Placental Pathology: Chronicling Intrauterine Life

Elizabeth Cornacchio

Heidell, Pittoni, Murphy & Bach, LLP

99 Park Avenue, 7th Floor New York, New York 10016 (212) 286-8585 [email protected] Elizabeth Cornacchio is a senior principle at Heidell Pittoni Murphy & Bach LLP. Her practice focuses on defending health care providers and institutions in medical liability litigation and licensing issues in both New York and Connecticut. Ms. Cornacchio has been one of New York’s “Best Lawyers” and a “Super Lawyer” for 15 years. She is a member of DRI and FDCC and has previously served as Chair for this seminar. She also has lectured extensively in the local and national legal community. Placental Pathology: Chronicling Intrauterine Life

Table of Contents I. Introduction...... 5 II. Placental Awareness...... 5 III. The Human Placenta Project...... 6 IV. Desperately Seeking Helpful Placental Pathology Review...... 6 V. Placenta Overview...... 8 VI. Chorioamnionitis...... 9 VII. Acute or Chronic...... 10 VIII. Fetal/Neonatal Complications...... 11 IX. Conclusion...... 12 Endnote...... 12

Placental Pathology: Chronicling Intrauterine Life ■ Cornacchio ■ 3

Placental Pathology: Chronicling Intrauterine Life

I. Introduction To address the routine allegation of multiple departures from the standard of obstetrical care, the defense of a birth injury case often takes the “kitchen sink” approach; in other words, multiple aspects of the treatment rendered are scrutinized, evaluated, submitted to expert review and presented to the court, jury, or mediator in search of a favorable outcome. The pre-natal care is assessed and hoped to be in compliance with the standard of care. Labor and delivery techniques and fetal heart monitor strips are also reviewed with the expectation that appropriate medical judgment was utilized in the decision making process leading up to delivery, all with the support of expert opinion to explain the processes behind the obstetrical management. Assuming tissue is available, a potentially dispositive element in this multi-factorial approach is a review and assessment of the placenta relating to the delivery at issue. The structure of the placenta, its photo- graphic depiction as demonstrated to the court or jury or mediator may be the key factor that not only proves that the labor and delivery management were not at fault, but may also provide the Holy Grail of defense strat- egy: a clear alternative reason for the infant-plaintiff’s outcome. The reality is that many times the placenta pathology fails to provide any of the hoped for information or results. Nonetheless, given the potential for evidence that may push a case into the winning side of the defense ledger, a review of placental tissues should be undertaken in every case alleging birth injuries; the data that an experienced placental pathologist can glean from review of the appropriate slides can be so dramatic as to shape the entire defense of the case. It is also important to be prepared to attack the placental pathologist retained by plaintiff’s counsel who may be called to testify against the defense as well; the experienced litigator will know the terminology, be familiar with what the relevant slides depict and have explanations for the physical findings present and whether they are normal or abnormal.

II. Placental Awareness The American College of Obstetrics and Gynecology Committee Opinion Number 102 on Placental Pathology, published in December 1991observes as follows: The benefit of securing specimens on a routine basis is as yet unproved, a standard approach to placental pathology cannot be recommended. In retrospect, this was a most unfortunate statement from a defense standpoint, given lost opportu- nities in the 1990s and even early 2000s to utilize the insights from placental pathologic review for the benefit of claims of negligence. Current thinking could not be further from this point of view; the placenta, a long neglected, understudied organ has taken a major place in determining the causes of poor infant outcomes. The placenta may provide a window into the developmental flaws responsible for poor infant outcome and allow the pathologist to identify not only causes, but the time of adverse occurrences. The placenta itself may demonstrate some significant malformation or lesion or it may be that other external factors lead to abnormal placental function—thrombosis, poor maternal perfusion, fetal thrombotic conditions or others. Even a normal pathologic review is useful as it points the defense of the case to other causative factors and can help elim- inate allegations of failure to diagnose abnormalities in the prenatal period.

