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(BQ) Part 2 book Keelings fetal and neonatal pathology presentation of content: The respiratory system, the alimentary tract and exocrine pancreas, liver and gallbladder, the urinary system, the reproductive system, the endocrine system, the reticuloendothelial system,...and other contents.
Iatrogenic Disease 17 Peter G.J Nikkels Abstract Injury is a feature of all medical practice, but it is perhaps nowhere more accepted as an unavoidable consequence of therapy than in obstetric and neonatal medicine Treatment is usually beneficial, but therapeutic procedures may sometimes result in adverse side effects or cause iatrogenic damage Most side effects are minor problems, but some can be serious and may result in a major handicap, long-term sequelae, or death of the infant Invasive antenatal investigation and treatment and the increasingly complex interventions in neonatology have resulted in the appearance of new types and patterns of pathology Recognition of side effects, especially with the advent of newly developed therapeutic strategies in the neonatal intensive care unit, is very important, and the clinician must be alert and carefully monitor these children This is important to minimize side effects and serious damage The pathologist is sometimes the first to recognize these adverse effects but should be very well informed about the therapeutic interventions and therapies that were performed before beginning an examination to be able to recognize these side effects Keywords Iatrogenic disease • Iatrogenic pathology • Lesions • Amniocentesis • Chorionic villus sampling (CVS) • Cordocentesis • Fetoscopy • Fetal surgery • Maternal drugs • Teratogenic • Organogenesis • Over-the-counter medicines (OTCs) • Birth injuries • Cesarean section • Neonatal therapy • Infection • Monitoring • Vascular cannulation • Blood sampling Injury is a feature of all medical practice, but it is perhaps nowhere more accepted as an unavoidable consequence of therapy than in obstetric and neonatal medicine Treatment is usually beneficial, but therapeutic procedures may sometimes result in adverse side effects or cause iatrogenic damage Most side effects are minor problems, but some can be serious and may result in a major handicap, long-term sequelae, or death of the infant [1–3] The development of new therapeutic strategies may result in not previously observed combinations of pathology Invasive antenatal investigation and treatment and the P.G.J Nikkels, MD, PhD Department of Pathology, University Hospital Utrecht, Utrecht, The Netherlands e-mail: p.g.j.nikkels@umcutrecht.nl increasingly complex interventions in neonatology have resulted in the appearance of new types and patterns of pathology Recognition of side effects, especially with the advent of newly developed therapeutic strategies in the neonatal intensive care unit, is very important, and the clinician must be alert and carefully monitor these children This is important to minimize side effects and serious damage Over the last decades, neonatal care has been very successful, especially with the impressive improvement of survival of very premature infants The pathologist is sometimes the first to recognize these adverse effects but should be very well informed about the therapeutic interventions and therapies that were performed before beginning an examination to be able to recognize these side effects All medical devices, like tubes, catheters, etc., should, of course, be left in situ after death It is equally important to perform a thorough autopsy © Springer International Publishing 2015 T.Y Khong, R.D.G Malcomson (eds.), Keeling’s Fetal and Neonatal Pathology, DOI 10.1007/978-3-319-19207-9_17 413 414 as completely as is permitted Only in these circumstances is valuable information not lost and the optimal and early detection of serious side effects made possible If these conditions are met, the pathologist can contribute markedly to the improvement in the quality of care for children The decline in autopsy rates, however, could make it more difficult to determine the incidence of iatrogenic lesions [4] A recent study estimated that preventable complications accounted for at least 4,400 deaths per year among hospitalized children in the USA [1] Children younger than 30 days were at particular risk of complications [2] Gestational age, birth weight, severity of initial illness as assessed by the Score for Neonatal Acute Physiology and Perinatal Extension (SNAPPE II), and length of stay were significantly associated with iatrogenic events Furthermore, univariate analysis for environmental characteristics showed that type of shift, but not nursing workload, was significantly associated with iatrogenic events [5] The role of the pathologist in the investigation of child death is central to the monitoring of iatrogenic pathology and brings with it considerable responsibilities in the light of potential medicolegal consequences and the need to recognize new problems It is vital that the pathologist should be familiar in identification of iatrogenic lesions and should record with great care unusual findings in cases where novel therapeutic modalities are being employed Iatrogenic lesions may be of varying degrees of clinical significance Many, perhaps the majority, are minor and accepted as a consequence of intervention, while others represent serious complications and medical mishaps or reflect poor clinical judgment Perinatal autopsy examinations provide a vital opportunity to monitor any potential teratogenic effects of drug therapy In addition the ability to keep very ill babies alive in neonatal intensive care has resulted in the maturation or evolution of pathological processes in various organs resulting in the development of new patterns of pathology, which need to be recorded and explained As discussed by deSa, iatrogenic lesions can be classified in three categories: (1) the lesion can be directly traced to the procedure or is a direct consequence of the procedure; (2) lesions are an untoward complication of the initial procedures (a procedure used to treat one complication may cause another); and (3) complex lesions evolved from earlier lesions, including lesions related to prolonged survival and/ or an improved outcome, i.e., lesions related to therapeutic success One lesion may affect the other, and sometimes it is difficult to determine the pathogenesis of the lesions [6] Iatrogenic Lesions in the Prenatal Period There is a large literature regarding the safety of the various invasive procedures employed in antenatal diagnosis In general it appears that midtrimester amniocentesis is the safest P.G.J Nikkels procedure, while chorionic villus sampling (CVS) and early amniocentesis have a slightly higher incidence of subsequent pregnancy loss of approximately of 0.6–2 % [7–9] CVS on the other hand should not be performed before 10 weeks’ gestation due to a possible increase in risk of limb reduction defects [9] Amniocentesis can give rise to hemorrhage and infection and sometimes puncture marks on the skin, liver laceration, or lung damage Injection of dyes (i.e., methylene blue) in the amniotic sac in twins to study which amniotic sac was punctured first is associated with jejunal atresia [10– 12] Umbilical cordocentesis can be associated with cord hematomas, but this is extremely rare Ultrasonography Modern ultrasound machines have enormously increased the potential for prenatal intervention and diagnosis The use of ultrasound in obstetrics is now routine practice, but there is no evidence that the use of ultrasound at diagnostic intensities has any deleterious effect on the fetus or the mother [13–15] Detailed scanning is operator dependent and ultrasound diagnoses are not infallible Some anomalies can be identified with a very high success rate (e.g., neural tube defects), but others (such as cardiac defects) are much more difficult to identify and diagnose Accordingly, the real risk would appear to be related to the skill of the operator and resultant misdiagnoses rather than dangers of standard equipment [16] Magnetic Resonance Imaging Magnetic resonance imaging (MRI) is now a routine antepartum and neonatal diagnostic tool