Current status of paediatric post-mortem imaging: an ESPR questionnaire-based survey.

BACKGROUND: The use of post-mortem imaging, including skeletal radiography, CT and MRI, is increasing, providing a minimally invasive alternative to conventional autopsy techniques. The development of clinical guidelines and national standards is being encouraged, particularly for cross-sectional techniques. OBJECTIVE: To outline the current practice of post-mortem imaging amongst members of the European Society of Paediatric Radiology (ESPR). MATERIALS AND METHODS: We e-mailed an online questionnaire of current post-mortem service provisions to members of the ESPR in January 2013. The survey included direct questions about what services were offered, the population imaged, current techniques used, imaging protocols, reporting experience and intended future involvement. RESULTS: Seventy-one percent (47/66) of centres from which surveys were returned reported performing some form of post-mortem imaging in children, of which 81 % perform radiographs, 51% CT and 38% MRI. Eighty-seven percent of the imaging is performed within the radiology or imaging departments, usually by radiographers (75%), and 89% is reported by radiologists, of which 64% is reported by paediatric radiologists. Overall, 72% of positive respondents have a standardised protocol for radiographs, but only 32% have such a protocol for CT and 27% for MRI. Sixty-one percent of respondents wrote that this is an important area that needs to be developed. CONCLUSION: Overall, the majority of centres provide some post-mortem imaging service, most of which is performed within an imaging department and reported by a paediatric radiologist. However, the populations imaged as well as the details of the services offered are highly variable among institutions and lack standardisation. We have identified people who would be interested in taking this work forwards.

Lifting the lid on unborn lethal Mendelian phenotypes through exome sequencing.

PURPOSE: Mendelian phenotypes in humans vary from benign variants to lethal disorders. Embryonic lethal phenotypes that are similar to what has been known for a long time in mice have remained largely unknown because of the difficulty in arriving at a molecular diagnosis. The purpose of this study is to test whether next generation sequencing can reveal the underlying etiology of recurrent fetal loss. METHODS: We hypothesized that exome sequencing combined with autozygome analysis can reveal the underlying mutation in a family in which recurrent fetal loss was likely to be autosomal recessive in origin. RESULTS: A novel mutation in CHRNA1 was identified. This gene is known to cause multiple pterygium and fetal akinesia syndrome. CONCLUSION: This is the first report of exome sequencing to identify the cause of recurrent fetal loss and reveal the diagnosis of a lethal human phenotype. Our results should inspire a systematic examination of the extent of "unborn" Mendelian phenotypes in humans using next-generation sequencing.

Second trimester fetal death caused by varicella-zoster virus infection.

A 31-year-old woman contracted acute varicella at 13 weeks of gestation. Severe hydrops fetalis, hepatomegaly, and intrauterine fetal death were detected at 16 weeks of gestation by ultrasound examinations. An examination at autopsy, histopathology, and polymerase chain reaction (PCR) provided evidence of varicella-zoster virus (VZV) infection of the fetus. Second trimester intrauterine fetal death caused by mother to fetus infection of VZV is extremely rare.

Customized growth charts for twin gestations to optimize identification of small-for-gestational age fetuses at risk of intrauterine fetal death.

OBJECTIVE: Customized growth charts developed for singleton pregnancies have been shown to be more effective than population-based ones at identifying small-for-gestational age (SGA) fetuses at risk for intrauterine fetal death (IUFD). We sought to compare the association between SGA and IUFD in twins using customized growth charts designed for twin gestations compared to those designed for singletons. METHODS: This was a retrospective cohort study using a database including singleton and twin pregnancies undergoing ultrasound examination between 16 and 20 weeks' gestation. After excluding preterm births < 34 weeks, congenital anomalies and stillbirths, we identified 51, 150 singleton births. Coefficients for significant physiological and pathological variables affecting birth weight for singletons were derived using backward stepwise multiple regression. The same process was repeated for twin births (1608 pairs), also adjusting for chorionicity. Customized growth charts for each pregnancy were derived using these two regression models for optimal birth weight at term and a proportionality equation. The association between SGA < 10(th) percentile, defined using the twin and singleton-customized charts, and IUFD were compared. Statistical analysis, including calculation of adjusted odds ratios (OR) for IUFD and screening accuracy using each chart, was performed. RESULTS: The derived coefficients for optimal birth weight for twins were different from those for singletons, with lower constants and root mean square error (3422 and 288.9, respectively, in twins vs 3543 and 416 in singletons). Among 3786 twin infants, IUFD was seen in 123 (3.2%). The numbers of fetuses identified as SGA were 575 (15.2%) and 504 (13.3%) by the singleton and twin charts, respectively. Fetuses classified as SGA by the twin-specific customized charts were at a significantly increased risk for IUFD (adjusted OR, 2.3 (95% CI, 1.4-3.5)), whereas those classified as SGA by the singleton-customized charts were not (adjusted OR, 1.2 (95% CI, 0.7-2.0)). CONCLUSION: Customized charts designed specifically for twins are more effective at identifying twin pregnancies at risk for IUFD than are those derived using singleton birth data.