Placental Pathology: Chronicling Intrauterine Life ■ Cornacchio ■ 5 III. The Human Placenta Project The National Institute of Child Health and Human Development has undertaken a collaborative research project to understand this most poorly understood organ, but certainly one with huge impact and importance. Among the goals of the project is the development of tools to study the placenta in real time—in vivo as opposed to in vitro and long-range to utilize such tools to treat and if possible prevent placental and pregnancy complications. The HPP is intended to have far reaching impact, improving care in other areas of medicine such as organ transplantation and cancer treatment as well. As described by NICHD the Human Pla- centa Project has five main research objectives: • Improve current methods and develop new technologies for real-time assessment of placental development across pregnancy. • Apply these technologies to understand and monitor, in real time, placental development and function in normal and abnormal pregnancies. • Develop and evaluate non-invasive markers for prediction of adverse pregnancy outcomes. • Understand the contributions of placental development to long-term health and disease. • Develop interventions to prevent abnormal placental development, and hence improve pregnancy outcomes. Unfortunately, at present defense counsel are still dealing with an organ that is not overwhelmingly well understood and often times subjected to pathologic review by physicians with limited placental experience and no in depth training. This necessitates the retention of outside experts to unlock the information the placenta holds and with luck, provide useful information for the defense of the case, or confirm that alternative resolution methods are important to pursue.

IV. Desperately Seeking Helpful Placental Pathology Review The basics of expert pathology review start with credentialing of the expert, the adequacy of slide preparation, the pathology report descriptions (gross and microscopic), the diagnoses identified by the clinical pathologist reading the specimens at the time of care and treatment and the diagnoses reached by the expert pathologist at the time of case preparation. The American Board of Pathology certifies in Anatomic and Clinical Pathology with most practitio- ners certified in both. There is no sub-certification in placental pathology; typically the best expert is one with a wealth of experience in evaluating placental tissue. American Board of Pathology Pathology-Anatomic/Pathology-Clinical* Blood Banking/Transfusion Medicine Pathology – Anatomic* Clinical Informatics Pathology – Clinical* Cytopathology Dermatopathology Hematopathology Neuropathology Pathology – Chemical Pathology – Forensic Pathology – Medical Microbiology Pathology – Molecular Genetic Pathology – Pediatric

6 ■ Medical Liability and Health Care Law ■ March 2017 Depending on your jurisdiction and knowledge of your jury pool you may decide to utilize an expert with an appointment as Chair or Director of the Placental Pathology section of a major medical center if you think this credential will carry weight with your jury. However, a mere title does not compensate for intensive exposure to placental interpretation, training and experience. Confirmation of the proper slides is obvious, but key! Correlation of the slides—whether originals or recuts—to the published pathology report confirms that the proper specimen is being reviewed and that the conclusions are actually relevant to the case at hand. Expert evaluation may reveal that the slides were prepared so poorly as to render their value questionable due to poor technique—information that is crucial to either attack the opinion of the opposing expert or explain why the slide condition is not a critical flaw under- mining your own expert’s opinion. The pathology report is the first source for determining if the placenta played a role in the dire outcome of the infant plaintiff in the defense of the case being prepared. The report may lead the investigation to identify an anomaly of the placenta, such as a structural abnormality, or the presence of an ascending infection leading to preterm, premature rupture of membranes and inevitable preterm delivery, or an unfavorable environment with negative results caused by chronic or acute hypoxia or placental insufficiency. Metabolic factors may also be revealed in the placenta which may explain the progress to pre-term labor in an otherwise unexplained pre-term delivery. The gross description, while usually fairly brief, may provide some clues on which you might ask your pathology expert to focus. Are the weight, measurements and appearance of the placenta consistent with the chronological development? Is the umbilical cord measured? This may not be particularly useful unless the remaining, unsubmitted portions of the cord were measured at birth, but may inferentially identify some anomaly. Is the placenta blood laden as would be expected? During pregnancy a mother’s blood volume increases over time by 40-50% in volume with increased cardiac output. The placenta should be essentially a “bag of blood.” Sections should be taken from diverse areas in the middle area of the placenta which is the most representative; any grossly abnormal areas should also be sectioned such as obvious infarct, signs of abruption, accreta, or other abnormal implantation. In 2016 the Amsterdam Placental Workshop Group Consensus Statement published a report of a conference which was convened to “establish agreed-upon protocol for sampling the placentas, and for diagnostic criteria for placental lesions.”1 These recommendations were intended to apply across the board, from tertiary medical centers to community hospitals. This Consensus Statement is a useful resource for defense counsel; it sets forth separate conditions and describes criteria the placental pathologist may use to reach a diagnosis or conclusion. This Consensus Statement does not identify, with rare and not particularly relevant exceptions, the timing of various stages or the progress of villous deterioration or damage or an hourly account of placental change as a result of a pathologic process, and of course, in and of itself does not establish a standard of care for all placental analysis. But it is useful as a tool to help defense counsel consider possible etiologies. In addition to relevant prenatal and birth records, any prior maternal obstetrical and gynecologic history including past caesarean section, termination procedures and any dilatation and curettage should also be provided to the examining pathologist as possible explanations for endometrial abnormalities or explanations of obvious implantation issues. While the pathologic findings might demonstrate residual consequences of long remote treatment, the specific correlation with historical records may be of use in correlating the pathologist’s opinions.