particularly in instances of complex congenital malformation It is of particular value in the assessment of lung size in cases of congenital diaphragmatic hernia (CDH), central nervous system abnormalities including hydrocephalus, and some cardiac malformations There is no evidence that MRI scanning has any deleterious effect on the fetus or the progress of a pregnancy Amniocentesis Amniocentesis is the most commonly used diagnostic intervention in pregnancy It is usually performed between 16 and 18 weeks’ gestation when there is adequate liquor Used in conjunction with real-time diagnostic ultrasound, it is a safe technique Samples are usually taken by a transabdominal needle puncture using a narrow-gauge needle of between 18 and 22 g The 22 g needle is preferred as it has a lower rate of complications Certain complications are inherent in this invasive technique Infection is a potential hazard but should be extremely 17 Iatrogenic Disease uncommon with adequate aseptic technique Secondary infection may lead to intrauterine fetal demise or spontaneous abortion due to intra-amniotic infection and chorioamnionitis In addition it is known that fetal exposure to intra-amniotic inflammation is associated with the development of cerebral palsy in survivors [17, 18] In the case of women who are rhesus negative, it is necessary to provide anti-D treatment in order to prevent rhesus isoimmunization In assessing the potential complications of amniocentesis, it is important to differentiate between midtrimester and early (9–14 weeks’ gestation) amniocentesis as the range of complications varies Early amniocentesis, at 9–14 weeks’ gestation, is associated with increased risk to fetal development Although the procedure is technically similar to midtrimester amniocentesis, the fluid volume around the fetus is much smaller and it can be more difficult to obtain a sample The incidence of unsuccessful attempts may be as high as 20 % There is clear evidence that the incidence of talipes is greater in the children of women undergoing amniocentesis prior to 14 weeks’ gestation [19, 20] Amniocentesis performed prior to 15 weeks had a significantly higher miscarriage rate than chorionic villus sampling or midtrimester amniocentesis and also increased the risk of talipes equinovarus [20, 21] Midtrimester amniocentesis is associated with a significant increase in spontaneous and induced preterm delivery for which the etiology remains unclear [22] Recent data show a procedure-related miscarriage rate of 0.5– 1.0 % for amniocentesis [9], while a recent review of studies incorporating more than 68,000 midtrimester amniocentesis procedures concluded that the procedure-related excess pregnancy loss rate was 0.6 % [23] Significant fetal injury following midtrimester amniocentesis is not common Small cutaneous scars resulting from direct needle puncture are described but are seldom of significance Internal injuries of the fetus have also been described following inadvertent trauma [24] These injuries include fatal hemorrhage; intra-abdominal pathology in the form of ileal atresia and peritoneal adhesions; limb anomalies resulting from arterial injury, constrictions, and amputations; and intrauterine fetal demise secondary to amniotic bands and disruptive brain injury [25–29] More significant sequelae of midtrimester amniocentesis relate to potential impairment of lung development and maturation with an increased risk of respiratory distress syndrome (RDS) and neonatal pneumonia [30] It was suggested that the fetal problems resulted from removal of amniotic fluid and possibly from chronic amniotic fluid leakage that had not been noted by the patient Chorionic Villus Sampling The need for early diagnosis of karyotypic or metabolic disorders thus permitting technically safer and easy medical 415 termination of pregnancy has driven the development of chorionic villus sampling (CVS) Samples can be obtained either by a transcervical or a transabdominal approach The transabdominal approach has the advantage for some practitioners in that the technique is similar to that used for amniocentesis in which practitioners are familiar In a recent review, it was demonstrated that the miscarriage rates (i.e., spontaneous loss and procedure-related loss) after amniocentesis and CVS were 1.4 % and 1.9 %, respectively This difference may be explained by the difference in gestational age at the time of the procedures The miscarriage rate was inversely correlated with the number of procedures performed by the practitioners [31] It is hardly surprising that there is a significant incidence of fetomaternal hemorrhage following chorionic villus sampling by either technique [32, 33] This can lead to maternal rhesus sensitization in incidences of incompatibility or to a worsening of maternal immunization in a preimmunized patient Patients are therefore checked for the need to receive anti-D immunoglobulin The range of complications of chorionic villus sampling are wide and, while most are fortunately of minor clinical significance, some in individual cases can be more serious, giving rise to fetal anomaly particularly in the case of early chorionic villus sampling Firth and colleagues reported a cluster of limb reduction defects in babies of a series of women who underwent chorionic villus sampling before completed weeks’ gestation [34] Two subsequent studies identified similar pathologies, and it was proposed that these limb abnormalities were the result of vascular disruption and hypoxic tissue damage related to the needle movements [35, 36] In expert hands, using good ultrasound visualization and care with the needle, the risk is extremely remote A long-term follow-up of infants in pregnancies that had transcervical chorionic villus sampling or amniocentesis concluded that there was no difference in the incidence of congenital malformations, neonatal morbidity, pediatric morbidity, or functional disturbance between the two patient groups [37] Cordocentesis Fetal blood sampling is now a well-established procedure, which has applications in a number of clinical situations The usual sampling site is the placental insertion of the umbilical cord, but other sites that can be employed include the fetal cord insertion, the fetal intrahepatic vein, and the fetal heart Needle insertion (20- or 22-gauge spinal needle) is under continuous ultrasound visualization It is important that the fetal heart is observed throughout the procedure as fetal bradycardia indicates fetal distress and the site of needle insertion is observed during and after procedure in order to assess hematoma formation in the cord root and the invariable 416 Fig 17.1 Small hematoma at the placental cord insertion following fetal blood sampling blood leakage from the puncture site (Fig 17.1) Sampling is more problematic below 18 weeks’ gestation, and there is a higher rate of pregnancy loss in these early gestation pregnancies [38] The specific indications are the provision of rapid and uncontaminated fetal karyotype, the investigation and management of rhesus hemolytic disease, and the investigation and management of hematological disorders including autoimmune idiopathic thrombocytopenia and hemoglobinopathies Fetal intrauterine infection can also be investigated using fetal blood samples Many pregnancies where fetal blood sampling is done are, by definition, high risk This complicates assessment of fetal loss related to the procedure alone Loss rate estimates have been in the range of 1–2 % [39, 40] In one major study, the fetal loss rate for structurally normal fetuses was %, but this increased to 25 % in a group of fetuses with nonimmune hydrops fetalis [41] Fetoscopy and Fetal Surgery Fetoscopic intrauterine interventions can be separated into two broad categories The first is obstetric endoscopy, which includes surgical interventions on the placenta, umbilical cord, and fetal membranes, and the second is endoscopic fetal surgery [42] Obstetric Endoscopy The most frequent obstetrically related intervention is treatment of the complications of twin-twin-transfusion syndrome (TTTS) using a Nd:YAG laser or diode to coagulate the intertwin anastomoses [43] Given that TTTS can complicate up to 15 % of monochorionic pregnancies