Uma Reddy is Professor of Obstetrics, Gynecology and Reproductive Sciences and Division Director of Maternal-Fetal Medicine at the Yale School of Medicine. She spent much of her career at the National Institutes of Health, where she led the Maternal Fetal Medicine Units Network, which funds multiple clinical trials across the country. Dr. Reddy received her undergraduate degree in Biology from Brown University and her medical degree from The Warren Alpert Medical School of Brown University. Her internship and residency were completed at Johns Hopkins Hospital. She was a Robert Wood John Clinical Scholar during this period. She also completed a Masters in Public Health in Biostatisstics at Johns Hopkins Bloomberg School of Public Health. In 2000 she was a Fellow at Thomas Jefferson University. She received numerous awards and recognition for her work at the National Institutes of Health and has many published papers regarding her work.
Dr. Reddy’s current research focuses on stillbirth, including examining causes and ways to better prevent it.
Dr. Reddy has disclosed that she does not have any real or perceived conflicts of interest in making this presentation.
Elizabeth Minton: Hello. I’m Elizabeth Minton, and this is some pictures of my boy, Solomon, that was born at the end of December and died in early January, three weeks later. I’d like to go ahead and introduce Dr. Uma Reddy, who is Professor of Obstetrics, Gynecology and Reproductive Sciences at the Yale School of Medicine and Section Chief of Maternal-Fetal Medicine.
Dr. Reddy graduated from Brown University and received her MD degree from the Warren Alpert Medical School of Brown University. Dr. Reddy also earned a Masters in Public Health, MPH, from the Johns Hopkins Bloomberg School of Public Health. She completed her residency in Obstetrics and Gynecology at the Johns Hopkins Hospital and remained there as a Robert Wood Johnson Clinical Scholar. She completed her Maternal-Fetal Medicine fellowship at Thomas Jefferson University.
She was a faculty member at the University of Maryland School of Medicine prior to joining the National Institutes of Health, NIH, as a Medical Officer in the Pregnancy and Perinatology Branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NICHD.
Her research on stillbirth as part of the Stillbirth Collaborative Research Network, SCRN, preterm birth and labor management has had a profound impact on obstetrical practice both in the United States and internationally. She received numerous NIH awards for her role in advancing women’s health research agenda nationally.
Dr. Reddy has been selected to serve as a Member of the American College of Obstetrics and Gynecology, ACOG, Committee on Practice Bulletins – Obstetrics; Fellow of the American Gynecological & Obstetrical Society and was selected as Fellow in Executive Leadership in Academic Medicine, ELAM, Program for Women.
Dr. Uma Reddy: Hi, I’m Uma Reddy. I’m pleased to be able to speak to you virtually about an update on the management of stillbirth. Today I’ll be discussing obstetric care consensus statement that was issued by the American College of Obstetricians and Gynecologists, as well as the Society for Maternal-Fetal Medicine on the management of stillbirth. This document was issued in March of 2020. I’m going to define stillbirth, its impact in obstetrics. Describe the risk factors, etiologies, and conditions associated with stillbirth. Describe the workup for stillbirth as advocated by this document.
Infant mortality has decreased more than the stillbirth rate in the US. This graph shows how infant mortality has decreased, whereas stillbirth or fetal deaths 20 weeks or greater has been completely stable and has not changed in over the past decade. In the US, the stillbirth rate is 6 per 1000. There are 23,000 stillbirths in the US every year. That’s 1 in 165 pregnancies. The lack of decline in stillbirth over the past decade, plus the decline in infant mortality, resulted in 2013 that the stillbirth rate was even greater than that of infant mortality.
When we look at the rate of early stillbirths, 20 to 27 weeks, and then 28 weeks or more, you can see that the rates are equivalent about 3 per 1000. I’m going to review the maternal conditions associated with stillbirth, the fetal conditions associated with stillbirth, obstetric conditions associated with stillbirth, then other conditions, and then unexplained or stillbirths that despite a complete workup have no explanation.