Placental Pathology: Chronicling Intrauterine Life ■ Cornacchio ■ 7 V. Placenta Overview The placenta is an oddity in that it is a temporary organ existing for the sole purpose of diffusing nutrients and oxygen from mother to fetus. It is primarily a fetal organ and the only organ that grows, develops, is expelled and regrows as needed. Without the placenta two genetically distinct beings could not live side by side with the fetus surviving gestation. Without the placenta there is no oxygen transmission to the fetus. Spiral arteries (more about them later) present where the placenta attaches to the uterine wall, deliver oxygen and nutrient rich maternal blood into the spaces between the chorionic villi—the intervillous space. Oxygen and nutrients—everything the fetus needs—must cross the placental barrier, which means these nutrients must transfer from the intervillous spaces into the villi and then into the tiny blood vessels or capillaries inside the villi. The blood vessels inside the villi are fetal vessels, containing fetal blood, which then converge into larger and larger blood vessels until ultimately, they converge into the umbilical vein. The umbilical vein then carries not the mother’s blood directly, but fetal blood containing all the nourishing things transferred from the mother’s blood to the fetus. At the same time, carbon dioxide and fetal waste products follow a simi- lar reverse path: they leave the fetus by exiting the chorionic fetal vessels, exiting the villi, entering the intervillous space and then enter endometrial veins and ultimately the mother’s circulatory system. Every aspect of placental development over each trimester is geared for facilitating the exchange of oxygen between maternal and fetal blood as the fetus and the placenta each grow and develop. With growth of the fetus the oxygen requirements increase and the ratio of placental to maternal tissue changes, with the placenta—weighing about 1 pounds—initially many times larger than the developing fetus and eventually decreasing to about one-seventh of the size of the term fetus. The placenta is primarily a fetal organ; there is never any direct intermingling of maternal and fetal blood, rather the oxygen and nutrients are circulated through the placenta, with fetal waste products and CO2 transported via the umbilical arteries back to the mother. The oxygen and nutrients are transported across the placental barrier via diffusion at the level of the chorionic villi. Depending on the stage of placental development, the placental barrier is two cells, and as the placenta matures it becomes one layer of cells, which allows ease of transport of nutrients and waste products through the chorionic villi. Oxygen is, not surprisingly, the most critical need, and in the first and even the second trimester, oxygen is not typically in short supply. However, in the third trimester, to compensate for the increasing oxygen and nutritional demands as a result of increased fetal size, the chorionic villi get smaller and smaller to increase the surface areas of exposure to maternal blood to allow more area for diffusion. This relatively late developmental change of the placenta is all for increasing efficiency of oxygen transport. Any structural anomaly or flaw in any segment of this exchange can result in serious fetal developmental consequences or fetal demise. The chorionic villi also develop a larger number of blood vessels as the gestation advances and by the time of the third trimester are filled with blood vessels so that maternal blood, only one cell away, can transport via diffusion, oxygen and nutrients to the villi which are the location of oxygen and nutrient exchange for fetal tissue. Chronic intrauterine ischemia is deficient oxygen delivery to tissue on a consistent basis. As a result of chronic ischemia, sometimes the fetus will transfer oxygen from one part of the fetal body where it is not so essential, to the brain in order to protect the command center. A common example is the relaxation of the sphincter muscle, as sphincteric contraction compared to brain tissue survival in utero is of low prior- ity. Energy must be expended to keep the sphincter flexed and redirecting oxygen to the brain can result in sphincteral relaxation and the passage of meconium. Meconium stained amniotic fluid, while not uncom- mon, being present at approximately 10% of births, can lead to meconium aspiration syndrome which has high infant mortality in the range of 3-5% even with advanced neonatal intensive therapies. Examination of the membranes for placental staining and signs of amniotic fluid with meconium should be described and