and will present with a mortality rate of 80 % or more without intervention, laser coagulation is the treatment of choice for TTTS Laser therapy is normally offered to patients between P.G.J Nikkels 15 and 26 weeks of gestation If performed correctly, laser treatment results in a reversal of hemodynamic disturbances associated with TTTS in the following days after treatment Main complications after laser treatment include intrauterine fetal death of either fetus (13–30 %) and preterm rupture of membranes (10 %) Persistence of overt TTTS due to anastomoses missed during surgery (2–14 %) and twin-anemiapolycythemia sequence (2–13 %) can occur, but the rate of these complications is critically dependent upon the surgeon’s experience [43] The reported survival rates for at least one twin range from 76 to 88 %, and the reported incidence of severe neurodevelopmental impairment at to years of age is 13–17 % including a cerebral palsy rate of 6–7 % [43] A short cervical length (−15 mm) may indicate a higher risk of preterm delivery Amniodrainage is a palliative treatment that may prolong pregnancy by reducing the risks of polyhydramnios and relieve maternal discomfort In cases of severe TTTS before 26 weeks’ gestation, amniodrainage has been reported to be associated with survival rates of 51–60 % for at least one fetus and a rate of neurological handicap of 29 % Serial amniodrainage beyond 26–28 weeks’ gestation may prolong pregnancy in late TTTS cases with normal Doppler Amniodrainage performed before laser treatment increases the risk of complications and results in poorer outcome [43] Closed Fetal Surgery One of the first forms of closed interventions was the placement of shunts for drainage of pathological fluid collections in the fetus Pleural effusions and dilatations of the urinary tract resulting from obstruction at all levels from the pelviureteric junction to the posterior urethra are amenable to intrauterine drainage [44] In these cases, the decision to perform a drainage procedure is dependent on the exclusion of karyotypic anomaly and other serious fetal anomalies In poor prognosis cases, which in untreated situations result in 100 % fetal loss, the survival rate is in the order of 30 % Abdominal wall hernia has been reported as an uncommon complication of uterovesical amniotic shunt treatment for obstructive uropathy The hernias were amenable to postnatal repair In a report of three cases, the authors noted that while the drainage of urine into the amniotic sac improved pulmonary development in all three patients, two of the three had renal failure requiring dialysis after birth [45] Survival seemed to be higher in fetuses receiving vesicoamniotic shunting, but the size and direction of the effect remained uncertain, such that benefit could not be conclusively proven Results suggest that the chance of newborn babies surviving with normal renal function is very low irrespective of whether or not vesicoamniotic shunting is done [46] In terms of surgery on the fetus, an increasingly frequent indication is severe congenital diaphragmatic hernia as well as myelomeningocele Overall maternal safety is high, but 17 Iatrogenic Disease rupture of the membranes and preterm delivery remain a problem [47] Fetuses with isolated severe congenital diaphragmatic hernia are treated with fetoscopic endoluminal tracheal occlusion, generally performed at approximately 26–28 weeks’ gestation [48] It involves the percutaneous placement of an inflatable balloon in the fetal trachea under sono-endoscopic guidance The balloon prevents egress of lung fluid, causing airway stretch, which in turn results in lung growth The balloon is preferentially removed in utero at approximately 34 weeks by tracheoscopy or ultrasoundguided puncture Alternatives are ex utero intrapartum treatment or, at the latest, after birth by tracheoscopy or ultrasound-guided needle puncture through the neck Fetal intervention for severe congenital diaphragmatic hernia is associated with neonatal morbidity that is comparable with that of an expectantly managed group but with less severe disease [48] It should be cautioned, however, that the currently available evidence suggests that although there is lung enlargement following in utero tracheal occlusion, this appears to be due to abnormal dilatation of peripheral lung saccules with pooling of mucin The lung remains structurally abnormal with low radial alveolar counts and abnormally large alveolae The treatment did not prevent the development of lung pathology typically associated with pulmonary hypoplasia [49] Intrauterine fetal therapy has also been used for large solid sacrococcygeal teratomas Vascular flow to the tumors was interrupted by fetoscopic laser ablation, radiofrequency ablation, or interstitial laser ablation with or without vascular coiling [50] This treatment is often complicated by intrauterine death or premature birth Survival in fetuses with hydrops was 30–45 % and without hydrops 67 % [50] It can be expected that closed fetal surgical procedures will increase dramatically in number and scope in the next 5–10 years as improved endoscopic techniques and the development of specific fetoscopic instruments together with better management of tocolysis becomes available [42, 51] A recognized hazard of techniques that breach the amniotic sac is rupture of the membranes with amniotic fluid leak or premature delivery Most cases can be expected to seal spontaneously if infection does not develop, but active interventions to plug leaks either with an amnio patch of platelets and cryoprecipitate or application of fibrin sealant have been successfully reported [52] Open Fetal Surgery Many of the more complex fetal anomalies that severely compromise the fetus to the point where extrauterine existence is called into question are as yet not amenable to repair by closed techniques Because survival rates are so poor, these conditions have led to the development of open fetal surgical techniques Urinary tract obstruction, diaphragmatic hernia, congenital pulmonary airway formation, amniotic band 417 sequence, myelomeningocele, and sacrococcygeal teratoma have all been the subject of fetal surgery over the last 10 years Randomized controlled trials (RCTs) have demonstrated an advantage for open fetal surgery of myelomeningocele and for fetoscopic selective laser coagulation of placental vessels in twin-to-twin transfusion syndrome The evidence for other fetal surgery interventions, such as tracheal occlusion in congenital diaphragmatic hernia, excision of lung lesions, fetal balloon cardiac valvuloplasty, and vesicoamniotic shunting for obstructive uropathy, is more limited [53] The aim of postnatal myelomeningocele surgery is not to reverse or prevent the neurologic injury, but to palliate The neurologic defects result from primary incomplete neurulation and secondary chronic in utero damage to the exposed neural elements through mechanical and chemical trauma In utero repair to decrease exposure and alter the antenatal course of neurologic destruction was conceived Through animal models and human pilot studies, the feasibility of fetal spina bifida repair was demonstrated Subsequently, a prospective randomized multicenter trial revealed a decreased need for shunting, reversal of hindbrain herniation, and preservation of neurologic function when performed before 26 weeks of gestation, making in utero repair an accepted care alternative for select women carrying a fetus with spina bifida [54] Of mothers who had open maternal-fetal surgery, 40 % experienced complications One had uterine dehiscence, and another had uterine rupture requiring urgent delivery at 36 weeks In subsequent pregnancies, 20 % of open maternal-fetal surgery cases were complicated by uterine rupture, and % of ex utero intrapartum treatment patients had uterine dehiscence Future reproductive capacity and complication rates in subsequent pregnancies following ex utero intrapartum treatment procedure are similar to those seen in the general population In contrast, mid-gestation open maternal-fetal surgery remains associated with relatively morbid complications All had good maternal-fetal outcome [55] Maternal Medication During Pregnancy Maternal drug therapy