Examining the Evidence: Can COVID-19 Affect Fertility? Can It Affect the Fetus?

While the COVID-19 pandemic has been sweeping through the world, people have tried to carry on with their lives as much as possible. For many people this includes expanding their families, or undergoing fertility treatment. The second session at the Progress Educational Trust conference 'Fertility, Genomics and COVID-19', chaired by Fiona Fox, chief executive of the Science Media Centre, cast an expert look at whether COVID-19 affects fertility, and the health of a developing fetus.

The first speaker was Allan Pacey, professor of andrology at the University of Sheffield. He outlined what he considered to be a plausible hypothesis of how COVID-19 might impact male fertility. The virus responsible for the pandemic, SARS-CoV-2, enters human cells through a structure known as the ACE2 receptor. ACE2 receptors are concentrated in certain cell types, tissues, and organs of the body. These include, for example, the kidneys, the vascular system, the airway – but also, the testes. Studies have indicated that when the SARS-CoV-2 virus engages with ACE2, it prevents the receptor from carrying out normal functions for the body, and so can lead to local tissue damage and inflammation.

While Professor Pacey said this hypothesis was behind an 'absolute explosion' of review articles, opinion pieces and letters to journal editors, a search of existing research turned up just 14 studies looking specifically at this topic, from this year. He noted that the studies involved very small numbers of men – no more than 300 in total.

This of course indicates that more data is needed, but what do the current findings say? Professor Pacey described a few studies indicating decreased sperm concentration in men who have COVID-19, or who have recovered from it. However, he cautioned, this is exactly what he would expect to see in men who have had any febrile illness, and so may not be specific to this virus.

Sperm quality wasn't differently affected by having mild or severe COVID-19, and there was very little evidence that the virus could be detected in semen, and so sexually transmitted. Overall, Professor Pacey concluded, the current data does not support the hypothesis that the SARS-CoV-2 virus affects sperm quality or reproductive hormones in men.

He added that other aspects of testicular function remain to be investigated, and that there is a lack of epidemiological data at the population level, or from men who are engaging in assisted reproductive technology, who would be particularly vulnerable to any adverse effects on fertility.

The second speaker, Dr Rita Vassena, scientific director of the Eugin Group fertility clinic, looked at whether egg cells could be infected by the SARS-CoV-2 virus.

As the pandemic spread in the spring of 2020, Dr Vassena's clinic began testing patients for COVID-19 before beginning treatment, and found two egg donors tested positive, despite being asymptomatic. The patients gave their permission for their donated eggs to be studied, forming the basis of a study published by the clinic.

Even using their own highly sensitive PCR technique, the researchers could detect no SARS-CoV-2 proteins in the oocytes, but were unsure if the result would be the same in patients with high levels of the virus in their bodies.

To answer this question, the researchers looked for the presence of host proteins involved in two known routes of SARS-CoV-2 infection. These proteins act inadvertently as a 'door' for the virus, allowing it to enter and infect cells. There was no sign of these in the proteins or mRNA of the oocytes, indicating that SARS-CoV-2 would be unable to infect egg cells at least through these specific routes.

While these findings are based on eggs from just two donors, said Dr Vassena, the evidence indicates that women who test positive for COVID-19 after egg retrieval should probably not worry too much about the state of their oocytes.

The last speaker was Ashley Moffett, emeritus professor of reproductive immunology at the University of Cambridge who addressed the effect of COVID-19 on pregnant women and fetusues, and whether the virus can cross the placenta.

Professor Moffett focused on two studies of the UK population. The first, by the UK Obstetric Surveillance System (UKOSS), was pre-planned in 2012 in case of a pandemic. The study looked at women with COVID-19 infections which were severe enough to require hospitalisation: 427 women out of 90,000 births were surveyed. Those who were hospitalised tended to be from BAME communities or affected by obesity or pre-existing conditions.