8 ■ Medical Liability and Health Care Law ■ March 2017 the presence may imply intrauterine stressors that are acute or chronic depending on the histologic findings. Among the perinatal risk factors that have been seen with meconium aspiration syndrome is placental insufficiency, a short-hand term for inadequate transport of oxygen and nutrients across the placenta. The objective criteria that are seen on pathology to support poor placental exchange include accelerated maturation of the placenta, retarded maturation of the placenta, or both. This is a dysmature placenta. Acceler- ated maturation of the placenta is the presence of structural changes earlier in time than would be expected. For example, at or about thirty weeks, in the third trimester, one expects to see an increase in syncytial knots which up until this time are present in approximately 30% of the chorionic villi. If there is a premature increase in syncytial knots—the clumping together of nuclei—this suggests that the fetus is not getting sufficient oxygen and the placenta is compensating by generating syncytial buds to allow for additional oxygen exchange. Syncytial buds are the way the placenta generates new villi. However, if the placenta is generating syncytial buds when it typically wouldn’t need new villi, this suggests a chronic intrauterine state of deficient oxygen. Implantation issues may also be relevant. The endometrium has specialized blood vessels, called spiral arterioles, which are coiled blood vessels that have very thick concentric rolls of smooth muscle. This con- struction allows these blood vessels to respond to the decrease in hormonal levels at the end of a menstrual cycle causing these vessels to clamp down and stop the bleeding. This is not suitable for pregnancy when a robust blood flow is necessary to circulate through the placenta. However, during pregnancy the endometrial trophoblasts which are the lining of the placenta aggressively destroy the endothelium and the muscle and convert the implantation area to a large “sinusoidal lake,” which is a very low pressure system which allows the blood to pour into the placenta. If mother has had a history of prior dilatation and curettage on either one or more than one occasion, or prior cesarean section, the endometrium, either uniformly or not, may have suf- fered damage to the spiral arterioles, which adversely affects implantation and similarly appropriate exchange of oxygen and nutrients.

VI. Chorioamnionitis In most birth injury cases, the placental pathologist’s expert review is hoped to provide insight into when the inciting problem developed, and if possible place that problem outside the time when the individual defendant or institutional client can be criticized for either not responding, or not responding adequately or in a sufficiently prompt manner. Timing is critical. In other words, classically we look to the placenta to tell us: 1) The infant-plaintiff’s problems developed silently before the mother presented for labor and delivery when nothing could be done to effect the course of delivery, or, 2) The infant-plaintiff’s problem developed so severely and acutely, that even the efficient and prompt response of the defendants was not enough to preserve the infant-plaintiff from harm. The expert pathologist examines the placenta to see that growth and development are appropriate without either retarded or accelerated development of typical placental structures, possible signs of chronic hypoxia or placental insufficiency. In the presence of chorioamnionitis thought to be responsible for preterm delivery, the expert tries to identify the timeline for ascending chorioamnionitis that initiates the cascade of preterm labor, rupture of membranes, inevitable delivery and the attendant problems of prematurity for which the plaintiff is seeking recovery. Acute or chronic chorioamnionitis may not be relevant depending on whether there are any presenting signs of chorioamnionitis demonstrated by the mother, but the pathology may help determine when delivery became inevitable. Chorioamnionitis, the acute inflammation of the membranes of the chorion of the placenta, is most typically caused by ascending polymicrobial bacterial infection in the setting of membrane rupture, but can