Preoperative prediction of the individualized risk of early fetal death after laser therapy in twin-to-twin transfusion syndrome.

OBJECTIVE: The aim of this study is to evaluate the independent and combined value of gestational age, fetal weight, fetoplacental Doppler, and myocardial performance index for the prediction of individual risk of early (≤7 days) intrauterine fetal death (IUFD) after laser therapy in twin-to-twin transfusion syndrome (TTTS). MATERIAL AND METHODS: A consecutive series of 215 cases of TTTS treated with laser therapy in three centers was prospectively studied. Ultrasound evaluation within 24 h of surgery included estimated fetal weight discordance, umbilical artery, pulsatility index (PI) and diastolic flow evaluation, middle cerebral artery PI and middle cerebral artery peak systolic velocity, ductus venosus PI and atrial flow assessment, and modified myocardial performance index. Logistic regression analysis was used to explore the association of preoperative parameters with IUFD. RESULTS: Intrauterine fetal death occurred in 17 (7.9%) of the recipients and 33 (15.3%) donors (p = 0.016). The only independent predictors of IUFD in recipients was the middle cerebral artery peak systolic velocity >1.5 MoM (OR = 22, p = 0.015), but this event was present in only 3% of recipients. In donors, reverse end diastolic flow in the umbilical artery (OR = 14.748, p = 0.033), estimated fetal weight discordance (OR = 1.054, p = 0.036), and gestational age (OR = 0.757, p = 0.046) were independent predictors. CONCLUSION: In TTTS, preoperative fetal assessment can identify independent risk factors for early post-operative IUFD, particularly in donors.

Vanishing twins in diamniotic dichorionic in vitro fertilization gestation in mid-second trimester.

The authors report a diamniotic dichorionic twin pregnancy after in vitro fertilization (IVF) in mid-second trimester. The dead fetuses were delivered by cesarean section at the 20th week of gestation. The authors discuss management aspects and review of the literature.

Thirty-eight cases of acute pancreatitis in pregnancy: a 6-year single center retrospective analysis.

Thirty-eight pregnant inpatients with acute pancreatitis (AP) were retrospectively reviewed from 2006 to 2012 in our hospital. The incidence of pregnancy-associated AP was 2.27‰. Most (78.95%) of the attack occurred in the third trimester. The median of APACHE II score was 6 and severe AP accounted for 31.58% (12 cases). Primary diseases were absent in most cases (57.89%). The most common clinical presentations were abdominal pain (89.47%) and vomiting (68.42%). Pleural effusion and ascites were found only in the third trimester. Elevated white blood cell count, amylase and lipase were commonly found in biochemical examinations. Eleven cases required intensive care in ICU and 21 cases received caesarean section. There were 2 maternal deaths and 12 fetal losses including 4 abortions. It is concluded that AP is a rare entity in pregnancy. The incidence of pancreatitis increases with the gestational age. However, the severity is not necessarily related with the pregnancy trimesters. The diagnosis is based on clinical presentations, laboratory tests and imaging examinations. Although the treatment strategy of a pregnant woman with pancreatitis is similar to the general non-pregnant patient with AP, a multidisciplinary team consisting of gastroenterologist, gastrointestinal surgeon, radiologist, obstetrician, and ICU doctor should be set up.

Pregnancy loss and thrombophilia: the elusive link.

Recurrent pregnancy loss (RPL) affects 1% pregnancies and is multi-factorial in origin. The role of the acquired thrombophilia antiphospholipid syndrome (APS) as a common and potentially treatable cause of RPL is well established but this is less so for inherited thrombophilia. In obstetric APS the combination of aspirin and heparin has improved outcomes. By analogy, the use of low molecular weight heparin (LMWH) has become commonplace in women with inherited thrombophilia and also those with unexplained miscarriage to help safeguard the pregnancy. This review will examine the pathophysiological role of thrombophilia in pregnancy loss, and the evidence for anticoagulant-based intervention. The limited data supporting the use of heparin for women with RPL and inherited thrombophilia suggests adoption of a more cautious and judicious approach in this setting.

Sirenomelia and caudal malformations in two families.