poses risks to the fetus at all stages of development Current standards for testing of potential therapeutic agents for developmental toxicity have prevented any repetition of the thalidomide tragedy, and there have been no reported episodes of new unrecognized teratogens released into routine therapeutic use for more than two decades Although the deleterious effects of some agents may appear idiosyncratic, the recognition and understanding of certain principles regarding the harmful effects of drugs in general serve to guard against complacency We now recognize that agents that bind to steroid hormone receptors, the aryl hydrocarbon receptor, or retinoid receptors are potential developmental toxins with likely teratogenic effects 418 There is no effective maternal-fetal barrier against drugs ingested by pregnant women Although for some substances the transplacental dispersion is concentration dependent (i.e., dependent on the maternal dose ingested), it must be remembered that the placenta is a dynamic organ capable of facilitated and active transport by carrier molecules, which may well increase placental transfer of a given substance to a greater extent than simple diffusion would permit [56] Thus, it is possible that a drug or other molecule can achieve a higher concentration in the placenta and fetus than would normally be determined by the maternal serum concentration The harmful effects of drugs are substantially determined by the stage of development of the conceptus at the time of exposure Thus, developmental toxicity results from exposure in the embryonic period during which there is major organogenesis This critical period extends from fertilization until approximately 60 days postconception, and the pattern of abnormality reflects the phase of organogenesis during the time of exposure Six principal teratogenic mechanisms are suspected to be associated with medication use: folate antagonism, neural crest cell disruption, endocrine disruption, oxidative stress, vascular disruption, and specific receptor- or enzyme-mediated teratogenesis [57] In the fetal period (i.e., 60 days postfertilization until birth), drugs may exert their deleterious influence by changes in the growth and functional development of organs Drugs given late in pregnancy or during labor may also cause problems in the progress of labor or in the neonate postpartum It should also be remembered that certain classes of drugs have long half-lives and can be teratogenic for months after the cessation of maternal therapy, e.g., retinoic acid analogues Maternal ingestion of drugs that may affect the fetus can occur in the following circumstances: Inadvertently without the mother realizing she is pregnant Taken in diagnosed pregnancy without consideration or knowledge of the risks involved Therapeutic administration in the knowledge of pregnancy in the first trimester Therapeutic administration in the knowledge of pregnancy in the second and third trimesters Maternal administration of drugs intended to have a therapeutic effect on the fetus Maternal therapies during labor Maternal treatment postpartum in breastfeeding mothers It has been calculated that approximately one-third of all pregnant women receive at least course of drug therapy during pregnancy [58] This apparently high rate, given the widespread understanding of the risks of drug ingestion in pregnancy, is a gross understatement of the true incidence of fetal exposure in the first trimester to pharmacological agents as self-treatment by proprietary “over-the-counter” P.G.J Nikkels medications (OTCs) or continuation of prescribed therapy is frequent prior to the mother or her medical advisers knowing she is pregnant This may be particularly critical given the fact that exposure is occurring during the phase of organogenesis, which is the period of greatest risk to the embryo As it is not possible to conduct clinical trials of the effects of drugs in humans in early pregnancy, we rely on the results of anecdotal occurrence or therapeutic disasters to identify teratogenic agents and only a small number of drugs are definitely regarded as known teratogens if administered in the first trimester of pregnancy It should also be noted that teratogenic effects may be dose dependent or may require the coadministration of other agents or synergistic influences if serious sequelae are to ensue An additional complication in assessing the teratogenic effect of any agent is the background rate of congenital malformation in the community as a whole, some of which may be teratogenic in its own right, which is in the order of 1–2 % of all pregnancies An example of this difficulty is the thalidomide experience where it is now clear that some cases of limb reduction defect were in fact Robert’s syndrome and not the result of thalidomide exposure in the mother This has become apparent when children of apparent thalidomide victims are born with identical patterns of limb deficiency A significant proportion, perhaps 10 %, of congenital abnormalities result from environmental influences including preexisting maternal conditions, infective agents, mechanical disruptions, and chemicals, while in the majority of instances the etiology is unknown [59–61] Also, we are continually exposed to numerous chemicals in the environment for which the teratogenic potential is largely unknown It has been estimated that only approximately % of the 60,000 or more chemicals in commercial use have been assessed for their teratogenic potential In future, sophisticated structural analyses of chemicals may provide a means of predicting teratogenic potential and permit a rapid assessment of risk for any given agent [62] Only a few representative examples will be described here, and the reader is referred to other sources for a general review and more detailed information [63, 64] Over-the-Counter Medicines (OTCs) Many pregnant women use over-the-counter medications at some stage in their pregnancy In many instances, this use is in the critical developmental stages of the first trimester Werler et al [65] reported that in the USA, 65 % of women had used acetaminophen, 15 % had used ibuprofen, and % had used other drugs such as pseudoephedrine, aspirin, and naproxen during pregnancy This rate of consumption exposes a huge population of developing babies to a vast array of agents With such large numbers, even a small toxic effect will give rise to a clinically important and avoidable rate of potentially deleterious results Pain medication when taken in the first gestational months of pregnancy is reported as strongly 17 Iatrogenic Disease associated with stillbirths due to congenital anomalies and to be positively associated with all stillbirths [66] Implicit in these findings is a potential explanation for a number of unexplained congenital anomalies and stillbirths, and it is clear that more must be done to monitor the use of OTCs in pregnancy if these risks to pregnancy are to be removed [67] 419 important feature of retinoic acid embryopathy is the longterm teratogenic potential of some retinoic acid analogues used therapeutically, particularly for the management of skin disease, e.g., etretinate Some analogues may be teratogenic in excess of 12 months after the cessation of therapy Non-teratogenic Drug Effects Teratogenic Drugs The serious effects of thalidomide on the fetus are well known [68] Folic acid antagonists used as cytotoxic agents in cancer chemotherapy are also known to have serious effects on the developing embryo [69–71] Of more immediate clinical import are commonly used agents that are proven teratogens Examples of these include phenytoin, warfarin, retinoids, carbamazepine, lithium, sodium valproate, and danazol The teratogenic effect of anticonvulsant drugs was first described in relation to phenytoin by Meadow [72] It is probable that other related compounds may have potentially harmful effects, and it has been suggested that there may be a potentiation of phenytoin effects with co-treatment with barbiturates Children exposed to phenytoin present with a variety of malformations including dysmorphic facies, digital hypoplasia, nail hypoplasia, growth deficiency, and mental deficiency More serious structural defects of organs