Project Narrative
This project studies the causes of stillbirth that remain unknown after a complete evaluation that may include autopsy and placenta examination. MRI will be utilized while the deceased fetus is still in the uterus to identify foci of umbilical cord that are vulnerable to collapse of the vascular lumens by torsion and would not be discoverable after delivery. The study also expands the clinical history to look for sublethal events that combined with other factors could trigger progressive fetal acidosis and death.
Aims:
Fetal deaths today account for approximately 24,000 deaths/year. Of these deaths, we classify those the cause of which could not be discovered even after an autopsy and/or placental examination as Sudden Fetal Death Syndrome (SDFS). These SDFS deaths account for 25 to 80% of all fetal deaths, depending on the classification system. In the PI’s database of approximately 1000 personally performed autopsies of stillborn infants, the percentage is closer to 33%. In its 2010 Healthy Goals, the DHHS aimed to reduce fetal deaths from 5.9 to 4.1/1000 live births, but unlike the success with sudden infant death syndrome, no progress was made. The 2030 Healthy Goals now aim for a more modest reduction from 5.9 to 5.7/1000 live births. In the interval from 2010 until now, an NIH-funded collaborative stillbirth research network studied maternal risk factors, but failed to find a pathway to substantially reduce fetal deaths. Our study takes a needed new approach by focusing on finding causes of SDFS.
An autopsy elucidates a chain of causation of an individual infant starting with the immediate mechanism of death and working backwards to the proximate cause. Even in SFDS, there are autopsy findings of immediate cause. Based on findings in expected deaths, such as placental abruption, fetal asphyxia may demonstrate two anatomical patterns of immediate causation. One is intrathoracic petechiae, which result from fetal gasping following complete asphyxia, and the other is acute heart failure with pleural effusions from partial asphyxia. These same findings are common in SFDS, arguing for asphyxia as a frequent mechanism of death. To be classified as SFDS, a further requirement is that the proximate cause of death not be discoverable after birth. A plausible invisible cause of asphyxia is occlusion of umbilical cord blood flow. In vitro experiments of the perfused vein in the umbilical cord show that torsion can collapse the vein and stop flow with only a modest twist of a short segment such as that remaining after the cord is wrapped around a fetal part near the placental insertion. The lumen can also collapse if the cord is trapped and kinked. These causes of cord compromise would not be discoverable after delivery.
Our hypothesis is that cord configurations in utero may cause partial, intermittent, or sudden complete cessation of umbilical cord blood flow that is undetectable after delivery of the infant. Fetal MRI studies taken to study anomalies have already demonstrated their ability to visualize the umbilical cord in situ. The major innovation of this study is to use MRI of the mother prior to delivery of the deceased fetus to make visible the position and relationships of the whole umbilical cord in order to identify cord vulnerabilities that could account for fetal asphyxia and explain the fetal loss.
An alternative, but not mutually exclusive, explanation of SFDS is the tipping point hypothesis that postulates that less severe causes of fetal hypoxia/acidosis involving maternal risk factors and behavior, placental function, and umbilical cord compromise cause a positive feedback loop of fetal hypoxia causing decreased fetal cardiac output to the placenta, causing worse hypoxia, and ending in death. We will evaluate this hypothesis by a questionnaire focused on the maternal behavior just prior to fetal death and the integration of that history with the clinical risk factors, placental examination, autopsy, and MRI findings.
Aim 1: To obtain in situ MRI of the stillborn infant prior to delivery to evaluate the whole umbilical cord length and its relationships to the fetus, placenta, and pelvis.
Aim 2: To gather maternal history of events near the time of death, and with an evaluation of the known maternal risks of stillbirth, the placental examination, the autopsy, and the in situ MRI findings, identify plausible combinations of factors that would lead to an hypoxic tipping point.
This is a pilot study that if successful will lead to a larger multi-institutional study to improve understanding of specific causes of SFDS. This understanding could lead to improved detection and prevention and to novel therapies for SFDS. The insights into SFDS may also improve understanding of fetal hypoxic brain injury and fetal intolerance to labor, which may likewise improve prevention and clinical management.
Significance: Hypothesis 1: Some unexplained stillbirth is due to occlusion of umbilical blood flow due to torsional collapse of the lumen of umbilical vessels.
