The dream of becoming someone's parent

However, with rising age comes a decline in ability to conceive, which affects men as well as women. This makes age the most common reason for involuntary infertility among women in welfare countries.

It is a common misconception, shall we say, that infertility is something that mainly affects women in the wealthier world. This is not the case. In fact, Andres Salumets, Professor of Reproductive Medicine at the Department of Clinical Science, Intervention and Technology at Karolinska Institutet, has found that the proportion of infertile couples seems to be about the same, at around 10 to 15 percent, across different societies, with some exceptions.

“What differs, however, is the causes of infertility,” says Andres Salumets. “In Europe and other welfare countries, age is the most common reason for difficulties conceiving. In other countries it is more common for infertility to be due to infection or injury caused in childbirth.”

Andres Salumets explains that what is known as secondary infertility, where a woman has had one child but is then unable to conceive again, possibly due to injury during childbirth, is more widespread in countries with lower welfare. In Sweden and other welfare countries, it is more common to seek assistance with conceiving for the first time.

The first “test-tube baby”, Louise Brown, was born by in vitro fertilisation in 1978. By 2010, four million babies had been born with the help of the technique, and the researcher behind it, Robert Edwards, was awarded the Nobel Prize in Physiology or Medicine.

Six million 'test-tube babies'

Since then, a further around six million 'test-tube babies' have been born. In 2019, just over 4,800 Swedish babies were born by in vitro fertilisation (IVF) according to the most recent annual report from the quality register Q-IVF. This is equivalent to 4.2 percent of babies born in Sweden that year.

More and more babies are expected to be born following IVF treatment as increasing numbers of people are seeking this assistance. IVF is also becoming more widely accessible as the treatments develop in purely medical terms and the legal right to access them is broadened. For example, single women and lesbians are now able to have IVF in Sweden, as are young people whose fertility has been impaired by treatment for cancer (see the article on pages 42–43).

Andres Salumets also expects that it will become even more common to postpone starting a family. As a rough estimate, viewed as a group, women who start trying for a baby in their thirties have about five years left of fertility that is still unaffected by age because chances of conceiving start to plummet at the age of 35. This means those longing for a large family have quite a narrow window in which to fulfil their dream. About ten years before the menopause, which happens on average at the age of 51, few women are able to become pregnant spontaneously.

“People are aware of this but it isn’t sufficiently well understood,” says Andres Salumets. “We should attempt to make this information more widespread, as a picture that runs alongside the couples over 40 sharing their delight at being pregnant on social media. In many cases, these pregnancies have been achieved using egg donation. Doctors at IVF clinics see women who are not properly informed about their fertility and who have an unrealistic idea of their chances of conceiving unassisted. But we also see many couples who are aware that fertility declines with age but where other things in life, such as gaining a secure footing in the workplace, have led to them postponing starting a family.”

Would you like society to change on that point, to shift towards a society where people start families younger?

“I’m sceptical about attempting to change major social trends to do with having children. I think what we need to do is develop the treatments that do exist so we can help more couples and people wanting help by means of assisted fertilisation,” Andres Salumets says.

Men’s fertility also declines with increasing age. This has to do with the fact that health generally deteriorates with age. Obesity, diabetes and high blood pressure become more common, for example, and all of these are factors that affect male fertility. The link is so clear that fertility can be seen as a marker for male health in general.

“Many couples are dealing with age-related infertility in the woman combined with an accumulation of diseases in the man, who then loses fertility and sometimes also sexual function. All of this affects the couple’s chances of conceiving,” says Andres Salumets.

The quality of a woman’s eggs deteriorates as she grows older and increasing age goes hand in hand with a higher risk of chromosomal abnormalities in the foetus. Attempting to understand why a higher age in the mother leads to more eggs with chromosomal abnormalities is described as a research goal in reproductive medicine and Karolinska Institutet is one of the institutions conducting research on this issue. The quality of sperm also deteriorates as men age. However, this leads to other types of changes, such as abnormalities in individual genes, which can lead to a number of different diseases in the foetus.

In an international context, children born through IVF run a higher risk of being born prematurely, having a low birthweight or being small for their age. However, this is explained by the increased risk of multiple births, mainly twin pregnancies, which IVF can involve if more than one fertilised egg is put back into the womb.

In Sweden, the healthcare services have worked actively to reduce the number of multiple births. Since 2003, a binding regulation from the National Board of Health and Welfare has laid down that as a rule “only one fertilised egg is to be placed into the woman’s body”, unless the risk of twins is judged to be small.

Consequently, the number of multiple births has fallen “dramatically” in Sweden according to a 2019  report by the Swedish Society of Obstetrics and Gynaecology, SFOG. The number of multiple births in conjunction with IVF is now down to almost the same levels as the number of multiple births in spontaneous pregnancies. This has also dramatically reduced the risks of premature births and low birthweight among Swedish babies born through IVF.

