Unexplained Intrauterine Fetal Death Research Articles

Cardio-pathogenic variants in unexplained intrauterine fetal death: a retrospective pilot study

To describe the prevalence and spectrum of cardio-pathogenic variants in singleton fetuses after unexplained intrauterine fetal death (IUFD). DNA from post-mortem fibroblastic tissue samples of 16 fetuses after unexplained IUFD was retrieved at two tertiary university hospitals for clinical exome sequencing with subsequent filtering of 122 cardio-specific genes to elucidate underlying cardio-pathogenic variants. In total, we included 12 (75%) male and four (25%) female fetuses who were stillborn at a median gestational age of 34+6 (23+2–40+5) weeks. In two (12.5%) fetuses no cardio-pathogenic variants were found. In 14 (87.5%) fetuses, overall 33 variants were detected in 22 cardio-specific genes, involving 14 (63.63%) genes associated with cardiomyopathy, six (27.27%) arrhythmogenic susceptibility genes and two (9.09%) arrhythmia and cardiomyopathy associated genes. Among the 33 variants, five (15.2%) were classified as likely benign according to the American College of Medical Genetics and Genomics; 28 (84.8%) variants were considered as variants of uncertain significance. Compared to a cohort of explained IUFDs, the cases with and without fetal variants in cardiac genes differed not significantly regarding maternal age, previous history of stillbirth, time of stillbirth or fetal sex. Unexplained stillbirth may be caused by cardio-genetic pathologies, yet a high number of variants of uncertain significance merit a more detailed post-mortem examination including family segregation analysis.

Trends and Determinants of Perinatal Mortality in a Tertiary Care Hospital of Nepal

Introduction: Perinatal mortality rate (PMR) in Nepal is still very high. In major hospitals of Nepal, it is still ranging from 20 to 30 per thousand births. This study was carried out to review the different aspects of PMR and classifying them and identify the causes of perinatal and neonatal deaths and assessing the need for improvement in quality of pregnancy and newborn care. 
 Methods: It was a retrospective study carried out in Bharatpur Hospital, Chitawan, Nepal. Data of all stillbirths from 22 weeks of pregnancy and neonatal deaths up to seven days of life was taken from monthly perinatal audit and annual mortality review. The data was taken from July 2017 to Jun 2019. All the perinatal deaths were then classified. 
 Results: Over a two year period, there were total 25,977 births and total death was 369. Thus perinatal mortality rate was 12.3 per thousand births. Still births (fresh and macerated) contributed almost 82.4% of the perinatal deaths and neonatal death contributed 17.6% of total deaths. Deaths related to unexplained intrauterine fetal death (IUFD) showed an increasing trend and have increased by more than 20% in past two years from 39.1% to 60.8%. Deaths due to perinatal asphyxia, neonatal sepsis, respiratory distress syndrome and extreme prematurity were increased.
 Conclusions: PMR over the two years has shown increasing trend at our institute. There is need to improve antenatal, obstetric as well as intra-partum services to further reduce the still birth as well as deaths due to prematurity, RDS, neonatal sepsis and perinatal asphyxia.

Placental Abruption Is Not Associated With Clinically Significant Fetomaternal Hemorrhage [29O

INTRODUCTION: Fetomaternal hemorrhage (FMH) and placental abruption may both result in adverse fetal and neonatal outcomes but have differing pathophysiology. Abruption reportedly can lead to small volume FMH, but a positive test for FMH does not indicate a diagnosis of abruption. METHODS: We performed a case-control study within Kaiser Northern California (2008–2017), first identifying all cases of FMH within this time period (defined as a positive flow cytometry for fetal hemoglobin and adverse fetal or neonatal outcomes related to hypovolemia). Cases of FMH were compared to matched controls from the same delivery cohort. We reviewed delivery records and placental pathology reports to identify whether placental abruption was clinically suspected. RESULTS: Our study included 56 women in the FMH group and 132 in the control group. Concern for placental abruption was noted in 10.6% of those without FMH and in 12.5% of those with FMH, with no significant difference between the two groups (P=.71). The adjusted odds ratio was 1.33 (95% CI .49–3.62) after adjusting for maternal age and maternal race/ethnicity. CONCLUSION: Placental abruption is not more likely to occur in clinically significant FMH compared to other deliveries for which placental pathology is obtained. Obstetric providers should consider FMH and abruption as separate clinical entities. Flow cytometry for fetal hemoglobin should be ordered in the setting of clinical suspicion for FMH, unexplained intrauterine fetal death, or adverse outcomes related to fetal or neonatal hypovolemia. The Kleihauer-Betke and flow cytometry tests for fetal hemoglobin do not confirm or refute the possibility of abruption.