An unexplained stillbirth, even after a compete autopsy and placental examination, is a cause of anguish for parents and their obstetrical care givers that has diminished very little over the prior decades. The multiple efforts from the NIH to reduce this number, including an RFP for stillbirth in the mid 1990’s and the creation of the Stillbirth Collaborative Research Network are ample evidence of an effort to reduce the tragedy of stillbirth. Unfortunately, we still have not found a key to reduce this rate.
As a pathologist I have struggled to find a cause of death in more than 1,000 stillborn autopsies, an experience not easily available to obstetricians. There are only a few mechanisms that can cause death in uterosuch as shock from sepsis, or hemorrhage, fetal heart failure (non-immune hydrops), or fetal anoxia/hypoxia. Experience shows that known proximate causes of death often have some autopsy findings similar to those in unknown causes of death, particularly those that are the result of basic physiologic adaptations of the fetus to various stresses. To investigate this observation, I utilized a natural experiment of a variable severity of asphyxia, the premature separation of the placenta (clinically a placental abruption) in a series of stillborn autopsies1. I measured the area of infarcted placenta over the placental separation as a measure of the extent of lost gas exchange (asphyxia) and related that percentage of infarcted area to the autopsy findings. Large separations correlated with intrathoracic petechia in the fetus. I interpreted the petechiae as the consequence of fetal gasping analogous to the experimentally induced gasping in newborn monkeys with sudden complete anoxia from airway occlusion immediately after birth2. Lesser separations demonstrated only acute heart failure (dilated chambers and thoracic effusions) in the fetus which I interpreted to be analogous to Myer’s nonhuman primate experiments that demonstrated prolonged fetal hypoxia/acidosis led to fetal cardio-vascular collapse and death or if resuscitated, to massive fetal brain damage3. In Myer’s summary “The few animals that survived asphyxia to show the long-term clinical abnormalities and the specific patterns of brain injury simulating human cerebral palsy almost all experienced a marked hypoxia followed by a brief period of anoxia. The anoxia or near anoxia they experienced generally developed as a consequence of a circulatory failure that appeared late during the exposure to marked hypoxia.4” In my experience, these two patterns of asphyxial autopsy findings found in placental separation are also encountered in the majority of unexplained fetal deaths. The key to understanding unexplained stillbirth is therefore to find the cause of asphyxia in stillbirths of unknown cause.
One cause of fetal asphyxia when no other cause is evident is “umbilical cord accident”, a shorthand term for occlusion of umbilical blood flow. Like the umbilical cord of a deep-sea diving device, it is intuitively evident that the umbilical cord is the lifeline of the fetus, but it is unclear what could cause its failure, except in a few well-documented exceptions (cord prolapse, umbilical hematoma, tight true knot). There is indirect evidence of “cord accident” from epidemiologic correlation of stillbirth with knotted and complex wrapped cords5, and with the dual association of cord anomalies and stillbirth with fetal vascular malperfusion lesions in the placenta6,7. These studies do not clarify the anatomic cause of the cord accident. Previous studies of umbilical cord vascular occlusion have often failed to consider the natural anatomic mechanisms. This is particularly true with ovine cord compression studies using occluders8,9. In vitro studies have only considered transverse pressure on the cord10,11. Our experiments and experience with perfusing an umbilical cord and manipulating it around surrogate infant parts, clarified a likely anatomic mechanism of cord accident, which is collapse of the vein lumen from torsion12. This mechanism is intuitive. People stop the flow of water in a hose by folding it with a subtle torsion, not attempting to compress it with transverse force. When a garden hose stops flowing, it is from a kinked loop created by torsion that collapses the lumen. Short of an automobile on it, it is impossible to transversely compress the hose to stop flow. Our study further showed that twisting a short segment of cord (tube) collapses the lumen with less of a twist than needed with a longer segment. This relationship can be confirmed with a paper straw. The raw correlations with cord anomalies in the literature are indirect evidence that supports our conclusions in that both multiple nuchal loops and knots (the result of body loops) are likely to have produced functionally shortened cord segments in utero. There are multiple ways that a cord vein lumen could be collapsed by torsion of a short segment or by an entrapment. These vulnerable configurations would not be evident after delivery of the infant. Our study will search for them by looking at the umbilical cord configuration in situ prior to delivery.