Placental Pathology: Chronicling Intrauterine Life ■ Cornacchio ■ 9 be almost as frequently found with intact membranes. Blood borne spread is rare and the diagnosis is made more frequently on histologic review in the absence of clinical signs (sub-clinical) as opposed to the presence of clinical symptoms such as fever and tachycardia, either maternal or fetal. A temperature greater than 100.4 degrees Fahrenheit is abnormal in pregnancy and if it persists for more than one hour, or, a mother with fever at 101 degrees Fahrenheit or more for any length of time, requires assessment and treatment. Fever is present in almost all cases of clinical chorioamnionitis (95-100%). Of course, alternative etiologies must also be con- sidered particularly as the source of tachycardia (e.g. drug reaction), but the presence of both maternal fever and tachycardia are serious indicators of intrauterine infection and should be assessed and treated. While there are other signs of chorioamnionitis, such as abdominal pain and a foul odor, they tend to be more sub- jective and difficult to evaluate. By definition subclinical chorioamnionitis has no presenting clinical signs such as fever or tachycardia, but may be demonstrated by preterm labor and more commonly as preterm premature rupture of membranes. Funisitis is progression of the infection into the umbilical cord, characterized by leukocyte infiltration of the umbilical vessel wall or Wharton’s jelly. While the initial bacterial infection is maternal, if the infection progresses the fetus will have an inflammatory response which can lead to blood vessel damage and or thrombosis over days. The fetus itself can become infected and even progress to sepsis. Chorioamnionitis is among the major causes or preterm premature rupture of membranes and preterm labor and delivery with the attendant risk of cerebral palsy. The inflammatory response of the fetus to the presence of infection can lead to generation of cytokines and inflammatory mediators which can affect the development of neurons and the CNS, with toxic brain effects including cerebral palsy and periventricular leu- komalacia with devastating consequences. In addition, chorioamnionitis, which causes early onset sepsis in preterm neonates, can make preterm neonates acutely unstable, with septic shock, respiratory failure, dissem- inated intravascular coagulation (DIC), metabolic acidosis and hypotension. This instability in the first week of a premature baby’s life has high association with intraventricular hemorrhage (IVH), which may go on to cause seizures, PVL, or hydrocephalus which might require a neurosurgically placed diverting shunt into the cerebral ventricles. Placental culture may be obtained to help determine the bacterial cause of early onset sepsis, since preterm neonates are often “pre-treated” when the mother receives antibiotics to treat her chorioamnionitis. The neonate’s blood cultures may frequently be negative due to this pre-treatment. While the optimal antibiotic therapy is still not well studied, clinical standard intrapartum antibiotic treatment is effective in reducing chorioamnionitis in women with preterm premature rupture of membranes and may include IV ampicillin with gentamicin or metronidazole depending on whether the patient is antici- pated to have vaginal or caesarean section birth.

VII. Acute or Chronic As defense counsel we are concerned with whether any problem with the placenta is an acute or chronic process. Among acute processes are mechanical failures of some sort, such as uterine rupture, placental abruption, accreta/percreta, blood flow obstruction or umbilical cord occlusion, fetal trauma, fetal hemorrhage, disruption of fetal vessels, either large vessels or capillaries. These may be dramatic events but even “acute” processes may progress over hours or days, such as the progression of ischemic changes in the chorionic villi after partial abruption leading over time to infarction. Umbilical cord obstruction caused by compression, knots, or prolapse can cause interruption of the vital blood supply through the umbilical arteries and veins. Any interruption for even a brief period of time may cause severe consequences and even death. If fetal vessels are interrupted, the consequential fetal hemorrhage will result in severe hypovolemia and collapse of fetal circulation. All blood flow and oxygen delivery to the fetus will cease and every organ system will be adversely affected due to this hypoxic ischemic insult. The longer the blood flow interruption, the more severe

10 ■ Medical Liability and Health Care Law ■ March 2017 the damage becomes to the liver, heart, kidneys, and intestines. The effects on the brain are even more detri- mental given that these changes are wholly irreversible. Any of these manifestations may be the end consequence of processes seen in the placenta, or often from cord compression and cord accidents in utero. Chronic placental processes typically occur over days or weeks with decreased placental function and/or reserves. These may be primary placental lesions, inflammatory lesions, and problems with either maternal or fetal blood supply. Most worrisome is diminished maternal circulation with decreased perfusion, typically as a result of hypertension, including preeclampsia, eclampsia and chronic hypertension as well as lupus or other blood or clotting abnormalities. Changes in the chorionic villi are often the most telling feature, showing either accelerated or retarded maturation or ischemia. If severe, these can infarct and lead to partial or total placental separation and significant malperfusion with drastic results including fetal demise. Clini- cally, with partial separation or mild/moderate ischemia, this insult can be remote, occurring many hours to days before birth. The fetus may even stabilize or partially recover in utero. After birth, the neonate may show some mild features of hypoxic ischemic injury such as seizures, liver or renal injury, but because it is either chronic or occurred hours to days prior to delivery this is actually a “subacute” injury without the significant metabolic acidosis or depression that is usually seen with acute hypoxic ischemic injury. With chronic or subacute hypoxic ischemia, neurologic outcomes can be poor, including cerebral palsy and seizure disorder.