EP02.15: Obesity and unexplained intrauterine fetal death at term: is the placenta involved?

EP02.15: Obesity and unexplained intrauterine fetal death at term: is the placenta involved?

The incidence of retained fetal bones after 1,002 hysteroscopies in an environment with restrictive abortion laws

Background: Retained fetal bones within the uterine cavity are rare. The incidence in an environment with restrictive abortion laws is however unknown. Aim: To document the incidence of retained fetal bones in an environment with highly restrictive abortion laws. Methods: Case records of patients who had hysteroscopy on account of retained fetal bones from April 1, 2010 to March 31, 2017 were retrieved. Data including age, number of terminations of pregnancy, gestational age at termination of pregnancy, duration of infertility, and treatment outcome were retrieved. Results: A total of 1,002 patients had hysteroscopy for various indications. Of these, 26 patients had retained fetal bones giving an incidence of 0.26%. The age range of the patients was 28--42 years, mean 34.7 ± 4.6 SD. Duration of infertility ranged from 2 to 8 years, mean 4.6 ± 2.3 SD. The number of terminations of pregnancy ranged from 1 to 6, mean 2.6 ± 1.7 SD. One patient had an unexplained intrauterine fetal death of one of a set of twins at 20 weeks gestation with subsequent elective cesarean section at 37 weeks gestation. All the cases had histological confirmation of fetal bones. Of the 24 patients who had secondary infertility, 6 (25.0%) achieved spontaneous pregnancies. Eight women underwent in vitro fertilization treatment with 2 (25%) clinical pregnancies. Conclusion: The incidence of intrauterine retained fetal bones in our environment with highly restrictive abortion laws is 0.26%. A review of these laws is probably long overdue.

Elective Delivery at Term after a Previous Unexplained Intra-Uterine Fetal Death: Audit of Delivery Outcome at Tygerberg Hospital, South Africa.

ObjectivesTo assess the delivery outcome in a pregnancy with a previous unexplained intra-uterine death by elective induction of labour at term.MethodsAn audit of the pregnancy outcome of all women within the catchment area with a current singleton pregnancy; and a previous unexplained or unexplored singleton fetal demise ≥24 weeks (or 500 grams birth weight if gestation unknown) after planned routine induction of labour at full term (39-40 weeks).ResultsDuring the audit period, 306 patients with a previous intra-uterine fetal death were referred for further management. Of these, 161 had a clear indication for earlier intervention and were excluded from the protocol. Of the remaining 145 patients, 9 met further exclusion criteria and there were 2 patients who defaulted. Forty-two of the remaining study patients (with no known previous medical problems) developed complications during their antenatal course that necessitated a change in clinical management and earlier (<39 weeks) delivery. Of the remaining 92 patients in the audit, 47 (51%) went into spontaneous labour before their induction date; all 92 women delivered without major complications. There were no intra-uterine deaths prior to induction.ConclusionsCareful follow up at a high risk clinic identifies new or concealed maternal or fetal complications in 29% of patients with a previous intra-uterine death and no obvious maternal or fetal disease in the index pregnancy. When all risks are excluded and the pregnancy allowed to progress to full term (39-40 weeks) before an induction is offered, 50% will go into spontaneous labour.