Hypothesis 2: Some unexplained stillbirth is due to an additive convergence of sublethal hypoxic/acidotic fetal insults that reach a lethal tipping point.
In addition to cord accidents, it is likely that there are other mechanisms accounting for unexplained stillbirth. The existence of risk factors shown to increase the likelihood of stillbirth cannot be accounted for by cord accidents. A second cause of stillbirth that would not be detected as a specific anatomic lesion would be if a confluence of sublethal factors in and of themselves could provide a tipping point to a feed forward of heart failure and further hypoxia ending in fetal death. Risk factors may require secondary events to cause stillbirth. For example, obesity may cause sleep apnea in some mothers13, or a diabetic mother might be ill and develop a mild ketoacidosis14 or growth restriction with oligohydramnios could cause cord trapping and torsion. Some of the secondary factors utilized in Myer’s experiments to create fetal acidosis were maternal stress15, hypotension from aortic compression16, hypotension from anesthesia17, and carbon monoxide18. Sleeping position, respiratory problems, medications, and gastrointestinal illness or fasting have all been hypothesized to decrease fetal oxygenation and or increase acidosis14,19-29. We will gather the pre-mortem “microhistory” events by questionnaire, and integrate those data with the MRI, risk factors, placental examination, and autopsy to identify plausible mechanisms that could lead to stillbirth.
Our fundamental critique of previous studies is that they do not elucidate the entire causal chain from proximate to the immediate events that permanently stop cardiac activity. The classic example of a complete causal chain is Rh immunization. The most proximate cause is expression of a paternal allele of Rh to which the mother develops an alloimmune antibody that crosses the placenta, causing fetal red cell hemolysis that results in anemia leading to high output heart failure and ultimately causing a tipping point when low oxygen transfer and progressive heart failure reach hypoxia/acidosis that cannot sustain life. A second fundamental criticism is that studies often consider only single factors, but a chain of causation may require multiple independent factors, for example, an obese mother may have a placenta with delayed villous maturation, evidence of increased erythropoiesis in the fetus, and observable sleep apnea. Studies that do not rely on careful correlation of a chain of causation for an individual stillbirth miss steps in causation and the opportunity to discover interventions.
Classification systems of perinatal death have little agreement with each other since the classification categories often have only an indirect association with the causation of death such as placental abnormalities or fetal growth restriction, and as a result, the systems disagree on the numbers of deaths that are due to an unknown cause. This is exemplified in a study that classified 485 stillbirths (348 with autopsies) using the different systems30. The Wigglesworth system had 88.5% unknown; the Aberdeen 60%; the Hey 88% antepartum asphyxia; the Hovatta 19.4% unexplained, but 26% other placental deaths; the Galen-Roosen 26% unclassifiable, 22% problematic and 44.5% placenta; the Morrison 20% unclassified or problematic, 21% placental insufficiency; the ReCoDe 14.2 % unclassified, an additional 50% were FGR or “placental insufficiency”; and the TULIP classification 23.3% unknown, 64.3% placental. The classification systems do not define the criteria for a placental lesion to become a cause of death. Our experience with premature placental separation and with villitis of unknown etiology is that the threshold for fetal death requires semi-acute loss of half the functional placental volume1,31. Some systems also do not define the underlying cause of asphyxia.
This same weakness of an incomplete chain of causation limits the value of enumerating risk factors for stillbirth. These studies cannot account for the large number of patients with the same risk factors but without stillbirth. Another weakness of such studies is that the risk factor often cannot easily be modified to reduce the incidence of stillbirth. Risk factors for stillbirth include higher maternal age32, thrombophilia33, higher maternal hemoglobin concentration34, higher maternal weight35, chronic hypertension36, diabetes37, and many others. The Stillbirth Collaborative Research Network (SCRN) concluded that: “Multiple risk factors that would have been known at the time of pregnancy confirmation were associated with stillbirth but accounted for only a small amount of the variance in this outcome”38. A later re-analysis of the SCRN data likewise showed little advantage to the data. For example, the data did not provide guidance on the relative risk of early delivery to that of stillbirth in fetal growth restriction39. The same re-analysis attempted to define features of placental insufficiency but failed to connect quantifiable placental findings to an immediate mechanism of death.