This just shows, in the US, the racial disparity in stillbirth. You can see that non-Hispanic Black women have double the rate of non-Hispanic white women of stillbirth. This is a paper where we looked at maternal age, the independent effect of maternal age on the stillbirth risk. What you see is these are about 5 million pregnancies where we took out chronic medical conditions, and we also took out fetuses that had anomalies. This top graph is women who are 40 years or greater at the time of delivery, and you see basically starting at 32 weeks, there is an increased risk of stillbirth, which dramatically takes off at 38 weeks. This line is women 35 or over, you see they have an increased risk of stillbirth increasing at 37 weeks. Then these are the rates for 35 and under.
Assisted reproductive technologies, we know is associated with an increased risk of stillbirth. This is due to an increased rate of multiple gestations, but even for singleton pregnancies, there’s a fourfold increased risk of stillbirth for IVF/ICSI pregnancies versus spontaneous pregnancies. The reason for this increased stillbirth risk is unclear. It wasn’t clear for a long time. Was it the underlying infertility that led to the predispose to stillbirth, or is it something in the IVF/ICSI process?
One of many papers, now we understand that when you look at women who have IVF and ICSI, and you compare them to a group of women who took more than a year to get pregnant, or used non-IVF assisted reproductive technology, that there is an increased risk of stillbirth. That indicates that there is something with the ART process that increases the risk.
Obesity is associated with conditions that increase the risk of stillbirth. Diabetes, major congenital anomalies, preeclampsia are increased in women with obesity, but even without any of these conditions, obesity by itself is an independent stillbirth risk factor.
Smoking is a modifiable risk for smoking. There’s a 36% increase in the odds of stillbirths for women who smoke. Women who quit smoking between the first and second pregnancies, their stillbirth risk declines to that of non-smokers in the second pregnancy.
This is a chart that just shows various maternal conditions, the prevalence, and the stillbirth rate per 1000. Just remember in the US the rate is 6 per 1000. Chronic hypertension, there’s an increased risk of stillbirth anywhere from 6 to 25 per 1000. Preeclampsia, 9 to 51 per 1000. Preeclampsia with severe features, the risk of stillbirth is even higher at 12 per 1000. Diet controlled diabetes, gestational diabetes. In most studies, well controlled gestational diabetes and diet, there is not an increased risk above the population.
Insulin requiring stillbirth is associated with an increased risk of stillbirth anywhere from 6 to 35 per 1000 and women who have type 2 diabetes have an increased risk of stillbirth compared to women with type 1 diabetes. We think that women with type 2 diabetes have other conditions that increase their risk such as obesity, and then they’re less likely to receive a preconception consult to get their blood sugars under good control prior to pregnancy.
Lupus, even though the prevalence is very low, less than 1%, the rate of stillbirth is greatly increased 40 to 150 per 1000. Renal disease also is very low, less than 1% prevalence, but also an increased risk of stillbirth, 15 to 200 per 1000. Thyroid disorders, 0.2 to 2%, an increased risk of stillbirths, particularly for hyperthyroidism. Then cholestasis of pregnancy is less than 0.1%, but an increased risk of stillbirth of 12 to 30 per 1000.
Next, I’m going to move to fetal conditions. Fetal conditions, we divide into genetic conditions that are associated with stillbirth, infectious causes of stillbirth, and then I’ll talk about fetal growth restriction itself.
Genetic conditions, there are chromosomal abnormalities associated with stillbirth. There are syndromes and malformations, single gene disorders that are associated with stillbirth. There are X-linked conditions that result in male stillbirths. There are autosomal dominant mutations, so skeletal dysplasias which are sporadic mutations associated with stillbirth, but there’s Long QT syndrome, which is parentally inherited associated with stillbirth. Then confined placental mosaicism, which is when the placenta has an abnormal karyotype, abnormal chromosomes, but the fetus has a normal karyotype.
