The COVID-19 pandemic has had a profound impact on healthcare systems, societal structures and the world economy. The adverse effects of the COVID-19 pandemic on maternal and perinatal health are not limited to the morbidity and mortality caused directly by the virus itself. Nationwide lockdowns, disruption of healthcare services and fear of attending healthcare facilities may also have had an impact on the wellbeing of pregnant people and their babies. In this presentation we will focus on the effect of the COVID-19 pandemic on stillbirth.
Asma Khalil is a Professor of Obstetrics at St George’s Hospital, University of London. She is a subspecialist in Maternal and Fetal Medicine. She gained her MD at the University of London in 2009 and also has a Masters degree in Epidemiology from the London School of Hygiene & Tropical Medicine as well an MRC scholarship. Asma is the Lead for the Multiple Pregnancy service at St George’s Hospital.
Asma has published more than 300 peer reviewed papers, and many published review articles and chapters. She has been awarded many research prizes, both at national and international meetings. Her research interests include twin pregnancy, fetal growth restriction and hypertensive disorders in pregnancy.
Asma is passionate about innovation and the inventor of the HAMPTON, an award-winning digital innovation which enables pregnant women to monitor their blood pressure safely at home. She is also a National Innovation Accelerator (NIA) Fellow.
Asma is committed to the implementation of clinical guidelines in practice and believes that they could reduce inequalities in care across the NHS. She had a three year Fellowship with NICE and has been a member of the NICE Clinical Standards and Expert Advisor to the NICE Centre for Clinical guidelines.
Asma is also an Editor for the Ultrasound in Obstetrics and Gynecology Journal and she works closely with the Twins Trust Charity and together they have set up the world-first Twins Trust Centre for Research and Clinical Excellence at St George’s Hospital.
Asma Khalil is a professor of Maternal Fetal Medicine at St George’s Hospital in London. She is the Lead of the Twins Trust Centre for Research and Clinical Excellence. She is the Obstetric Lead of the UK National Maternity and Perinatal Audit (NMPA).
Dr. Khalil has disclosed that she does not have any real or perceived conflicts of interest in making this presentation.
Anna Calix: My name is Anna Calix, and this is my son Liam. He was stillborn on September 29th at 40 weeks because my providers didn’t listen to my concerns. He died of an unexplained fetal maternal hemorrhage and undetected placental insufficiency. In his memory, and with the hope that deaths like his can be prevented, it is my honor to introduce the next presentation.
Dr. Asma Khalil is a Professor of Obstetrics and Maternal Fetal Medicine at St George’s Hospital, University of London. She is the Obstetric Lead of the National Maternity and Perinatal Audit. She gained her MD at the University of London in 2008. She also has a Masters degree in Epidemiology from the London School of Hygiene & Tropical Medicine and an MRC scholarship. She is a subspecialist in Maternal and Fetal Medicine. Asma is the Lead for the Twin and Multiple Pregnancy service at St George’s Hospital. She also leads the Reproductive Health Research Group at St George’s Hospital.
She has published more than 350 peer reviewed papers, and many published review articles and chapters. She was awarded many research prizes, both at national and international meetings. Her research interests include twin pregnancy, fetal growth restriction, hypertensive disorders in pregnancy and infections in pregnancy.
Professor Khalil had a three-year Fellowship with NICE and has been a member of the NICE Clinical Standards and Expert Advisor to the NICE Centre for Clinical guidelines.
She is an Editor for the Ultrasound on Obstetrics and Gynecology Journal. She is an International Society of Ultrasound in Obstetrics and Gynecology Trustee, and is an Ambassador to North Africa and the Middle East. She works closely with the Twins trust Charity and together has set up the world-first Twins Trust Centre for Research and Clinical Excellence at St George’s Hospital. Her presentation is titled, Effect of COVID-19 on Stillbirth.
Dr. Asma Khalil: Hello, everyone. Thank you for inviting me to talk on COVID-19 and stillbirths. If you haven’t already read this report on the global burden of stillbirths, I’ll strongly encourage you to read it. Estimated that one stillbirth occurs every 16 seconds. That’s about four in every minute. For those who might not be aware that the three in four stillbirths occur in Sub-Saharan African or South Asia. Therefore, if you really want to make a difference for stillbirths globally, this is where you need to focus your efforts.