Classification systems and risk factor studies both make correlations with placental findings and stillbirth that fail to demonstrate the full chain of causation40. Naming a lesion is different than understanding how it causes death. Separately from this grant proposal, we are pursuing approaches to placental examination that use morphometric data to develop measures of placental reserve such as surface area of vascular syncytial membranes (the respiratory functional portion of villi) and the total capillary volume at standard perfusion pressure, both per gram of infant. Placental evaluation needs to look at quantitative features of function independent of cause.
We further are modifying autopsy protocols to obtain more direct information about physiologic findings that directly relate to the immediate mode of death, such as better measures of cardiac dilation and failure, blood redistribution, cortisol related stress, and evidence of fetal gasping that is missing from some epidemiologic studies41.
Innovation: Our innovations in Aim 1 are A. to postulate a novel mechanism of umbilical cord accident as a cause of fetal asphyxia in unexplained stillbirth, namely the collapse of a vessel lumen from torsion in a functionally short cord segment and B to use MRI of the fetus in situ to find this novel anatomic mechanism that would not be detectable after delivery of the infant. Our innovation in Aim 2 is to search beyond risk factors and associations to find potentially preventable causes of stillbirth by postulating a tipping point that leads to lethal hypoxia that would occur from summation of otherwise less than lethal factors. We will pursue this with a questionnaire of events just prior to death and correlate this information with the clinical history, autopsy of the infant and placental examination.
Approach:
Preliminary studies:
1) Stillborn autopsy experience including evaluation of the placenta: The Magee pathologists have performed more than 1000 stillborn autopsies that include the placental examination, as well as over 70,000 personally performed placental examinations.
2) Survey of Star Legacy parent group: A survey taken this year for this study parents of previous stillbirths through the Star Legacy organization found that of those 790 responding, over 82% would have agreed to an MRI and that over 67% would have had a sufficient interval for the MRI after the discovery of the death of their infant.
Research Proposal:
Methods:
Type of study: This is a prospective, observational study applying a new technology, MRI of the stillborn infant in utero, with clinical pathological correlation.
Recruitment: The patients will be recruited from mothers presenting to Magee-Womens Hospital who have an undelivered stillborn infant.
Eligibility: A program of education will be developed to inform obstetricians and physician assistants of the study. They will be asked to inform the study coordinator of the admission of an eligible patient to Magee hospital. The patient will be eligible after an obstetrician determines that 1) the patient is not in active labor and 2) a fetal death has been confirmed.
Consent: An investigator will explain the study to the patient and obtain informed consent for the MRI of her abdomen and pelvis and the request to interview the mother about the events around the time of the fetal death in order to help us understand these events. It will be explained that we have no evidence yet that any of these events are significant. A separate consent for the autopsy with placental examination will be obtained. The parents will be given the option of returning for a review of the study and autopsy findings approximately 6 weeks after the delivery.
Demographic Data: A chart review of each patient will be undertaken that includes completion of the NIH SCRN Initial Causes of Fetal Death Form 91 A. In addition, we will collect the basic demographic data available from the patient electronic medical record including the maternal age, weight, zip code, race, parity and gravidity, mode of delivery, gestational age at presentation, the last known documentation that the fetus was alive, the date that fetal death was first identified, and the date of delivery of the infant. The routine placental examination and report will be issued by pathologists at Magee-Womens Hospital and additional placental data will be obtained pending the results of an ancillary study of placental sampling. A fetal autopsy will be requested and routinely performed along with modifications for this study at Magee Hospital for Women.
Potential bias: This study of necessity involves only women of reproductive age. There is an established higher risk of stillbirth for male than female fetuses42. This is an unavoidable bias that is included in the investigation. There are known differences in epigenetic changes to placental growth genes between males and females43.
Aim 1: The MRI: After consent of an eligible patient, a full abdomen/pelvic MRI scan will be performed at Magee Hospital as soon as possible with the standard precautions and patient education. The scan will be interpreted by the radiologists at Pittsburgh Children’s Hospital. The complete course of the umbilical cord will be identified. The following points along the cord will be identified and measured from the placental insertion: the beginning of a cord wrapping around a fetal part, the beginning and end of a cord segment between a fetal part and the bony pelvis (with only the uterus between them), the beginning and end of cord segments that are thin or compressed, and the apex of any acute angle made by the cord. Findings of less than a 10 cm segment of the cord between the placental insertion and beginning of fetal wrapping will be considered a positive scan. A focus of the cord between the fetal part and the bony pelvis with either narrowing or an acute angle will also be considered as a positive scan. The fetus, placenta and maternal structures will be routinely evaluated.