We report on two families with co-occurrence of sirenomelia and caudal malformations. In the first family, the mother had undergone surgery for a short form of imperforate anus. Her first pregnancy was terminated because of bilateral renal agenesis with oligohydramnios. Her second pregnancy was interrupted because of sirenomelia. The second family was referred to us because of caudal malformation in their two children. The parents' spinal radiographs were normal. The first pregnancy resulted in a girl with imperforate anus, absence of S3-S5 and coccyx, abnormal pelvic floor, and an almost bifid anteriorly located bladder. The second pregnancy resulted in a baby girl with sirenomelia. No diabetes was present during the pregnancies in either of these two families. These families confirm the hypothesis that major genes are responsible for the embryogenesis of the caudal part of the embryo, with variable expression, as has been already described in sirenomelia mouse models (CYP26A1, BMP7/tsg). Molecular studies are underway in these families and in sporadic cases in our laboratory to explore the genetic basis of sirenomelia in humans.

Evaluation of 1025 fetal deaths: proposed diagnostic workup.

OBJECTIVE: We sought to evaluate the contribution of different diagnostic tests for determining cause of fetal death. Our goal was to propose a workup guideline. STUDY DESIGN: In a multicenter prospective cohort study from 2002 through 2008, for 1025 couples with fetal death ≥20 weeks' gestation, an extensive nonselective diagnostic workup was performed. A panel classified cause and determined contribution of diagnostics for allocating cause. RESULTS: A Kleihauer-Betke, autopsy, placental examination, and cytogenetic analysis were abnormal in 11.9% (95% confidence interval [CI], 9.8-14.2), 51.5% (95% CI, 47.4-55.2), 89.2% (95% CI, 87.2-91.1), and 11.9% (95% CI, 8.7-15.7), respectively. The most valuable tests for determination of cause were placental examination (95.7%; 95% CI, 94.2-96.8), autopsy (72.6%; 95% CI, 69.2-75.9), and cytogenetic analysis (29.0%; 95% CI, 24.4-34.0). CONCLUSION: Autopsy, placental examination, cytogenetic analysis, and testing for fetal maternal hemorrhage are basic tests for workup after fetal death. Based on the results of these tests or on specific clinical characteristics, further sequential testing is indicated.

Uterine artery Doppler velocimetry and obstetric outcomes in connective tissue diseases diagnosed during the first trimester of pregnancy.

OBJECTIVE: To evaluate the effect of connective tissue disease (CTD) diagnosed during the first trimester on uterine arteries (UtA) Doppler velocities and on pregnancy outcomes. METHOD: Pregnant women were screened for CTDs during the first trimester, using a questionnaire, testing for autoantibodies, rheumatologic examination and UtA Doppler evaluations. RESULTS: Out of 3932 women screened, 491 (12.5%) were screened positive at the questionnaire; of them, 165(33.6%) tested positive for autoantibodies, including 66 eventually diagnosed with undifferentiated connective tissue disease (UCTD), 28 with a definite CTD and 71 with insufficient criteria for a diagnosis. Controls were 326 women screened negative for autoantibodies. In logistic analysis, women diagnosed with either UCTD (OR = 7.9, 95% CI = 2.3-27.3) or overt CTD (OR = 24.9, 95% CI = 6.7-92.4), had increased rates of first trimester bilateral UtA notches compared with controls. The rates of bilateral UtA notches persisting in the second (15/94 vs 0/326, p < 0.001) and third trimesters (7/94 vs 0/326, p < .001) were higher among women with CTDs than in controls. The risk of complications (preeclampsia, fetal growth restriction, prematurity, diabetes, fetal loss) was higher (OR = 7.8, 95% CI = 3.6-17.0) among women with CTDs than in controls. CONCLUSION: Women with undiagnosed CTDs have higher rates of bilateral UtA Doppler notches throughout pregnancy and increased rates of adverse pregnancy outcomes than controls.

Early embryonic lethality in genetically engineered mice: diagnosis and phenotypic analysis.

Embryonic lethality is a common phenotype that occurs in mice that are homozygous for genetically engineered mutations. These phenotypes highlight the time and place that a gene is first required during embryogenesis. Early embryonic lethality (ie, before and up to mid-gestation) can be straightforward to analyze because the stage at which death occurs suggests why an embryo has failed. Here we summarize general strategies for analyzing early embryonic lethal phenotypes in genetically engineered mouse mutants.

Pathology methods for the evaluation of embryonic and perinatal developmental defects and lethality in genetically engineered mice.

The normal embryonic development of organs and other tissues in mice and all species is preprogrammed by genes. Inactivation of a gene involved in any stage of normal embryonic development can have severe consequences leading to embryonic or postnatal developmental defects and lethality. Pathology methods are reviewed for evaluating normal and abnormal placenta and embryo, especially after E12.5. These methods include pathology protocols for necropsy and histopathology in addition to references that will provide additional knowledge for embryo assessment including histology atlases and advanced embryo imaging techniques.

Twins--twice more trouble?