The risks, Professor Moffett said, were no different from women the same age who were not pregnant and were similar to what would be seen for flu. Therefore, the Royal College of Obstetricians and Gynaecologists guidelines state that there is no evidence that pregnant women are at greater risk of death from COVID-19. Vitamin D supplements are encouraged, as is the flu vaccine. No pregnant women have been included in COVID-19 vaccine trials yet, so more data is needed before making recommendations.

Professor Moffett also reviewed the evidence for whether neonates could acquire COVID-19 infection from their mothers. It seems unlikely that the virus could cross the placenta, with results potentially confounded by false positives and contamination after birth. The 'gold standard' of neonate infection would be to assess fetal blood for SARS-Cov-2 antibodies, but so far there have only been anecdotal reports.

She also outlined a second study by the British Paediatric Association. which looked at babies in the first 28 days of life, showing that very few are infected within the first seven days. Again, infection is less rare in black or ethnic minority babies and, although the study suggests two possible vertically acquired infections, more data is required to be certain.

So placental or congenital infection is unlikely but there is certainly a risk of perinatal infection after birth, concluded Professor Moffett.

After the presentations, the panel answered questions from the audience. Asked how concerned they remained about this topic, Dr Vassena commented that scientists are always worried in the face of uncertainty – until more data comes in. Professor Pacey said he was no longer concerned at a population level, and that a 'Margaret Atwood' scenario was certainly unlikely now. Professor Moffett reiterated that there has been no report of congenital abnormalities resulting from COVID-19 infection, but that there is still some uncertainty surrounding women who are severely ill.

All experts also reflected on the 'infodemic' of COVID-19 related publications and media articles that had flooded 2020. Should fertility experts be 'ruder' about the quality of studies, wondered Fiona Fox, issuing a call-to-arms to the session's attendees to call out poor science and poor reporting. Professor Pacey reflected that good evidence and clear writing is difficult to find, with a mix of good and terrible science papers out there. He hoped that PET's summary of the day's session could help by presenting a good resource for patients.

The experts were asked if people should delay conception following the COVID-19 vaccine. Professor Pacey said he was not aware of any similar vaccine to set a precedent. Professor Moffett said that she did not believe there would be any significant risk posed by this mRNA-based vaccine, yet it was now time to seriously think about including pregnant women in trials, in order to answer this question definitively. Dr Vassena said that there are inevitably risks to attending a clinic for fertility treatment, just as there are risks in living in the everyday world under the pandemic, and that in her clinic for example, the strict testing for COVID-19 kept the risk of infection at a clinic very small.*

Audience members and experts discussed the difficulty in separating confounding factors in fertility studies, including stress, depression, and lifestyle changes during the pandemic. Professor Pacey emphasised that funding bodies needed to be encouraged to support studies in long-lasting COVID-19 and fertility, and to support community-based collection of data and samples from men who are affected by COVID-19. On the topic of collecting further data about mother-child transmission, Professor Moffett said that guidelines had been published for post-birth data collection, but it would be very important to further study fetal blood for antibodies.

The panel's concluding advice to those hoping to become parents was upbeat: take the vaccine when offered, get healthy, get on with it, said Professor Pacey. Try not to get infected, get the vaccine as soon as you can, and this will be over eventually, said Dr Vassena.

Professor Moffett cautioned that there are unanswered questions, such as why BAME women seem to be at higher risk. But on the whole, she concluded, one can be optimistic.

*Public Health England has issued guidance that conception should be delayed for 3 months, given that the Pfizer-BioNTech COVID-19 vaccine has not yet been assessed in pregnancy. It therefore recommended that until more information is available, those who are pregnant should not have this vaccine.

PET would like to thank the sponsor of this session, the Edwards and Steptoe Research Trust Fund, and the other sponsors of its conference - the Anne McLaren Memorial Trust Fund, ESHRE, Wellcome, the European Sperm Bank, Ferring Pharmaceuticals, the London Women's Clinic, Merck, Theramex, Vitrolife and the Institute of Medical Ethics.