Certainly the pattern and the causes of stillbirths differ in low- and middle-income countries compared to high income countries. For example, according to this report, more than 40% of stillbirths occur intrapartum, while for example, in the UK where I work, less than 10% of stillbirths occur intrapartum.
What about the COVID-19 pandemic? If you look at the impact with group them into direct and indirect, and that’s important for later in my talk, for example, if you look at the maternal mortality during COVID-19 pandemic in the UK, and this is an MBRRACE report. It was a rapid report that looked at the cases of maternal deaths during the first wave of the COVID-19 pandemic. That’s between the beginning of March, 2020 and end of May, 2020. During this period, 10 women died. Unfortunately, nearly 90% of them were from Black and ethnic minorities, and in these women, two had a stillbirth. If you look at the causes of the deaths, to reiterate, 30% were not directly related to the COVID-19 or the infection itself.
What about stillbirths? Well, after the first wave of the pandemic, a number of reports that was written in the JAMA that was actually published from my center, my hospital at St George’s London where we reported an increase in stillbirths during the first wave of the pandemic. That was shortly followed by other reports. There’s one from Nepal and also one from India reported a significant increase in stillbirths.
That was the one that we published, the one from the UK, and we looked at the stillbirths during the pandemic, particularly the first wave, and we compared it with preceding few months before the pandemic, and the status was there was 9 per 1000 compared to 2 per 1000 pre-pandemic. When we looked at other outcomes like preterm births, caesarean section, neonatal admission, there were no significant difference.
The report from Nepal, large number. They reported significant increase in stillbirths as you can see in these figures, but not just stillbirths, but also the neonatal deaths. Again, from India, you can see the stillbirth rate in India is obviously much higher than, for example, in the UK. It was 31 per 1000 compared to 22 per 1000 pre-pandemic.
What about the media? Well, also there were some reports in the media that highlighted maybe a peak or increase in stillbirths. For example, this is The Times in the UK and data from Scotland suggested that there was an increase in July, 2020. As you can see in the bottom of the slide, 6 per 1000 in 2020 compared to about 4 per 1000 in the year before, 2019.
Not just that, but also the HSIB, that’s the Healthcare Safety Investigation Branch, that’s an organization in the UK, which investigates cases of intrapartum stillbirths, they have referral of intrapartum, and they also reported that they noticed a large rise in the number of intrapartum stillbirth referrals. If you see here from between April 2020 and June, 2020, they had 46 referrals compared to only 24 referrals in the preceding year. Almost nearly double.
The obvious question is why? Because at that time, the literature did not suggest that coronavirus causes stillbirths. In fact, here in our letter in JAMA, we reported that none of the stillbirth cases had COVID, none of the pregnant women that actually had COVID had stillbirths, and as I mentioned earlier, the literature at that point did not suggest that coronavirus causes stillbirths.
Therefore we wanted to look at other possible explanation. At that time, in the UK, there was a report of excess deaths during the first wave. Excess deaths not related to the infection itself, at the same time reported a significant reduction in number of attendances to accident and emergency. We looked, again, in my hospital at St George’s where on the obstetric attendance and activities during the pandemic. We compared the data between 1st February and mid-June, 2020, compared to the same period, so 1st of February to mid-June in the preceding year, 2019. We looked at a number of outcomes, including the triage or out of hours attendance, the number of births and bookings.
You see here in this graph, the red line is the triage attendance in 2020, and the blue line is 2019 in the same period. We’ve observed a significant reduction in triage. I think that’s by about 20%, which is consistent with what we saw at the time that triage was empty. Patients were not coming to the hospital because they were either afraid of catching the infection or the public health message of stay at home unless you have to go to the hospital or maybe worried about that the hospitals are overwhelmed with COVID patients, and the fact that the staff are really stretched and on half capacity. When we looked at the number of births there was very small reduction, about 6%, and there was no change in number of women booking or registering for antenatal care, but this was done really virtual.
What about national in the UK? We did a national survey among maternity hospitals in the UK and we had some interesting results. 70% of the unit reported reduction in antenatal appointments. More than half reduction in postnatal appointments, 60% of them stopped the midwifery birthing center or home births, 90% offered virtual consultation, and again, nearly 90% reported reduction in emergency or triage visits, similar to what we observed in my hospital.