Umbilical cord examination: The umbilical cord will be examined according to standard protocols at Magee Womens Hospital. In addition, the umbilical cord insertion will be twisted and its vascular stability noted. The defined cord points described in the MRI evaluation will be measured with the reference point as the distance from the placental insertion and marked on the cord. After marking, the whole cord will be photographed. Multiple 2-3 mm sections around each of the marked points will be labeled by location and submitted for histological evaluation along with standard sections from the fetal and placental insertion portions of the cord, and sections of any possible compression of the cord.
Potential problems and alternative approaches: Aim 1
The hypothesis could be wrong 1) if the anticipated cord vulnerabilities are naturally reversed in utero prior to the MRI, 2) if the anticipated cord lesions are not a cause of compromised umbilical cord blood flow 3) if compromised umbilical blood flow is not a cause of unexplained stillbirth, and 4) if there are other mechanisms that cause the autopsy findings seen with asphyxia in premature placental separation. Our alternative approach is encompassed in the second hypothesis and Aim 2, which evaluates multiple sub-lethal events that could lead to asphyxial fetal death. If neither approach yields a testable mechanism of stillbirth, we must conclude that our hypotheses are wrong, and that we must identify alternative hypotheses that are now unanticipated.
Anticipated results and interpretation of data: Aim 1
Based on 224 records of autopsies of stillborn infants that the PI performed in Louisville, KY from 2000 to 2014, approximately 31% have no specific cause of death after a complete autopsy and placental examination. This group was composed of 58 cases classified as “unknown” and 12 classified as “unexplained acute asphyxia” based on the finding of intrathoracic petechiae. Eleven of the “unknown” cases were also coded as having fetal thrombotic vasculopathy which is considered a possible indicator of umbilical cord blood flow occlusion, totaling 33 patients with highest probability of compromised umbilical cord blood flow (12 with acute asphyxia and 11 “unknown” with fetal thrombi). Therefore, in a stillborn population we would expect to have approximately 1/3 (58/224) with an unknown cause of death of which approximately ½ are most likely to have an umbilical cord lesion. Magee Womens Hospital had 35 autopsies of stillborn infants performed last year. We would anticipate that those parents would also consent to an MRI. Based on the Star Legacy survey and current autopsy rate we would expect approximately 2/3 of the autopsied cases (23) to be eligible for the study (not in labor) per year. We would anticipate 1/3 of these (8) to be in the unknown group study with 4 of those likely to have an acute asphyxia lesion that could be due to umbilical cord occlusion.
We anticipate that the in situ MRI will identify umbilical cord vulnerabilities to torsion (and hence vascular collapse) either from wrapping, entrapments, kinking, or weak (furcate or marginal) cord insertion. These vulnerabilities, individually or in aggregate, will be more frequent in cases of unknown cause of stillbirth than in those with known causes of death, such as fetal hydrops, exsanguination, or premature placental separation (placental abruption). The difference will be evaluated by the Fisher exact test for a 95% probability. We anticipate that we may not have enough cases with sufficient statistical power to prove our hypothesis in this small pilot study, but any positive trend would justify assembling a multi-institutional trial to further test the hypothesis.
We will also anticipate that in cases with MRI identified cord vulnerabilities, the pathology of the cord may correlate with very focal evidence of acute injury such as mural fibrin or neutrophils and that the autopsy findings will fit one of the two patterns seen with premature placental separation. This correlation will strengthen our confidence that the cord vulnerabilities are clinically meaningful.
Aim 2: The Questions:
The parents will be asked to answer questions relating to events within the prior three days with reassurance that these are neutral questions and we do not know of their significance to the fetal death. The questions will be asked, if possible, in the interval, before or after the MRI scan but prior to delivery. If necessary, they will be asked after the delivery and recovery of the mother. When possible, both parents will be present for the questions, but this is not required.