I’m going to focus on chromosomal abnormalities because that’s the most common genetic condition associated with stillbirth. The rate is anywhere between– for 6 to 12% of all stillbirths, there is a chromosomal abnormality. The rate is underestimated because of the failure to culture cells. There is an increase with chromosomal abnormalities if there’s malformation. Also, with earlier stillbirths, there’s an increased rate of chromosomal abnormalities. Similar to live births, the distribution is predominantly monosomy X and trisomy 21, and then followed by trisomy 18 and trisomy 13.
Infections cause 10 to 25% of all fetal deaths. Higher in developing countries. More common at early gestational ages in developed countries.
The mechanism of stillbirth. Infection can directly cause fetal infection, damaging organs and leading to developmental abnormalities. There can be placental damage. There can be severe maternal illness or intrauterine infection, which precipitates preterm labor, and when the gestations are periviable that leads to a stillbirth.
This is an example of stillbirth from the second trimester, and this is the fetal spleen. What you can see is that there’s this cell which is an erythroblast and has marginated chromatin and amphophilic intra-nuclear inclusions, and this is significant for parvovirus B19. This is important because this is not something that will recur, parvovirus B19.
In one study in Sweden, 8% of all stillbirths had evidence of parvovirus B19 by PCR. We know the virus is trophic for fetal red blood cells precursors or cardiac cells. It attacks these cells and it could cause anemia and hydrops. Parvovirus B19 can also directly attack the fetus’s heart causing direct myocardial damage leading to stillbirth.
This unfortunate baby has succumbed to CMV, which is the most common congenital viral infection in pregnancy. 1% of pregnant women acquire primary CMV during pregnancy. Primary CMV has the highest rate of transmission and the most severe consequences. CMV causes placental damage, fetal growth restriction, and has direct fetal effects that we can see on ultrasound.
I need to mention COVID-19. What is the relationship of COVID-19 and stillbirth? On one study, this was reported in a hospital in the UK where they found that the incidence of stillbirth was increased during the pandemic. There was a rate of 9.31 per 1000 births, versus 2.38 per 1000 before the pandemic. However, all the stillbirths, none of them were associated with COVID-19. The authors theorized that because of COVID-19, women were not seeking care promptly because of fears of COVID-19, and that’s what resulted in increased rate of stillbirth.
However, with larger numbers, the CDC has shown that there really isn’t a relationship between COVID-19 and stillbirth. The CDC collected pregnancy and infant outcomes among 4,442 women who had SARS-CoV-2 and known pregnancy outcomes. As you can see, the miscarriage rate was 0.3%. The stillbirth rate was 0.4%. So not higher than the general population. There was a higher rate of C-section at 34% versus 31.9%, and a high rate of preterm delivery with preterm delivery at 13% in COVID positive women versus 10% in the population rate. Outcomes did not differ by maternal symptom status, but only 8.5% of women were asymptomatic in this study.
Fetal growth restriction is accompanied by stillbirth often, but we need to understand why the fetus is growth restricted. It’s by itself not a cause of stillbirth. This just shows that if you look at babies that are less than the third percentile, which is this green line here, there’s a much-increased risk of stillbirth as gestational age goes on and it really takes off starting at 37 weeks. There’s a much-increased risk. This is the third to fifth percentile and the risk starts to take off at 37 weeks. Then for the 5th to 10th percentile at 39 weeks, you see an increased risk. In summary, compared to the less than third percentile, it has a threefold increased risk versus the third to fifth percentile and a four to seven times stillbirth risk compared to the 5th to 10th percentile.
Obstetric conditions. Abruption, cord prolapse, cervical insufficiency, preterm labor, preterm prelabor rupture of membranes can all cause stillbirth if it occurs at a periviable gestation because you’re not going to intervene by performing a C-section.
Maternal hemorrhage occurs in 4% of all stillbirths, and it depends on the volume of blood transfused. 50 to 75% of the total fetal placental blood volume needs to be lost to result in stillbirth. You need a reliable method for identification and quantification of fetal maternal hemorrhage, ideally before labor induction, and there should be evidence of hypoxia, anemia on autopsy.