such as the heart are also occasionally identified [73–77] Of particular interest in relation to the effects of phenytoin is the apparent variation in the susceptibility of a fetus The risk of a fetus exposed to phenytoin developing the full spectrum of effects is approximately 10 %, with perhaps a third of fetuses having lesser abnormalities Numerous studies now suggest that the fetal susceptibility depends on the fetal genotype, with inherited defects in phenytoin detoxification contributing to the increased sensitivity to the drug [78–82] Warfarin embryopathy was first recognized in 1975— although previous case reports had described similar pathology in the babies of mothers with valve prostheses receiving anticoagulation—and is now well characterized [83–85] Despite the condition being well recognized, new cases still occur [86–88] Approximately one-third of exposed fetuses will be born with the classical features of nasal hypoplasia, depressed nasal bridge, and stippled calcification of the epiphyses A significant proportion will also have mental retardation and a variety of other abnormalities are recognized The critical period of exposure appears to be between and weeks, but there is debate as to the additional risks from exposure in the second and third trimesters with reports of central nervous system abnormalities [89] Retinoic acid embryopathy was first reported by Rosa [90], and subsequently the spectrum of structural defects in prenatally exposed children has been described [91] Retinoids are potent teratogens and give rise to craniofacial, cardiovascular, and central nervous system abnormalities A particularly Drugs administered to mothers outside the period of organogenesis can disrupt structural and functional growth and development of organs Examples include the angiotensinconverting enzyme (ACE) inhibitors, sex hormones, antithyroid drugs, and beta-blockers Angiotensin-converting enzyme inhibitors are associated with fetal renal abnormalities including proximal renal tubular dysgenesis (Fig 17.2) giving rise to neonatal renal failure [92–94] Intrauterine growth restriction and skull ossification defects are also frequently present An increased incidence of intrauterine Fig 17.2 Renal tubular dysplasia secondary to fetal ACE-inhibitor exposure; the proximal tubules have an immature morphology and glomeruli are crowded 420 Fig 17.3 Thyroid enlargement in a fetus at 20 weeks’ gestation exposed to carbimazole death, stillbirth, and perinatal death resulting from oligohydramnios and related abnormalities has also been described in the fetuses of mothers receiving ACE inhibitors Diethylstilbestrol (DES) was identified as having a transplacental carcinogenic affect in females The majority of female children of mothers who received this drug in pregnancy developed vaginal adenosis, and a very much smaller proportion are at risk of subsequent development of adenocarcinoma [95] Decades later, DES is known to enhance breast cancer risk in exposed women and cause a variety of birth-related adverse outcomes in their daughters such as spontaneous abortion, second trimester pregnancy loss, preterm delivery, stillbirth, and neonatal death Additionally, children exposed to DES in utero suffer from sub/infertility and cancer of reproductive tissues [96] Male fetuses of exposed mothers developed genital anomalies [97] Oral contraceptives, frequently taken in the first trimester of pregnancy, not appear to be associated with a risk to the development of the fetus [98] The administration of antithyroid drugs can produce thyroid enlargement in the fetus (Fig 17.3) These drugs readily cross the placenta and are thought to act by suppression of thyroxine production by the fetus with subsequent enhanced TSH secretion from the pituitary gland [99–101] The use of P.G.J Nikkels beta-blockers in the treatment of essential hypertension in pregnancy is associated with an increased risk of intrauterine growth restriction [102] Neonates of mothers treated with the beta-blocker labetalol for severe preeclampsia have a higher risk of hypotension and patent ductus arteriosus [103] There are relatively few instances where maternal drug therapy inhibits breastfeeding Most drugs will be secreted in the breast milk, but the dose ingested by the baby is usually insufficient to cause deleterious consequences [104] Atkinson et al [105] provide practical guidelines on the common drugs that pass into breast milk in significant quantities and make recommendations as to breastfeeding or drug treatment to be avoided if breastfeeding is intended Among the drugs that should be avoided in these circumstances are amiodarone, aspirin, barbiturates, benzodiazepines, and carbimazole Cytotoxic agents are highly toxic, and breastfeeding is contraindicated by mothers on these therapies The potential for synergistic effects between drugs that are not thought to be teratogenic and other environmental influences should not be forgotten Hyperthermia is associated with the development of a variety of birth defects [106, 107] Animal experiments have identified potentiation of the teratogenic effects of hyperthermia by aspirin in nonteratogenic doses [108] The effect is thought to be due to suppression of prostaglandin E, which is cytoprotective as a result of its induction of heat shock proteins [109] Deleterious effects of intrauterine exposure to therapeutic agents need not be confined to structurally identifiable abnormalities Recent work has raised the issue of more subtle effects that may manifest themselves in terms of organ function or effects on intellectual development of exposed individuals Antenatal glucocorticoid therapy has reduced the rate of complications seen in preterm deliveries Glucocorticoids have important effects on brain development and in animal studies can be shown to modify the structure and functioning of the brain Recent work has suggested that the limbic system (specifically the hippocampus) and the hypothalamo-pituitary-adrenal axis are particularly sensitive to steroid exposure in utero with resultant alteration in behavior and learning performance, and it also reduces life span in an animal model [110, 111] There is also increasing interest in the impact of prenatal glucocorticoid therapy on cardiovascular disease later in life [112–114] In an animal model, treatment of pregnant mice with antidepressant drugs (selective serotonin-reuptake inhibitors) affected fetal development, resulting in cardiomyopathy and a higher vulnerability to affective disorders in a dose-dependent manner [115] Neonates from mothers treated with selective serotonin-reuptake inhibitors have a higher risk of developing persistent pulmonary hypertension [116] Not all harmful drug effects need necessarily be teratogenic or act directly on the fetus Antibiotic prophylaxis for group B streptococcal infection is widely utilized, particularly 17 Iatrogenic Disease in the USA The recommended treatment protocols include the use of penicillin G or ampicillin It has been shown that the antepartum use of ampicillin in this context appears to result in an increased incidence of early-onset neonatal sepsis with non-group B streptococcal organisms that are resistant to ampicillin [117] A study of Towers et al highlighted the increased frequency of antibiotic utilization in pregnancy from a level of less than 10 % in 1991 to 16.9 % in 1996 [118] The implications for antibiotic resistance and subsequent difficulties in neonatal care are obvious Drugs in Labor and Effects on the Fetus Obstetric analgesia and anesthesia have the potential to affect the progress of labor, the fetus in utero, and the neonate after delivery The use of epidural anesthesia can have significant deleterious effects on the progress of labor There is a decrease in uterine performance with increased need for oxytocin augmentation, prolongation of the first and second stages of labor, and increased risk of operative delivery (cesarean section) [119–122] Both anesthetic gases and analgesic agents such as opiates pass readily across the placenta and into the fetus These agents can cause respiratory depression, which may complicate the early neonatal period [120, 123] The reader is encouraged to consult recent review