Umbilical Hypercoiling in 2nd- and 3rd-Trimester Intrauterine Fetal Death

Cases of unexplained intrauterine fetal death (IUFD) can be reduced by full placental examination, with or without autopsy. Determination of the umbilical coiling index (UCI) is considered to be a part of full placental examination. Umbilical hypercoiling (UCI above 0.30 coils/cm) is associated with IUFD. In a large retrospective study, we found an incidence of 18% umbilical hypercoiling in IUFD. We explored the association between umbilical hypercoiling and 2nd- and 3rd-trimester IUFD in 77 cases. There was a significant negative correlation between the UCI and gestational age of IUFD (P<0.001). More severe cases of hypercoiling were observed in the categories of IUFD at a younger age and with a longer duration. Signs of fetal thrombosis were significantly more present in IUFDs with umbilical hypercoiling. An umbilical cord stricture and hypercoiling seem to be significantly more common in IUFD. The severity of hypercoiling was of no influence on the presence or absence of an umbilical cord stricture. Furthermore, there was no significant difference in signs of cardiac failure between the groups of IUFD with and without umbilical hypercoiling. Our findings may be explained by the theory that hypercoiling leads to a disturbed fetal-placental circulation. Therefore, determination of the UCI should be part of the routine placental examination of cases of IUFD.

Third trimester intrauterine fetal death caused by complex cord entanglement

Umbilical cord entanglement occurs during early pregnancy. Typically, fetal asphyxia and demise because of umbilical cord entanglement is a unique characteristic of mono-amniotic twin pregnancies. We describe a case of a woman in late pregnancy that presented to medical consult at 36 weeks of amenorrhea because of the absence of fetal movements. The ultrasound found no fetal heartbeat and because the patient had two previous cesarean sections, another one was performed. We discovered a complex entanglement of the umbilical cord around the leg of the fetus that proved to be the cause of the fetal demise. Cord entanglement must be considered in cases of unexplained intrauterine fetal death. For all cases of intrauterine demise, it is important to look for marks of this condition around different parts of the body.

The placental vascular component in early and late intrauterine fetal death

ObjectiveTo compare the placental histopathological findings between pregnancies complicated by early (<34weeks' gestation) and late (≥34weeks' gestation) intrauterine fetal death (IUFD) and pregnancies with live births. Material & MethodsPlacentas of patients with unexplained IUFD between 22–42weeks of gestation were analyzed for maternal vascular supply lesions that include those related to maternal underperfusion (villous changes and vascular lesions), fetal vascular supply lesions that include findings consistent with fetal thrombo-occlusive disease (villous changes and vascular lesions) and maternal and fetal inflammatory response lesions. The clinical characteristics and placental findings were compared with those from live birth controls adjusted for gestational age. ResultsIn the early IUFD group (n=28), compared to controls with early delivery, a higher rate of vascular lesions consistent with fetal thrombo-occlusive disease (28.6% vs. 0, p=0.002), villous changes consistent with fetal thrombo-occlusive disease (21.4 vs. 3.6%, p=0.043), and cord related lesions (46.4% vs. 0, p<0.001), respectively, were observed. A similar high rate of maternal vascular supply lesions was detected in both groups. In the late IUFD group (n=30), compared to controls, a higher rate of cord related lesions, 40% vs. 0, respectively, p<0.001, were found. In contrast, maternal and fetal inflammatory response lesions were more common in controls than in placentas from early and late IUFD. ConclusionsThe involvement of placental fetal vascular supply lesions is more extensive in early IUFD than in late IUFD, when compared with matched controls.

Pregnancy in patients with β-thalassemia intermedia: Outcome of mothers and newborns

Little is known about the outcome of pregnancy in women with beta-thalassemia intermedia (TI). Over 10 years, maternal and neonatal outcomes of women with TI followed at a single thalassemia center were reviewed. Nine spontaneous pregnancies in five women with TI were studied. Six pregnancies resulted in live newborns; two were complicated by first-trimester abortions and one by an unexplained intrauterine fetal death at 36 weeks' gestation. Two patients had splenectomy before pregnancy: one required cesarean delivery and splenectomy at 31(2/7) weeks' gestation for worsening hemolytic anemia and thrombocytopenia and another had splenectomy 8 weeks postpartum for symptomatic hypersplenism. Two patients had received transfusions before pregnancy, and two required them for the first time during pregnancy and developed antibodies, which contributed to worsening of their anemia and repeated transfusions. The mean number of transfusions received during pregnancy was 8.0 +/- 5.2 units. The mean lowest hemoglobin level in pregnancy was 5.2 +/- 2.0 g/dl. Cesarean delivery was performed in 42.9% of cases. Mean gestational age at delivery was 36.7+/- 3.1 weeks with intrauterine growth restriction (IUGR) complicating 57.1% of cases. In conclusion, IUGR complicates more than half of pregnancies with TI. Transfusions are needed in most cases, even in non-transfusion-dependent patients. Postpartum splenectomy might be necessary in some patients.