Umbilical cord accidents are associated with 10% of stillbirths. Possible mechanisms include cessation of blood flow, intermittent disruption of blood flow, fetal blood loss, cord entanglement, but you have to be careful, 30% of normal pregnancies, there is a nuchal cord. To establish causality; cord occlusion and hypoxic tissue injury on autopsy, and excluding other accepted causes of stillbirth helps you understand if nuchal court accidents are the cause of stillbirth.
What is the optimal evaluation of stillbirth? It’s very controversial, there’s cost versus the yield. You need to focus on common causes, focus on recurrent conditions, pay attention to clues, and of course it’s emotionally challenging with varied levels of comfort with autopsy and genetic testing.
According to the ACOG stillbirth obstetric care consensus, a new document, you should definitely do a thorough clinical history, fetal autopsy, placental evaluation, fetal karyotype and microarray. Microarray picks up small changes in DNA. Small deletions and duplications that cannot be picked up by karyotype but can be associated with stillbirth. Screened for fetal maternal hemorrhage, lupus anticoagulant screen, anticardiolipin, beta-2 glycoprotein antibodies also associated with stillbirth. If this is diagnosed, then for the next pregnancy you could treat with heparin, and then syphilis, if that hasn’t been performed before.
Tests that are performed in selected cases include testing for specific infections, the maternal serum and fetal tissues. Additional genetic testing depending on what you find on autopsy. Indirect Coombs if it hasn’t been performed previously. Performing glucose screening again, either with OGTT or hemoglobin A1C if the baby is large for gestational age, and then toxicology screening in select cases.
Tests that are not useful are placental cultures, routine TORCH titers, ANA testing, testing for a large number of thrombophilia, and then bile acids, glycohemoglobin or thyroid function if there are no features of the disease. Meaning that if a woman is asymptomatic that just testing for bile acids or for thyroid disease or glycohemoglobin will not be useful.
What about pregnancy after stillbirth and management? This is a very difficult pregnancy for families. You really need to be there to support them at the preconception or initial prenatal visit, obtaining a detailed medical or obstetrical history, getting the evaluation or workup of the previous stillbirth, determination of recurrence risk. There’s an increased risk of recurrence stillbirth, fivefold increased risk in the next pregnancy. Smoking, alcohol, illicit substance cessation. Weight loss and obese women pre-pregnancy. Genetic counseling if a family genetic condition exists, performing in diabetes screen, testing for lupus anticoagulant, anticardiolipin antibody, and beta-2 glycoprotein if that hasn’t been performed yet, and providing support and reassurance.
In the first trimester, dating ultrasound by crown-rump length is important to have a sure due date. You can perform first trimester screen or cell free fetal DNA testing, and then support and reassurance. Second trimester, fetal anatomic survey at 18 to 20 weeks. You can offer genetic screening if there wasn’t performed the first trimester, and MSAFP if the first trimester screen was already performed, and then support and reassurance.
In the third trimester, serial ultrasounds starting at 28 weeks are recommended to allow fetal growth restriction. As I showed you, the risk is stillbirth goes up with fetal growth restriction. Fetal movement county starting at 28 weeks. Antepartum fetal surveillance starting at 32 weeks or 1 to 2 weeks earlier than the prior stillbirth.
Then at delivery, this is a big change. Prior it was that delivery could be done at 39 weeks if there was no indication for earlier delivery. The statement has been changed with this latest guideline. Planned delivery at 39 weeks or as dictated by other maternal or fetal comorbid conditions. In cases of severe patient anxiety, where there is a preference to proceed with early term delivery, such decisions must incorporate the understanding of the increased risk of neonatal complications with early term delivery compared with the potential benefit. Basically, performing a delivery at 37 or 38 weeks can be done as long as the woman and her partner understand the neonatal risks with an early term delivery compared to waiting to 39 weeks.
I just want to spend the last few slides on research on prevention. This was a well-done trial by Jane Norman and colleagues called AFFIRM, the awareness of fetal movements and care package to reduce fetal mortality. They studied a reduced fetal movement care package, which included increasing women’s awareness for prompt reporting of reduced fetal movements. Then also performing standardized management, CTG, NST, amniotic fluid assessment, growth ultrasound, including timely delivery for women reporting reduced fetal movements.