articles on problems in obstetric anesthesia [124] Complications of the Intrapartum Period The pattern of complications that arise in relation to labor and delivery are the result of the interaction of maternal factors, the intrauterine well-being of the fetus and its position, and the decisions made by medical and nursing staff as to the manner of delivery It cannot be overemphasized that “birth injury” and related defects are as often the result of the fetal condition as they are the consequence of apparent errors of judgment on the part of medical and nursing staff supervising and managing the delivery Therefore, pathologists should proceed with caution in attributing apparent traumatic abnormalities, particularly related to the head and intracranial lesions, as being solely the responsibility of the attendants at a delivery Some facets of intrapartum asphyxia can be due to or accentuated by clinical decision-making, but frequently asphyxiated babies are in poor condition as a result of prepartum intrauterine pathology affecting the placenta or have congenital defects that impair their capacity to withstand the normal rigors of labor The complexities of this area are reviewed by Wigglesworth [125] Serious birth injuries occur, however, and many of these are wholly traumatic in nature The breech presentation is most likely to be associated with traumatic lesions O’Mahony et al 421 reviewed singleton delivery intrapartum-related deaths in which traumatic cranial or cervical spine injury or difficult delivery was a significant feature [126] They identified that the vast majority of cases meeting the criteria for inclusion in the study presented with fetal compromise prior to delivery Where cranial and traumatic injury was seen, it was typically associated with a difficult instrumental delivery together with illjudged persistence with attempts at vaginal delivery Elective cesarean section delivery is associated with a number of initial problems in the neonate In the emergency situation, the underlying pathology requiring urgent delivery by this route usually supersedes those abnormalities that result from cesarean section alone and that are manifest in babies born electively by this route and particularly those born prematurely Extracranial Hemorrhage Edema and bleeding into the soft tissues of the scalp and extracranial tissues is not uncommon and most usually is of little clinical consequence Caput succedaneum is the accumulation of fluid and blood in the skin and superficial soft tissues of the scalp and usually affects the presenting part of the head over the vertex It is thought to develop as the cervical canal compresses the skull during the passage of the head through the birth canal This swelling usually subsides in a few days Chinon is a somewhat similar lesion resulting from the application of a ventouse extractor with soft tissue edema underlying the area held by the extractor cap In this instance, the edema and hemorrhage is more tightly localized than with a caput succedaneum Subaponeurotic or subgaleal hemorrhage originates deep to the epicranial aponeurosis, and substantial hemorrhage can accumulate in this layer and be associated with serious clinical consequences including hypovolemic shock [127] (Fig 17.4) Fig 17.4 Massive subgaleal hemorrhage occurring after ventouse extraction 422 Cephalhematoma is hemorrhage underlying the periosteum over the surface of the skull bones This is usually a lesion limited by the boundaries of the individual skull bone plates, and thus the volume of hemorrhage is usually much less than that seen in subaponeurotic hemorrhages Simple linear fractures of the parietal bone are not infrequent in instances of cephalhematoma [128] (see Fig 15.22) Bofill et al reported the development of cephalhematoma in 37 of 322 cases of delivery employing the vacuum extractor [129] All of these extracranial fluid accumulations and hemorrhages have been associated with the use of the ventouse vacuum extractor, particularly in instances of multiple applications as a result of technical failures in the procedure [130–132] Extradural hemorrhage is also often associated with skull fracture but is usually of minor severity and is located between the periosteum and the inner surface of the skull bones Skull Fractures Fracture of the skull is most usually associated with forceps delivery but can also be seen as a result of pressure of the skull against the prominences of the maternal pelvis Skull fracture has also been reported as a consequence of use of the ventouse vacuum extractor [133] Minor depressed skull fractures, most typically of the parietal bone, are usually of little clinical import Similarly linear fractures involving only one skull bone usually not lead to significant clinical sequelae It is likely therefore that the frequency of skull fracture is higher than the reported incidents Dupuis et al reported that in a series of 68 cases of neonatally diagnosed depressed skull fracture managed in their unit, no fewer than 18 cases were of a “spontaneous” etiology, i.e., not associated with instrumental delivery or use of the vacuum extractor [134] More significant and more typical of a true traumatic birth injury is a multiradiate fracture of the skull bones, most typically affecting the parietal bones and frequently bilateral These injuries are associated with significant intracranial hemorrhage as a result of tearing of subdural veins and of the venous sinuses Serious intracranial injury is more likely to be associated with instrumental delivery [134] In cases where a traumatic delivery results in formation of a leptomeningeal cyst, an associated fracture may grow in size in the neonatal period A case has also been reported of expanding fontanelle secondary to delivery trauma with leptomeningeal cyst formation following use of the ventouse extractor [135] P.G.J Nikkels bone, which are joined by cartilage and not fuse until the second year of life [136] Pressure on the suboccipital region during delivery causes inward displacement of the squamous portion of the bone with resultant tearing of the underlying venous sinuses and subsequent hemorrhage often associated with direct injury to the cerebellum In recent times, this has not been a frequently reported pathology, although it is more likely to occur in vaginal breech delivery Minor forms of this traumatic lesion can easily be missed unless specifically excluded by direct and careful inspection The diagnosis can also be made on lateral skull or cervical spine roentgenograms showing specific changes in the area of the innominate synchondrosis [137] Subdural Hemorrhage This results from tearing of the bridging veins in the subdural space but can also follow tentorial and venous sinus hemorrhage resulting from precipitant or traumatic delivery However, the presence of unilateral and bilateral subdural hemorrhage is not necessarily indicative of excessive birth trauma [138] Subdural hemorrhage has also been described following the use of vacuum extraction [139, 140] Although many of these hemorrhages appear to be related to instrumental delivery and in particular the use of the vacuum extractor, it should not be forgotten that these lesions have also been described as arising in utero and not related to the delivery process Petrikovsky et al reported seven cases of cephalhematoma and caput succedaneum not related to labor [141] Subdural hemorrhage arising in utero and identified in stillborn babies and antenatal subdural hemorrhage that resulted in intrauterine death were described several times [142–145] In some cases, this was due to a severe fetal thrombocytopenia [146] Extracranial Injuries A large variety of additional injuries are reported related to birth These include fractures, hemorrhage into soft tissues and related to major organs, and injuries to the spinal cord and nerves The risk factors and other morbidities associated with the development of these injuries include birth weight greater than kg, prolonged second stage of labor, use of epidural anesthesia and oxytocin, forceps delivery, shoulder dystocia, and fetal compromise as evidenced by meconium passage in labor and low Apgar scores [147–149] Occipital Osteodiastasis Wigglesworth