Polymorphisms within the Interleukin‐1 Gene Family and Unexplained Late Intrauterine Fetal Death: A Multi‐center Study

Interleukin-1 (IL-1) mediated inflammatory processes have been proposed to be involved in the pathogenesis of late unexplained intrauterine fetal death (IUFD). We determined whether common polymorphisms within the IL-1 gene locus can serve as candidate genes for this condition. In a multi-center case-control study, we evaluated the -889 C/T polymorphism of the IL-1alpha gene (IL1A), the -511 C/T polymorphism of the IL-1beta promoter (IL1B promoter), the +3953 C/T polymorphism of IL-1beta exon 5 (IL1B exon 5), and a 86 base pair repeat in intron 2 of the IL-1 receptor antagonist gene (IL1RN) in 94 women with IUFD and 94 healthy controls using pyrosequencing. No significant associations were found between the presence of polymorphic alleles of IL1A (P = 0.9), IL1B promoter (P = 0.3), IL1B exon 5 (P = 0.9), and IL1RN intron 2 (P = 0.7) and the incidence of IUFD. In women with IUFD, polymorphisms were not associated with the timing of fetal death and birth weight. Polymorphisms within the IL1 gene family are not associated with the occurrence of IUFD overall and do not modulate the clinical characteristics of affected pregnancies in a large series of Caucasian women.

Polymorphisms of the Nos3 gene and unexplained late intrauterine fetal death

Objective: Genetic polymorphisms associated with vascular diseases have been proposed to be involved in the pathogenesis of late unexplained intrauterine fetal death (IUFD). The Nos3 gene is known to regulate vascular tone via the endothelial nitric oxide synthase/nitric oxide pathway. Study design: In a multicenter case-control study, we evaluated two Nos3 polymorphisms (exon 7 Glu298Asp and a 27 bp-repeat in intron 4) in 92 women with IUFD and 92 healthy control women. Results: The investigated Nos3 polymorphisms were not associated with the occurrence of IUFD. In the subgroup of pregnancies affected by IUFD, women with at least one mutant allele of the Nos3 intron 4 polymorphism were diagnosed with IUFD at a significantly earlier gestational age (31.8 [standard deviation (S.D.) = 4.9] weeks versus 34.6 [S.D. = 4.8] weeks, p = 0.02) and showed a significantly reduced birth weight (2113 g [S.D. = 1028] versus 1571 g [S.D. = 568], p = 0.03). Conclusion: We are the first to report on Nos3 polymorphisms and IUFD. While not being associated with the incidence of IUFD overall, the intron 4 Nos3 polymorphism might modulate the timing of IUFD in affected pregnancies.

An Angiopoietin-2 gene polymorphism in unexplained intrauterine fetal death: a multi-center study

Objective: Angiopoietin-2 (Ang-2) is a potent regulator of angiogenesis and vascular tone. As vascular processes have been proposed to be involved in the pathogenesis of pregnancy associated complications such as late unexplained intrauterine fetal death (IUFD), we determined whether a common G/A polymorphism of the Ang-2 gene ( ANGPT2) is associated with this condition. Methods: In a multicenter case-control study, we evaluated the common G/A polymorphism within exon 4 of the ANGPT2 gene using PCR in 90 women with IUFD and 90 healthy women with at least one uncomplicated full term pregnancy and no history of IUFD. Results: Genotype ( p = 0.2; OR = 1.4 [0.8–2.6]) and allele frequencies ( p = 0.1; OR = 1.4 [0.9–2.1]) of the ANGPT2 polymorphism did not differ between women with IUFD and healthy women. A multivariate regression analysis with smoking habits and preexisting diabetes as covariates did not change the results. Conclusions: We are the first to report on a common polymorphism of the ANGPT2 gene in patients with late IUFD. The investigated ANGPT2 poylmorphism does not seem to be a candidate gene for IUFD in Caucasian women.