They looked at 409,000 pregnancies, and what they found was the stillbirth rate was 4.4 births per the control period, so before this package of interventions was introduced. Then after the intervention was introduced, it was 4.06. Basically, there was no difference by using this reduced fetal movement package of making women aware of prompt reporting to reduce fetal movements and the standardized management. In fact, there was an increased risk of induction of labor, C-sections, and prolonged NICU admission after the intervention period.
Antenatal testing for advanced maternal age. This is a hot topic. Women 35 and over comprised 15% of all births in the US. Women 40 and over, 3% of all live births. The ACOG Committee Opinion just came out actually, SMFM. This just came out a couple of months ago on Indications for Outpatient Antepartum Fetal Surveillance. What does it say? It says for maternal age greater than or equal to 35, antepartum fetal testing should be individualized based on cumulative risk when present with other factors. What that means is that they’re leaving it to the practitioner to individualize it. If there are other risk factors, then you may want to perform antepartum testing.
There are very few studies directly looking at this. This is a study that was done of 4,469 singleton pregnancies. 34% of the women were advanced maternal age and 65% were not advanced maternal age. For the women who were advanced maternal age, they did weekly biophysical profiles starting at 36 weeks and planned delivery, 41 weeks or sooner if indicated. They took out fetuses with lethal and chromosomal abnormalities.
What the authors found was that stillbirth in the advanced maternal age tested group was similar to that of the non-advanced maternal age group. The rate 3.9 in the tested group versus 3.4 per 1000 were similar. The authors concluded, if there isn’t the increased risk of stillbirth, as I said, there’s usually a fivefold increased risk in stillbirth. The rates were saying testing must work. This is very indirect evidence.
What about obesity? We talked about that as being a risk factor for stillbirth. This is a paper that looked at thousands of stillbirths. What they did is they looked at it by BMI, body mass index here on the X-axis and the risk of stillbirth. What you see over here on the X-axis– I’m blocking the number 40, but a body mass index of 40 that the relative risk of stillbirth is twofold increase. This is similar to the risk with hypertension and diabetes, so an increased risk.
What does this recent ACOG committee opinion SMFM document on indications for outpatient antepartum fetal surveillance say? It says that if the pre-pregnancy BMI is 35 to 39.9, that you should do antepartum fetal surveillance starting at 37 weeks. If the pre-pregnancy BMI is 40 or above, that you should start weekly antepartum testing at 34 weeks.
What about timing of delivery or induction as an intervention? The ARRIVE trial, A Randomized Trial of Induction Versus Expectant Management studied the question if elective induction of labor in nulliparous women at 39 weeks improves perinatal outcome compared with expected management. The primary outcome was a composite of stillbirth or neonatal death or severe neonatal morbidity, and the sample size was 6,100. This study was very important to do because previous studies, the thought was that induction of labor increased the C-section rate. Really you shouldn’t do an induction unless there’s a reason to do an induction. A medical obstetric complication.
However, the comparison group in all those studies were women who were already spontaneously laboring. If you can think about this, if you’re already spontaneously in labor, you’re that much closer to having a vaginal delivery and have a decreased risk of C-section. When really the comparison group should have been women who you leave alone at 39 weeks. Either you can induce a woman at 39 weeks or you can continue prenatal care until she goes into labor on her own or needs to be induced for some other reason.
This trial was patterned on comparing these two groups and what they found was the primary perinatal outcome was 4.3% in the induction arm and 5.4% in the expectedly managed arm. The relative risk was 0.8. The risk of the primary outcome was reduced in the induction arm. However, just statistically, we said this was not significant and it’s because this competence interval includes one. We said there was not a significant difference.
When we looked at respiratory support, the induction arm had a lower rate of the respiratory support compared to expectedly managed arm. The induction arm had a lower rate of C-section, 18.6% versus 22.2% in the expected arm. Why is that? Why would expectedly manage women have a higher risk of C-section? That’s because at 39 weeks, if they’re not favorable, they can go to 41 weeks and not be favorable. Yet the baby has gotten that much bigger, women develop preeclampsia, oligohydramnios, placental issues develop. There are a whole host of reasons why the C-section rate ends up being higher. Then one of the explanations is hypertensive disorder. Pregnancy induction arm had a much lower rate, 9.1%, compared to the expectedly managed arm. Really, in the ARRIVE trial, induction of labor arm had all the benefits.