At that time, there was potential fear of this increase in stillbirths that was reported in the UK and other countries, but certainly quickly, the people responded and certainly government and Royal College of Obstetricians and Gynecologists by ensuring the public health messages that, “If you need to come to the hospital, if you have any concern, if you have reduced fetal movements, you need to contact a healthcare professional or the midwife or the obstetrician.” That was really important, particularly in the second wave in the UK. You see this posting was in January, 2021. That’s the second wave of the pandemic.
What about other outcomes? I’m just going to show you very briefly about the preterm births, because around the same time, the reports– and this is large data from Denmark, from the Netherlands, and from Ireland reporting a significant reduction in preterm births during the pandemic. What about the UK? Obviously, we wanted to look at the national data and therefore the office of national statistics report that that was in December, 2020, and on the left-hand side are the stillbirth, and each of these columns is the stillbirth in one month in 2020 until September, 2020. You see the dotted green line here is the five-year average stillbirths for the preceding year.
There was no significant actions, significant increase or significant change really, and the stillbirth rate to some extent in the UK is there’s a trend towards decline. Interestingly, you see in April, that’s during the first wave, there’s a bit of peak there, but that was not significant.
What about the preterm births? On the right-hand side, that’s again data from the UK. You see this is from 2011 until 2020 on the X axis and the different lines, this is the different preterm various category. These are all like less than 37 weeks, or extreme preterm births less than 28 weeks, or very preterm births, so different categories. Essentially, there was no really significant change in preterm births in the UK, which is different from what has been reported in other northern European countries.
What about on a global level? We did this large systematic review on meta-analysis. We included 40 studies. A large number of women. More than 6 or 7 million. We looked at a large number of outcomes and obviously mortality that was maternal mortality or stillbirths or neonatal mortality. We looked at other things as well like ectopic pregnancy or ruptured ectopic that involves stress and anxiety, pregnancy complications, mode of delivery, so a large number of outcomes. We did sensitive analysis to see whether the results differ, whether the results come from high income countries or low- and middle-income countries.
For the time, I’m not going to go through the results of this meta-analysis, but I’m going to show you some of the key findings of maternal mortality. Again, in this meta-analysis, we compared the outcomes during the pandemic compared to before the pandemic or pre-pandemic. We observed that there was about 30% or 37% increase in the maternal deaths, maternal mortality during the pandemic, which I think is expected.
What about the stillbirths? A large number of studies, and if you combine them together, you found that there was a significant increase in stillbirths during the pandemic. About 30% increase. But when you do the sensitivity analysis, according to low middle-income countries, or high middle-income countries, the low-income countries, again, same, 30% increase. In high income country, again, you found almost nearly 40% increase in stillbirths, but actually their results were not significant.
If you’re familiar, this is something called forest plot. We combine data or pool data from various studies. Each one is a study and then the pooling is a diamond shape, the black diamond there on the bottom. If it crosses this line of no effect, that means it’s not significant.
Again, for other outcomes, we did a report or noticed that there was increase in ruptured ectopic pregnancy about six times higher during the pandemic. Also the level of maternal anxiety, again, was significantly higher during the pandemic as expected.
Very briefly about preterm births. A large number of studies, and we did not find a significant change in preterm births during the pandemic. We look at high income countries or low- and middle-income countries, high income countries about 10% reduction in preterm birth. Very small, but that’s also consistent with the recent data also from England. For the low- and middle-income countries, there was no significant change. There’s a big question mark about the mechanism of preterm births.
If we go back again to what I showed you earlier, is that the impact of COVID is either direct or indirect. I showed you the indirect effect. What about the direct? Women actually get the infection. Really the best, probably, summary of the literature is in this WHO living systematic review meta-analysis. It was published in The BMJ and I’m fortunate to be a member of this group. Living means is continuously updated.
The first version really concluded that women were potentially more likely to need intensive care unit admission, and the key findings with the fact that women who have the infection have high risk of preterm births and caesarean section, and then the fact that majority of these preterm births were probably iatrogenic or medically indicated and the baby seems to be doing well.
The most recent update that was published early in 2020, again, this is the key findings. Definitely, pregnant women have a high risk of admission to intensive care units, ventilation and so on, and they did have increased risk of preterm birth and babies admission to neonatal intensive care unit, most likely because of pre-maturity.
Interestingly, in the systematic review, actually stillbirth was significantly increased. Higher in women who had COVID compared to women who did not. In fact, here, the alteration is 2.84. That means about three times higher. The 95% confidence interval does not include one. That means significant. However, the numbers were relatively small. Only nine studies and nine cases in the women who had COVID. Therefore we wanted to wait until the next update to ensure that we have bigger numbers and we have robust data.