Unexplained intrauterine fetal death is accompanied by activation of complement

Activation of the complement system has recently been implicated in the mechanisms of fetal loss in the antiphospholipid syndrome. It is, however, possible that complement activation is also involved in other causes of fetal death in the second and third trimesters of pregnancy. We therefore conducted a study to determine whether fetal death is associated with changes in the maternal plasma concentrations of complement split products or anaphylatoxins (C3a, C4a and C5a). A cross-sectional study was designed to include normal pregnant women (n=60) and patients with fetal death (n=60). Patients with fetal death were classified according to the cause of fetal demise into: a) unexplained (n=44); b) associated with preeclampsia (n=8); and c) associated with chromosomal abnormalities or major congenital fetal anomalies (n=8). The plasma concentrations of C3a, C4a and C5a were measured using sensitive and specific ELISAs. Non-parametric statistics were used for analysis. A P value of <0.05 was considered significant. 1) The median plasma concentration of C5a was higher in patients with fetal death than in normal pregnant women [median 16 ng/mL (range 4.5-402.5) vs. median 11.6 ng/mL (range 1.2-87.1), respectively; P<0.001]; 2) patients with an unexplained fetal death and those associated with preeclampsia had a higher median plasma C5a concentration than normal pregnant women (P=0.002 and P<0.001, respectively); 3) no differences were observed in the maternal plasma concentrations of C3a and C4a among the study groups. Unexplained fetal death is associated with evidence of complement activation.

An lnterleukin-6 Gene Promoter Polymorphism and Unexplained Late Intrauterine Fetal Death: A Multicenter Study

Interleukin-6 (IL-6)-mediated inflammatory processes have been proposed to be involved in the pathogenesis of pregnancy-associated complications such as late unexplained intrauterine fetal death (IUFD). Therefore we determined whether a common guanine/cytosine polymorphism at position -174 of the promoter of the IL-6 gene (IL6) known to affect in vivo protein activity can serve as candidate gene for this condition. In a multicenter case-control study, we evaluated the IL6 promoter polymorphism by pyrosequencing in 92 women with IUFD. Ninety-four healthy women with at least one uncomplicated full-term pregnancy and no history of IUFD served as the control group. No significant association was found between the presence of at least one mutant allele of the IL6 promoter polymorphism (P = .2; odds ratio = 1.5 [95% confidence interval, 0.8-2.7]) and the incidence of IUFD. In women with IUFD, the presence of at least one mutant allele of the IL6 promoter polymorphism did not influence timing of fetal death (33.9 [5.1] gestational weeks vs 34.1 [4.9] gestational weeks, P = .8) or birth weight (2055 [1119] g vs 1963 [992] g, P = .7). To our knowledge, we are the first to report on a common polymorphism of the IL6 promoter gene in women with late IUFD. The investigated IL6 promoter polymorphism can not be seen as candidate gene for IUFD in Caucasian women.

Unexplained intrauterine fetal death is accompanied by activation of complement

The complement system has recently been implicated in the mechanisms of fetal loss in the anti-phospholipid antibody syndrome (JCI 2003; 112:1644). We propose that complement activation may also be involved in other causes of intrauterine fetal death (IUFD) in the second and third trimesters of pregnancy. This study was conducted to determine if IUFD is associated with changes in maternal plasma C5a concentration, the most biologically relevant product generated during complement activation.

Participation of the 27kDa heat shock protein (hsp27) in mid-trimester amniotic fluid: Ethnic variability and association with anti-inflammatory immunity