This was an interesting editorial about antepartum testing for the prevention of stillbirth. Where do we go from here? The authors stated, beyond 39 weeks of gestation, if the established risks of stillbirth are deemed unacceptable, delivery is a more rational evidence-based approach than antepartum testing. Meaning instead of doing a non-stress test, it would make more sense to deliver women at 39 weeks if you’re concerned about the risk of stillbirth.
What about low dose aspirin? It’s widely available. It has anti-inflammatory effects, it impacts blood flow, there are few maternal side effects, it’s safe during pregnancy, and it’s inexpensive. This was a study done by the Global Network. They did a study called the Aspirin Supplementation for Pregnancy Indicated Risk Reduction in Nulliparas, ASPIRIN. This study was based on the fact that another study showed that women who took low dose aspirin before trying to conceive actually had a lower rate of preterm delivery.
This study was based on that finding and the primary hypothesis was that nulliparous women treated with low dose aspirin starting at 6 to 13 weeks gestation through 36 weeks gestation will reduce the rate of preterm birth. This was done in low- and middle-income countries, and this was a prospective randomized placebo-controlled trial. 11,976 women were included and there was a secondary outcome of stillbirth.
What were the results? Low dose aspirin was associated with a lower risk of preterm delivery, less than 37 weeks. 11.6% versus 13.1%. Low dose aspirin was associated with the decrease in perinatal mortality, so death greater than 20 weeks, and neonatal deaths less than 7 days, and decrease fetal loss, which was defined as death after 16 weeks and before seven days postpartum. Aspirin did reduce stillbirth.
Genomics is another area. There’s a lot of research going on. Long QT syndrome or LQTS, we know it’s associated with 9.5% of SIDS cases. If you imagine sudden infant deaths syndrome, there’s a continuum that term stillbirths, these stillbirths, unfortunately, we don’t find a cause for them. It’d be a continuum from SIDS to these term late stillbirths that are unexplained?
These authors did targeted sequencing on a panel of 70 genes associated with cardiac channelopathies and cardiomyopathies. These basically cause Long QT syndrome, and what they found was there were pathogenic variants. Meaning variants that are associated with disease, and 12% of the 290 cases is stillbirth. Indicating that there is a continuum probably between these unexplained late stillbirths and sudden infant death syndrome.
Now we’re looking to exome sequencing. As you know, this is a chromosome and there are genes and the parts of the gene it’s a nonfunctional part of the intron. There’s the exon, which is a functional part of the gene, and this is responsible for making the protein. What is the exome? It’s all these exons in a genome. When you sequence all the protein coding regions of a gene in a genome that’s called whole exome sequencing. Whole exome sequencing, we’re sequencing all the functional parts of a gene.
On the Stillbirth Collaborative Research Network, which is a study that took place in 2006 to 2008 we did whole exome sequencing of the stillbirths. We had 246 stillbirths, where there was normal microarray. They had normal karyotype, normal microarray, and no identified cost. What we found was 6.1% of cases had seven known disease genes implicated in stillbirth. There were 2.4% of cases that had a suggestive genotype in either a known stillbirth gene or a gene candidate. Whole exome sequencing found a probable molecular diagnosis of 8.5% of cases.
Based on what we know about stillbirth from the Stillbirth Collaborative Research Network, 18% of all stillbirths had a known genetic cause. 6.9%, the aneuploidy, which is when there’s a chromosome missing or additional chromosome. 2.6% had the pathogenic copy number, which means they had a microarray either additional microdeletion or duplication of genetic material, which is known to be associated with stillbirth. Then another 8.5% by whole exome sequencing.
I’m going to end here with Lighthouse State Park in Connecticut which is nearby, and thank you for your attention.
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