and Husemeyer describe a serious fracture of the occipital bone resulting from disruption of the relationship between the squamous and lateral parts of the occipital Fractures Clavicular fractures are seen particularly in difficult deliveries of large infants or in cases of shoulder dystocia (Fig 17.5) They are not uncommon in breech presentations Published 34 Forensic Aspects of Perinatal Pathology skeletal surveys are readily available in most major hospitals and, in the UK, are carried out to standards for the investigation of child abuse as specified by the Royal College of Radiologists [36] Mortuary babygrams (where whole babies are radiographed on single imaging plates) are not sufficient Postmortem cross-sectional imaging, particularly postmortem CT (X-ray computed tomography), is becoming an essential adjunct to the pediatric autopsy and has proved to be particularly useful in the perinatal forensic context [37– 39] (see Chap and Fig 34.1) Postmortem magnetic resonance imaging (MRI) is also available in some centers and promises to be of utility in the assessment and documentation of organ and soft tissue injuries Radiographic images should be reported by a pediatric radiologist (the images are often double-reported), and the report must be made available to the pathologist(s) prior to the commencement of the invasive autopsy Autopsy The purpose of the investigation of a neonaticide serves several goals: to establish the gestational age (viability), to determine whether or not the infant was liveborn or stillborn, to help in confirming the identity of the mother, and to establish the cause and manner of death [33] Estimation of Gestational Age The perinatal pathologist will have the most experience in any particular forensic team in relation to the estimation of fetal viability and gestational age Routine morphometric measurements, particularly body weight, body length, and foot lengths, are useful when compared with standard population-based growth centile charts and data tables that are stratified for gestational age However, estimations of gestational age are subject to errors related to biological or pathological variation in intrauterine growth and to postmortem changes, especially in severely macerated or decomposed fetuses Radiological patterns of epiphyseal ossification and macroscopic assessment of cerebral cortical gyral development of the fixed brain may be more reliable (see Chaps and 14) Postmortem CT imaging is emerging as a better tool for the estimation of gestational age in the cases that display advanced postmortem changes compared to the traditional autopsy-based assessments and should therefore form a standard part of the work-up of such cases [38] Was the Baby Born Alive? Proof of live birth is of central importance in cases of suspected neonaticide However, undertaking this task can be extremely difficult, if not impossible, particularly in cases where resuscitation was attempted or in bodies with advanced 867 postmortem decomposition Soerdjbalie-Maikoe et al [40] described a series of neonaticide cases where, in most, decomposition was already too advanced to be able to determine whether there was any sign of life at birth or to establish the cause of death Whereas changes of maceration (see Chap 14) definitively indicate intrauterine fetal death if the observer can distinguish them from postmortem putrefaction, a microscopic vital reaction (i.e., neutrophil infiltration) in the umbilical cord stump and milk present within the stomach indicates survival for some time after birth However, the latter findings will not be present in most deaths that occur soon after delivery Most methods of assessment of whether or not a baby survived beyond the birthing process utilize the presence or absence of gas (air) within the aerodigestive tract Although not without controversy and somewhat unreliable, the lung flotation test has traditionally been the mainstay method used at autopsy to assess inflation of lungs The procedure involves tying off the trachea and immersing the lungs and attached heart in water to determine whether or not the organ block floats A similar method can be employed to detect air within the stomach and upper gastrointestinal tract Both procedures are well illustrated by Guddat et al [39] According to Knight, floating a block of heart and lungs together is more indicative of significant lung expansion than floating just the lungs themselves [41] Pulmonary interstitial emphysema as a useful finding in determining a live birth has been described [35] deRoux et al have described a case of an abandoned newborn showing features of pulmonary interstitial emphysema attributed to smothering and compression of the chest and neck [42] Histology can also help in distinguishing between naturally aerated lungs and hyperexpansion of airways due to ventilation or postmortem putrefaction but can suffer from a degree of uncertainty and subjectivity However, unexpanded lungs filled with amniotic squamous debris and/or meconium without obvious airspace expansion provide good evidence that the baby had not breathed following delivery [35] (and was subject to intrauterine fetal distress, perhaps leading to late stillbirth) Failure to demonstrate the presence of air in the lungs does not necessarily exclude live birth as air may be resorbed if the circulation has continued after the airway becomes occluded [43] Nevertheless, demonstration of gas in the stomach and upper gastrointestinal tract along with uniform gas distribution within the lungs by 3D reconstruction of postmortem CT data provides convincing evidence that a neonate has breathed naturally prior to its demise and was, therefore, liveborn [39] (Fig 34.1) Injuries The pathologist must be cautious when attempting to differentiate between intrapartum and postpartum injuries 868 a L Kiho and R.D.G Malcomson b c Fig 34.1 Neonaticide (a) Sagittal postmortem CT imaging showing a foreign object (wadded baby wipe) in situ, obstructing the airway (b) The CT data has been manipulated to digitally straighten the airway, confirming that the airway was completely obstructed above the larynx Vertical lines indicate the axes around which the data has been transformed (c, d) 3D reconstruction of the postmortem CT data to high- d light air (c) The body surface and internal air are represented (d) Air is present within the airway, esophagus, and stomach as well as inside the expanded lungs, consistent with natural breathing prior to the placement of the airway obstruction (compare with Figure in Guddat et al [39] where no gas was demonstrable in the lungs and upper GI tract of a stillbirth) 34 Forensic Aspects of Perinatal Pathology Fig 34.2 Neonaticide A bladed weapon (penknife) was used to sever the umbilical cord and to inflict multiple incised wounds to the chest and neck Precipitate deliveries, in which the child is forcibly ejected from the uterus, may result in injuries from impact with the ground or drowning if the birth occurs into a toilet or bathtub However, such deliveries are more common in multiparous women or preterm neonates [34] Externally, the baby may show caput succedaneum, cephalhematoma, or other skin reddening or bruising consistent with prolonged labor Other bruises may have been deliberately inflicted Skin abrasions, particularly on the anterior neck may represent marks from maternal fingernails occurring during a self-delivery Marks relating to the use of medical instruments, such as obstetric suction cups or forceps blades, suggest that the baby was born in a health-care environment or that delivery was otherwise professionally assisted Incised wounds are unusual but can be associated with the separation of the umbilical cord using an edged or pointed object (Fig 34.2) Asphyxiation is the most common mode of death associated with neonaticide caused by smothering, strangulation, or 869 suffocation using a hand or a pillow to cover the neonate’s mouth or by placing the baby in a plastic bag [34] Bruises or abrasions may be found on the baby’s cheeks, nose, or lips; injuries may be faint and superficial and hence difficult to recognize Less frequently, there are injuries to the oral mucosa and frenula as a result of pressure applied over the