Twin gestations are fascinating and are also high-risk pregnancies. They account for approximately 3% of all pregnancies in the United States. Major obstetrical complications associated with twin pregnancies include hypertensive disorders of pregnancy, gestational diabetes, and preterm delivery. In addition, the death rate for twins and the rate of severe handicap in very low birth weight survivors of twin pregnancies is greater than that for singleton pregnancies. Ultrasound allows for stepwise evaluations at any time during a twin gestation. Current evidence suggests that uncomplicated diamniotic twins with concordant and appropriate growth beyond 24 weeks' gestation should be managed conservatively and the time and mode of delivery should be determined on the basis of obstetrical history and fetal presentations. Perinatal management of the remaining twin pregnancies depends on good clinical judgment, which is improved by the use of ultrasound imaging.

Imaging practices in the diagnosis and management of gestational trophoblastic disease: an assessment.

This article discusses several of the problems associated with imaging in gestational trophoblastic disease based on critical assessment of the literature. (1) Ultrasound scanning has revolutionized the diagnosis of abnormalities of the first trimester of pregnancy. Fetal death can now be diagnosed as early as 6 weeks of gestation, resulting in uterine evacuation. Histologic and genetic analysis of the conceptus therefore becomes essential as otherwise the diagnosis of hydatidiform mole and other chromosomal anomalies of the fetus may be missed. If such investigation is not performed, human chorionic gonadotropin should be measured after early pregnancy loss to make sure it is negative. (2) The routine use of ultrasound or Doppler flow to follow hydatidiform mole regression is clinically and fiscally counterproductive. (3) To diagnose lung metastases and assess the FIGO risk factor score, chest X-ray is mandated. However, CT scanning may show lung micrometastases indicative of possible chemotherapy resistance. (4) positron emission tomography scanning in trophoblastic neoplasia needs to be validated. Previous studies have been small, with some 30% false positive and false negative findings. The International Society for the Study of Trophoblastic Disease should undertake carefully designed prospective studies to validate imaging practices in the management of trophoblastic disease.

Maternal level of pregnancy-associated plasma protein A as a predictor of pregnancy failure in threatened abortion.

Threatened miscarriage is a common complication of pregnancy. Despite initial viability confirmation by ultrasound scan, some of these patients had further spontaneous abortion. A highly sensitive and specific biomarker would be useful to determine the outcome of pregnancy and to prevent emotional impact to these women. A prospective 14-month cohort study was conducted in the Obstetrics and Gynaecology Department of Universiti Kebangsaan Malaysia Medical Centre to determine whether low serum levels of pregnancy-associated plasma protein A (PAPP-A) measured in early pregnancy can predict the outcome of threatened abortion. 42 pregnant women between 6 to 22 weeks of gestation with threatened abortion and 40 controls were enrolled. Serum samples were collected at presentation and PAPP-A was assayed by electrochemiluminescent immunoassay technique. Pregnancies were followed-up until 22 weeks of gestations and the outcome documented. Nine patients (11%) developed spontaneous abortion and 73 patients (89%) had successful pregnancy. The median PAPP-A level was significantly lower in patients with spontaneous abortion compared to those who had successful pregnancies in the threatened abortion group: 0.78 MoM (0.41-1.00 MoM) vs 1.00 MoM (1.00-2.0 MoM) respectively (p < 0.05). The best sensitivity of 44% and specificity of 93% were obtained at the cut of value of 0.66 MoM (95% CI, 0.561-0.773). In conclusion, low PAPP-A value in threatened abortion women is associated with pregnancy failure, although the use of PAPP-A as a one-time single marker has limited value.

Mothers' experiences of the time after the diagnosis of an intrauterine death until the induction of the delivery: a qualitative Internet-based study.

AIM: This study aims to describe how mothers spend the period of time between being diagnosed with a dead baby in utero and the induction of the delivery. MATERIAL AND METHODS: Data were collected using a web questionnaire. Five hundred and fifteen women who had experienced a stillbirth after the 22nd week of gestation answered the open question: 'What did you do between the diagnosis of the child's death and the beginning of the delivery?' A qualitative content analysis method was used. RESULTS: The results show that some mothers received help to adapt to the situation, while for others, waiting for the induction meant further stress and additional psychological trauma in an already strained situation. CONCLUSION: There is no reason to wait with the induction unless the parents themselves express a wish to the contrary. Health care professionals, together with the parents, should try to determine the best time for the induction of the birth after the baby's death in utero. That time may vary, depending on the parents' preferences.

Perinatal deaths and lymphatic system involvement: a diagnostic flow-chart applying immunohistochemical methods.

A diagnostic flow chart is presented for use in case of perinatal death or still birth with non-immune hydrops fetalis, visceral effusions, or increased nuchal translucency. Immunohistochemical staining with CD-31, CD-34, D2-40, and smooth muscle actin is recommended.