The baseline time and date of the questions will be recorded. Then a member of the research team will ask the questions and record the answers on a digital data sheet. The presumption is that most deaths will have occurred within 3 days. In a study of timing of fetal death, approximately 75% (Table 6) of births occurred within 96 hours of death44. However, if preliminary evidence from the history, recent ultrasound, or parental questioning suggests that the death may have been even earlier, the questioner can adapt the questions to this longer time span.
Consent will be obtained in an equal number of liveborn pregnancies matched for being within 2 weeks of the gestational age, and for major risk factors: maternal diabetes, hypertensive disorders of pregnancy, fetal growth restriction, or prior stillbirth. They will be asked while on the labor and delivery unit.
A correlation of findings report for each patient will be produced in conference using the Stillbirth Collaborative Research Network forms, the placental pathology using our standard protocols and Amsterdam consensus diagnostic criteria, and our enhanced stillbirth autopsy protocol in addition to the questionnaire and MRI findings. The evidence for the immediate and underlying cause of death, and steps between, as well as evidence for timing, will be recorded for each patient.
The questionnaire:
1: Perceived Fetal Movement:
Has there been any change in your perception of fetal movement in the previous days?
Y/N, if Y:
A: Have there been an episode or episodes of decreased fetal movement?
Y/N, if Y, then record when in hours before interview, more than one period can be recorded.
B: Have there been an episode or episodes of increased movement?
Y/N, if Y the intervals can be recorded as above but in addition there is data space for duration
C: Has there been a change in the pattern of fetal movement?
Y/N if Y, this is an open-ended text entry.
2: Sleeping:
A: How would you describe your sleep pattern?
Open ended text data field
B: Do you have a diagnosed history of sleep apnea?
Y/N
C: Do you take any medications to help you sleep?
Y/N, if Y, text with name of medication, dose, when taken
D: What is your preferred sleep position during this pregnancy?
lateral, prone, supine, unknown
3: Respiratory:
A: Over the last few days have you been unusually short of breath?
Y/N if Y text description including clinical history asthma, etc.
B: Have you used an inhaler?
Y/N if Y type, dose last used
C: Have you had a cold or cough in the last week?
Y/N if Y open text
4: Acidosis:
A: Have you had over the last 3 days any gastrointestinal upset that led to vomiting or diarrhea?
Y/N if Y open text about amount, duration, and effect on oral intake
B: Have you been eating and drinking normally over the last 3 days?
Y/N if yes text details
5. Medications:
A: Have you taken any medications to relieve pain including aspirin, Tylenol, acetaminophen, Advil, Motrin, ibuprofen?
Y/N record dose, timings and reason for
B: Are you taking other medications including over the counter, herbal?
Y/N if Y record dose, timings and reason for
Other:
A: Was there anything else unusual occurring in the last three days?
Y/N if yes, free text
Potential problems and alternative approaches Aim 2.
If the interval was more than three days between the questions and time of intrauterine death, as determined by postmortem examination based on the published time intervals determined by gross examination of the fetus, histological examination of the fetus, or placenta44-46, then the patient will be contacted to re-ask the questions for the time interval prior to the fetal death.
We have no way to confirm the accuracy of the answers to the questions. If there are false answers, then it will obscure any correlations. We have considered alternate approaches such as asking, when possible, each parent the questions separately or asking them at an early and late time in the patient stay, but these approaches still cannot determine which answer is accurate.
This is a pilot study. We will be simultaneously evaluating more quantitative techniques for measuring placental reserve to maintain homeostasis with interruptions in maternal or fetal circulation. We will be evaluating both histological morphometry and MRI. We will also be evaluating more quantitative morphologic approaches to fetal autopsy findings related to fetal stress, hypoxia, shock, circulatory redistribution and heart failure. We anticipate that these data will be correlated with the findings from this study to gain insight, and to suggest further hypotheses about the factors that directly lead to fetal death.
Anticipated results and interpretation of data Aim2
We anticipate that there will be significant differences (P<.05) in the answers of some of the questions compared to the answers given by the controls based on a Fisher exact or chi square analysis. However, the low numbers of anticipated cases may not give us the power to identify significant differences. We also anticipate some correlations with the clinical risk factors, placental findings and autopsy findings, but again, our number of cases in the pilot may not have sufficient power. This is a pilot study to test methods for an anticipated multi-institutional trial.
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obstetrical pathology 