mouth [34] Fractures, particularly of the clavicles or skull bones, may relate to birth trauma, especially if there has been cephalopelvic disproportion or macrosomia in gestational diabetes A skull fracture may be the result of a fall of the baby to the floor if the mother has delivered in a standing position Occipital osteodiastasis, if present and associated with hemorrhage and antemortem trauma to the hindbrain, is likely to be the cause of death and is the consequence of inexperienced or professionally negligent fingers forcibly compressing the back of the neck in the region of the squamous part of the occipital bone during delivery (see Chaps 17 and 29) Rib fractures are extremely rare birth injuries but have been described They are possible inflicted injuries if they are present in the posterior arcs but can be identified as birth injuries, especially when in association with ipsilateral clavicular fracture and/or shoulder dystocia [44, 45] If anterior, they are usually related to attempted cardiopulmonary resuscitation Dural tears (mainly shearing tears of the tentorium) are frequent findings in early neonatal deaths, and almost all are the result of birth-related head trauma associated with excessive or rapid molding of the fetal head during delivery They can be associated with significant subdural hemorrhage, especially involving the posterior parts of the cranial cavity, particularly within the posterior fossa Such extensive subdural hemorrhages should be carefully distinguished from the trivial subdural hemorrhages that commonly occur in otherwise normal births (see Chap 29) Retinal hemorrhages have been described as being common in otherwise normal live newborns and are more frequent in instrumental deliveries They are typically few in number, are trivial in extent, and generally disappear quickly (within weeks, exceptionally up to months) after birth [46] Extensive, bilateral, multilayer hemorrhages extending to the ora serrata should prompt careful consideration of abusive head trauma, especially if associated with significant subdural hemorrhage Toxicology Forensic toxicology may help to determine whether or not the mother and baby had been affected by illicit drugs, alcohol, or medications Certain toxins, including carbon monoxide and cyanide, may also be detectable DNA Sampling DNA profiling of samples from the deceased neonate or the placenta may help to establish identity and is particularly important in the analysis of partial, mummified, or 870 a L Kiho and R.D.G Malcomson b Fig 34.3 Partial remains (a) Dismembered right leg and (b) degloved left leg were the only remains discovered in this case skeletonized remains (Figs 34.3 and 34.4) if the identity of the mother is suspected or known According to a study by Csete et al., blood-stained vernix caseosa is a useful tissue for identifying the putative mother because vernix caseosa can be a carrier of the mother’s blood [47] Paternity testing may be of forensic importance if the mother was herself legally still a child at the time of conception or delivery and she may therefore have been the victim of statutory rape Placenta The placenta is often disposed of separately in cases of neonaticide [33] and, when available, can reveal details of the circumstances of the pregnancy and delivery In particular, estimates of fetal viability, gestational age, and fetal health can be made from routine placental weight measurements Gestation and periods of intrauterine retention following fetal demise can be roughly estimated from the histology of the placental tissue Maternal and fetal health problems can also be identified (see Chap 4) The placenta is a plentiful source of genetic material from both the mother and the fetus, and DNA extracted from placental tissue samples can aid in the identification if the placenta is the only material recovered from a scene It may also be useful for paternity testing A forensic examination of a placenta may also provide useful information to law enforcement investigators in other medicolegal contexts, including maternal physical trauma occurring in pregnancy, such as that due to motor vehicle collisions or assault Informed interpretation of the particular physical characteristics of the placenta may help to narrow the focus of large-scale police operations to find and safeguard the well-being of potentially vulnerable mothers 34 Forensic Aspects of Perinatal Pathology 871 such as knives or scissors Discoloration (dark red) and desiccation of the fetal end of the cord suggest stillbirth and live birth, respectively If drying has set in, soaking the umbilical stump in tepid water may permit a meaningful examination [34] The distal end of the umbilical stump should also be examined for signs of tearing or cutting from the placental disk Histology of the cord insertion site to the baby’s abdomen may reveal a vital tissue reaction if an infant survived for more than 24–48 h [29, 48] Microscopic features of the vital reaction at the end of the umbilical stump may include hemorrhage, a cellular reaction, or necrosis [34] True knots of the umbilical cord increase the risk of stillbirth fourfold but are not usually problematic for surviving liveborns [49] Tight true knots reflect excessive tension on the cord that has probably occurred during delivery of the baby or, possibly, owing to traction on the cord during the delivery of the placenta Interpretation is dependent on circumstances and the autopsy findings in the baby Other lethal cord accidents may suggest a natural death by exsanguination in the peripartum period (e.g., rupture of fetal blood vessels in vasa previa), but care should be taken to exclude negligence or accidental death owing to failure to ligate the fetal end of the umbilical cord before it was severed Consideration should be given to the possibility of the umbilical cord acting as a ligature in accidental or homicidal strangulation Spontaneous strangulation by nuchal cords is generally considered to be unusual, and the particular configuration and appearance of the umbilical cord around the neck should be assessed in context Potential ligature marks should be distinguished from the normal postmortem appearances of fat folds of the neck Petechial hemorrhages of the face, conjunctivae, oral mucosa, and intrathoracic tissues are considered to be neither sensitive nor specific enough to provide reliable evidence of asphyxiation, contrary to earlier belief [33] Cause of Death Fig 34.4 Skeletonized remains An almost complete skeleton from a term infant was retrieved from a covert burial site, several years after the delivery, from under concrete and an oildrum placed at the scene Umbilical Cord The site of umbilical cord detachment may be of forensic interest and its appearance (cut or torn) may be consistent with or refute accounts given by those involved, particularly with reference to the use or otherwise of cutting instruments, The lack of precise pathological markers for live birth, and/ or cause of death, often precludes definitive statements about the cause and manner of death Pathological findings are often nonspecific in cases where deaths occurred by suffocation, drowning, or failure to provide adequate supportive care (e.g., feeding, thermal support) In some cases, a confession may be the only method in establishing the cause of death [48] Potential causes of death and their differential diagnoses should be considered in the context of all of the information available about a particular case and the relative contributions of any comorbidities estimated (Table 34.3) [50] Caution should be exercised in cases where a late stillbirth cannot be excluded Where a cause of death cannot be 872 L Kiho and R.D.G Malcomson Table 34.3 Comparison of typical characteristics of neonaticide and infant homicide (After West, 2007 [50]) Perpetrator characteristics Mean age Sex Psychiatric problems Suicide General Means Discovery of body Neonaticide 21 years (89 % under 25) Female (very rarely male) Uncommon Rare Unmarried, no involvement with the father Passive/sexually submissive Primipara (65–81 %) Concealed/denied pregnancy (75–100 %) Evades prenatal care Substance abuse Unattended, secret delivery at mother’s parental home or in toilet