VIII. Fetal/Neonatal Complications Placental abnormalities can lead to intrauterine death, sepsis, fetal inflammation/FIRS, cytokines and chemokines; similarly, neonates can suffer asphyxia, sepsis, septic shock, pneumonia, persistent pulmo- nary hypertension (PPHN), intraventricular hemorrhage, white matter damage and multi-organ injury with neonatal death and long term consequences including cerebral palsy. Meconium—the intestinal contents of the fetus consisting of intestinal epithelial cells, mucus, amniotic fluid, bile, enzymes and water with a tar-like texture—is a common event and does not usually injure the fetus unless aspirated; if meconium aspiration syndrome develops it may lead to significant morbidity and mortality. Placental insufficiency may contrib- ute to meconium passage in utero because the fetus may be “stressed”, but meconium passage does not always occur in these fetuses. Meconium passage in utero can also cause damage to the amniotic cavity, the umbilical cord and fetal vessels if it remains in the amniotic fluid for a significant amount of time. Within in a few hours macrophages, which respond to the presence of meconium, become pigment filled and can be seen histologi- cally. After 12-16 hours of meconium, umbilical cord damage can occur and is seen as necrosis of the walls of the umbilical vessels and may also be seen on microscopic examination. Meconium can be responsible for vasoconstriction of umbilical vessels with long term exposure leading to a risk of neurologic injury and death. Additional neonatal signs related to placental insufficiency: • Intrauterine growth restriction (IUGR) is a consequence of placental insufficiency; • Early Thrombocytopenia – within first 72 hours of life; • Neonatal anemia; • Leukopenia; • Metabolic Deficiencies: • Hypoglycemia – potentially leading to brain damage and PVL; • Acidemia – from lactic acidosis; • Hormonal changes; • Cardiovascular changes;

Placental Pathology: Chronicling Intrauterine Life ■ Cornacchio ■ 11 • Long range metabolic issues in adulthood (diabetes, obesity); and • Still birth. In cases of severe placental insufficiency with IUGR, very poor fetal growth over time, or absent end diastolic umbilical arterial blood flow, or reversal of end diastolic umbilical blood flow as seen on umbilical doppler, could necessitate emergent delivery of the fetus. Neonates may be born prematurely for severe IUGR, and then have both problems of prematurity in addition to those associated with placental insufficiency. Preterm infants that are IUGR do worse overall and have increased risk for all major preterm morbidi- ties including chronic lung disease, intraventricular hemorrhage, retinopathy of prematurity and necrotizing enterocolitis. Behavioral effects are also a concern, because children who were born IUGR are also at higher risk for ADHD compared to gestational aged matched appropriate for gestational age (AGA) neonates. While these neonatal conditions can have a multitude of causes, placental analysis may lead to a diagnosis allowing for focused therapy for the infant and providing a defense rationale. Similarly, placental pathology can be helpful in cases of perinatal stroke. Stroke in the newborn presents in the first few days of life as seizure (here it is not associated with severe acidosis such as in hypoxia ischemia), and focal neurologic deficit. It can be the result of hemorrhagic or thromboembolic injury in utero. The placenta can give clues, especially for thromboembolic neonatal stroke because there may be evidence of increased clots or other specific pathology in the placenta. The mother and the neonate may subsequently have laboratory investigations for bleeding or clotting disorders which could explain why the stroke occurred.

IX. Conclusion Even without a more detailed description of each of the above mentioned processes the wisdom of placental analysis is self-evident. With luck, expert placental review will give you a formidable defense and help you confidently proceed with case management.

Endnote

1 Arch Pathol Lab Med. 2016; 140:698-713 July 2016.

12 ■ Medical Liability and Health Care Law ■ March 2017