Again, in May, 2021, as you can see here, reports started in the media of stillbirths in women who have COVID, women who had the infection that was from Ireland and also from Israel. Also some studies that’s been published, looking at the placental histopathology and reporting that in pregnancies or women who had COVID that they actually have some histopathological findings in the place suggestive of placental dysfunction, which could have contributed to stillbirths.
For example, in this key study, really, they included two cohorts. One that the babies or the neonates were life born, but they definitely had evidence of transplacental transmission. Or stillborn, and the syncytiotrophoblast was positive for the virus, and they reported that they had chronic histiocytic intervillositis, which is, as you probably know, is a placental finding or placental marker which is associated with the risk of recurrent pregnancy loss et cetera.
Also more recently, so this paper in the American Journal which also reported significantly higher prevalence of fetal vascular malperfusion and villitis of unknown etiology in placentas of women who had COVID at term compared to controls or no COVID, you can see they’re significantly higher. 33% versus 4% or 21% versus 7%. That was the case even in asymptomatic patients and negative neonates for infection. There was this question mark about the placental findings. It’s a controversial subject but it could potentially contribute to the increased risk of stillbirth.
I’m going to show you some very recent data from England, from the NMPA, the National Maternity and Perinatal Audit where we looked at the maternal and perinatal outcomes in pregnant women who had confirmed infection at the time of birth, and that was a national data in England. We included women with singleton pregnancies between 29th of May 2020 and 31st of January, 2021. That included data also from the second wave of the pandemic. We looked at, again, a long list of outcomes, including risk of stillbirths, preterm births, small babies, induction of labor, and also neonatal outcomes.
I’m going to show you some of the key findings. This was almost one of the largest studies on COVID in pregnancy. We had more than 340,000 pregnancies. Of those, more than 3,500 had infection. We managed also to link with neonatal records for more than 96% of these pregnancies. We included, finally, in terms of neonates, more than 2,500 neonates of whom their mothers had confirmed infection.
We reported with what we found is that stillbirth was significantly higher in women who had the infection compared to those who didn’t. The odd ratio was 2.2, and just to highlight that this was adjusted for risk factors of stillbirths. The risk was twice essentially. That was also the case for preterm births, and that’s consistent with the previous studies that the preterm births were significantly higher for women who have COVID. Interestingly, we also reported increases in hypertension, pregnancy disorders, preeclampsia, and consistent with the previous studies, also, increased rates of caesarean section.
Finally, about the neonatal data, they had significantly higher risk of neonatal adverse outcomes and admissions in neonatal unit and length of stay and neonatal admissions. That was mainly due to preterm births because when we restricted the analysis to pregnancies which delivered at term, so 37 weeks or beyond, there was no significant adverse outcomes or admission to specialist neonatal care. For me, that really highlighted the priority for COVID vaccination for pregnant women.
Therefore, that brings me to the final part of my talk is about COVID vaccine for pregnant women. Just maybe highlight or share with you the most recent key landmark paper was in the New England Journal of Medicine, which included that there are more than 35,000 pregnant women, and they reported there was no safety signals. Hence the CDC had data on more than 120,000 pregnant women who received the COVID vaccine. That’s mainly the mRNA, so the Pfizer and Moderna, and reported no safety signal.
In the New England Journal of Medicine paper, of those 35,000 women, more than 800 had completed pregnancy and you see some of the adverse outcomes were comparable to the background instance in the general population in pregnant women.
Therefore my take home message is that COVID-19 pandemic has both direct and indirect effect, and we need to be aware of both and differentiate them. The effect of COVID-19 pandemic or the evidence really on its association with stillbirths has been controversial in the literature, but I showed you some of the data on evidence supporting a link or an association. In my opinion, pregnant women should be offered the COVID vaccines, and certainly that seems to be the case in a number of countries that they are offered, COVID vaccination.
National data in the UK on the indirect effect of COVID pandemic in pregnant women has been reassuring with no reported increase in stillbirth. Finally, I think we really need to be careful about the public health messages and its potential impact. However, we have been through an unprecedented pandemic, we’re still through it and therefore there will be obviously some lessons to learn.
I’m going to stop here. Thank you very much for your attention, and I’m happy to take any questions.
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