Not a cause for concern

The same report states that there are risks of other problems, including a slightly increased risk of certain malformations in these babies. However, this is judged not to be due to the IVF technique itself but to factors in the parents, i.e. something in the people who use assisted fertilisation is producing this higher risk.

This slightly increased risk should not be cause for concern, though, according to Andres Salumets, who says that the vast majority of babies born following IVF are completely healthy:

“These babies are the best-studied babies in the world,” he says. “Pregnancy is a powerful filter. Miscarriage is a hard blow for couples undergoing IVF but miscarriage is usually caused by there being a problem with the pregnancy. The same couple can conceive again and have a healthy baby.”

Nevertheless, the fact that fertility treatments mean that more babies are being born to older parents, which itself carries a higher risk, is one of many ethical questions that reproductive medicine needs to address.

“We have good prenatal screening programmes. We can carry out non-invasive tests and obtain a large amount of information about the foetus before it is born. It is possible, for example, to identify genetic abnormalities and potentially to make the decision to end a pregnancy,” says Andres Salumets.

Lalit Kumar Parameswaran Grace, docent and researcher in reproductive medicine at the Department of Women’s and Children’s Health at Karolinska Institutet, has worked clinically in IVF clinics in Sweden and India. He emphasises that childlessness is also a social problem that can have a more or lesser tangible impact in different cultures.

“In some parts of India, couples who do not have children become socially isolated,” says Lalit Kumar Parameswaran Grace. “Others look down on childless couples. In India I have seen childless couples no longer being invited to weddings or baptisms, for example, because they don’t have children. We don’t see this in Sweden or in the rest of Europe.”

Some of his research seeks to improve IVF outcomes, so that more treatments lead to pregnancy. This uses spare embryos from IVF clinics, with the consent of the parents. The IVF clinics grow the fertilised eggs in a liquid for several days before returning them to the woman’s womb. Lalit Kumar Parameswaran Grace thinks that studying the liquid in which the embryos are grown can provide important clues.

“Briefly, we want to attempt to create a molecular test that identifies good quality embryos. Today which embryo is transferred back into the woman is decided by an embryologist looking at all the embryos and assessing their quality. We are looking for molecular traces from those embryos that resulted in pregnancy.”

Using the same method, Lalit Kumar Parameswaran Grace and his colleagues hope to be able to develop a way of identifying potential diseases or genetic disorders in the embryo. Today this is done by taking a few cells from the embryo and studying them. Making diagnoses by finding traces in the fluid would be a less intrusive method of embryo diagnostics.

“We hope to be able to find molecular fingerprints in the fluid in which the embryos are grown,” he explains.

A molecular dialogue

Lalit Kumar Parameswaran Grace and his colleagues are also interested in what has been poetically called 'a molecular dialogue' between the endometrium, the lining of the womb, and the embryo. They influence each other and they must work together for conception to be able to take place. For example, the endometrium secretes different substances that make the embryo grow. But once the embryo has grown, it releases substances that make the endometrium more receptive.

To study this molecular dialogue, Lalit Kumar Parameswaran Grace and his colleagues have produced a 3D-model of the endometrium, made from cells donated by women who conceived without medical assistance. Studying fertility using mice, rats and other test animals is problematic; rats, for example, are highly fertile and it is difficult to replicate the situation of a woman seeking help at the end of her fertile period of life.

“We have now identified substances excreted by high-quality embryos. Our next step is to expose our artificial endometrium to these substances and see how they affect it,” says Lalit Kumar Parameswaran Grace.

Ultimately, this might lead to certain substances being added to the womb in conjunction with IVF, the vision being to be able to influence the environment in the womb, making it more favourable for a pregnancy. But as yet things are only at the trial stage.

Andres Salumets is also researching the molecular dialogue between the embryo and the endometrium; research that has already led to discoveries being used in IVF clinics around Europe. The research involves taking a piece of the endometrium of the woman in a menstrual cycle prior to IVF and analysing different gene expressions in the extracted cells. This makes it possible to obtain an exact picture of how quickly the endometrium matures, or thickens, in the woman being studied. Once this is known, it is possible to determine exactly which day an embryo should be transferred, a factor that can vary between different women.

“Up until now, IVF treatments have been fairly similar for all women, but we ought to factor in more individual aspects of the couple, and that’s something we will be starting to do. This test is one step in that direction,” says Andres Salumets.

Everything so far only applies to heterosexual couples who are involuntarily childless for different reasons but childlessness is something that also affects same-sex couples and single people. It is now legal in Sweden to provide medical assistance to lesbians and single women wanting to have a baby but there are no medical treatments to offer male couples or single men longing for a baby.

“This is a completely unresolved question. We can only say that humans are very inventive so we are going to see many interesting family solutions in the future. Society needs to have some kind of solution for men who desperately want children too,” says Andres Salumets.