital, said: “It doesn’t surprise us that twinning rates have increased because the availability of assisted reproduction has increased and also because women are slightly older when they have their first children, and both those things will increase the twin rate.[…]
“I think we’ve reached a peak in terms of twinning rates from medical interventions, certainly in the developed world, but the spread of IVF in Africa and South America is still rather limited on a per capita basis, and there are vast numbers of sub-fertile people in Africa particularly who don’t have access to IVF.
Dr Mathur added a note of caution about IVF, as twins have more risks such as lower birth weights and higher still birth and infant mortality rates
“The challenge will be how to spread IVF to them without also giving them higher twin rates. The majority of twin babies are absolutely fine, but there is no doubt that a twin pregnancy carries greater risks for the mother and the baby, so when we can avoid it we should avoid it. The principle we follow is neatly summed up by the phrase ‘one at a time’,” Mathur said.
The onset of “morning sickness”, the nausea and vomiting that often occurs near the beginning of pregnancy and normally resolves at 12-14 weeks, has been narrowed down in a new study from researchers at the University of Warwick.
The cause of nausea and vomiting of pregnancy (NVP) had historically been ascribed to psychological conditions, but currently is believed to have a multifactorial basis, involving various genetic, endocrine and gastrointestinal factors.
The study involved 256 women who became pregnant, keeping a diary recording the onset of nausea and vomiting, their last menstruation and date of ovulation as measured by a urine test.Determining the date of the start of pregnancy as determined by the date of their last ovulation, the first onset of NVP was 8 to 10 days, compared to 20 to 30 days as measured from the date of their last menstruation.
Lead author Prof Roger Gadsby, Warwick Medical School, said: “The precise course of pregnancy sickness is unknown, but this research shows that it occurs at a specific developmental stage, in a specific timeslot. For researchers it narrows our focus in terms of where we look for the cause. If we know that symptoms occur in a very narrow window 8-10 days after ovulation, researchers can concentrate their efforts on that particular stage of development to find the cause of the condition, both anatomically and biochemically.”
Knowing that the onset of NVP has such a tight timeframe will help future research narrow down a biological cause behind it, and help generate targets for treatment development.
An unexpected outcome of the study was a very high prevalence of NVP of 94%, compared to the 80% calculated in prior research. This is explained by the fact that data were regularly collected from participants from before they became pregnant to 60 days after their last menstruation, as opposed to most studies asking women to recall symptoms after they became pregnant.
Prof Gadsby added, “What we’ve shown is that more people get symptoms of pregnancy sickness than has ever been shown before, and one of the reasons for that is that this research has picked up mild early symptoms that tend to fade by 7-8 weeks. In other studies those symptoms would have faded by the time the research started.”
A team of researchers have investigated the effect of adding nuts to a Western style diet on epigenetic effects of sperm quality.
The epigenetic effects are expressed through DNA methylation, where methyl groups are added to DNA sequences, altering their activity without changing the actual sequence.
A range of lifestyle and environmental factors have been investigated in the search for the cause in the drop of human sperm fertility observed over the pasty 70years. Specific sperm DNA methylation signatures are associated with sperm quality.
The researchers took data from 72 young non-smoking adults from the FERTINUTS trial. In the assigned nut-eating group, the participants’ sperm was found to have significantly sperm count, viability, motility, and morphology. Additionally, alterations in 36 specific DNA methylation regions were observed compared to the control group, and hypermethylation was seen in 97.2% of them.
Albert Salas-Huetos, first author of the article stated that, “This work demonstrates that there are some sensitive regions of the sperm epigenome that respond to diet, and which can result in changes in sperm and in its ability to fertilise.”
Existing research has thus far indicated that women who used assisted reproduction technologies (ART) were at greater risk for ovarian cancer and non-malignant borderline ovarian tumours resulting from overstimulation of the ovaries.
The tumours were proposed to be caused by excess sex hormones and disruption of ovarian tissue from multiple punctures. A pair of meta-analyses in 2013 indicated that women who used reproductive technologies were at increased risk of ovarian cancer, but no causative link was established; infertility itself could have caused the increased risk.
Researchers in the Netherlands used a database of 30 625 women who received ovarian stimulation for ART between 1983 and 2001 and 9 988 women who were infertile but did not use ART. These were linked to the Netherlands Cancer Registry and the Dutch Pathology Registry to check for invasive and borderline ovarian cancers.
Though there was an increase in ovarian cancer in women who had received ART, the increase was due to women who had received ART but not been able to fall pregnant: not having had a pregnancy has shown to be a risk factor for ovarian cancer.