AMNIOTIC FLUID: ETHNIC VARIABILITY AND ASSOCIATION WITH ANTIINFLAMMATORY IMMUNITY SRIRAM C. PERNI, EMRE KARASAHIN, ROBIN B. KALISH, STEPHEN T. CHASEN, STEVEN S. WITKIN, Weill Medical College of Cornell University, Obstetrics and Gynecology, New York, New York OBJECTIVE: Modulation of pro-inflammatory immune responses during gestation is essential for pregnancy prolongation. The extracellular release of the 27 kDa heat shock protein (hsp27) induces anti-inflammatory immunity. However, the possible presence of hsp27 in amniotic fluid (AF) and its interaction with other AF components has not been determined. We investigated whether hsp27 was present in mid-trimester amniotic fluid and determined its relationship with other AF immuno-modulating components and with maternal ethnicity. STUDY DESIGN: 278 pregnant women with singleton gestations who presented for genetic amniocentesis were enrolled. Clara cell protein 16 (CCP16) and cortisol, two anti-inflammatory components of AF, as well as the cytokines interleukin (IL)-1b, IL-1 receptor antagonist (IL-1ra), IL-6, IL-13, and hsp27 were measured by ELISA. Mann-Whitney U tests and linear regression analysis were used for statistical analysis. RESULTS: Hsp27 was detected in all samples with a median (range) of 5.8 ng/ mL (0.2-43.3). Median AF hsp27 concentrations were higher in blacks (6.3 ng/ mL) than in whites (4.5 ng/mL) (P = .04). IL-1b was identified in 67.8% of the AFs with a median concentration of 13.8 pg/mL (1.0-92.8). AF concentrations of hsp27 were strongly negatively correlated with AF IL-1b concentrations (r = .4360, P ! .0001) and positively correlated with CCP16 (r = .2199, P = .0012) and cortisol (r = 0.1396, P = .04) levels. CCP16 concentrations were also negatively associated with IL-1b (r = .1753, P = .006), but not as strongly as hsp27. There was no relationship between cortisol and IL-1 b levels. There was no relationship between hsp27 levels and IL-1ra, IL-6, IL-13 concentrations or neonatal gender. CONCLUSION: Hsp27 is present in AF and contributes to the down-regulation of IL-1b-induced pro-inflammatory immunity during the mid-trimester. Whether differences in baseline hsp27 levels between blacks and whites contribute to observed ethnic variations in rates of preterm birth and neonatal morbidities remains to be determined. Supported by NIH HD41676. 568 UNEXPLAINED INTRAUTERINE FETAL DEATH IS ACCOMPANIED BY ACTIVATION OF COMPLEMENT KARINA RICHANI, ELEAZAR SOTO, JIMMY ESPINOZA, JYH KAE NIEN, TINNAKORN CHAIWORAPONGSA, JERRIE REFUERZO, SEAN BLACKWELL, SAMUEL EDWIN, MOSHE MAZOR, ROBERTO ROMERO, Wayne State University School of Medicine, Detroit, Michigan, Perinatology Research Branch, NICHD, NIH, DHHS, Bethesda, Maryland, Wayne State University School of Medicine, Department of Obstetrics and Gynecology, Detroit, Michigan, Soroka University Medical Center, Beer Sheva, Israel, Israel OBJECTIVE: The complement system has recently been implicated in the mechanisms of fetal loss in the anti-phospholipid antibody syndrome (JCI 2003; 112:1644). We propose that complement activation may also be involved in other causes of intrauterine fetal death (IUFD) in the second and third trimesters of pregnancy. This study was conducted to determine if IUFD is associated with changes in maternal plasma C5a concentration, the most biologically relevant product generated during complement activation. STUDY DESIGN: A cross-sectional study was designed to include normal pregnant women (n = 60) and patients with IUFD (n = 60). The IUFD group was classified according to the cause of fetal death into: (a) unexplained (n = 44); (b) associated with preeclampsia (n = 8); and (c) chromosomal abnormality or major malformation (n = 8). The plasma concentration of C5a was measured by ELISA. Non-parametric statistics were used for analysis. RESULTS: (1) The median plasma concentration of C5a in patients with IUFD was significantly higher than that of normal pregnant women (median 16.05 ng/mL, range 4.59–402.52 ng/mL vs. median 11.64 ng/mL, range 1.22– 87.13 ng/mL, respectively; P! .001); (2) Among patients with IUFD, those with unexplained fetal death and fetal death with preeclampsia had a median plasma C5a concentration higher than that of normal pregnant women (P = .002 and P ! .001, respectively); (3) There was no significant difference in median plasma concentration of C5a between IUFD with congenital anomalies and normal pregnancy. CONCLUSION: Unexplained IUFD is accompanied by complement activation.

Cord Blood Cardiac Troponin T and Troponin I Levels in Multiple-Gestation Neonates

The increased mortality and morbidity rates in multiple-gestation neonates are not completely understood. Troponin measurements have a role in situations where the evaluation of the cardiac damage is difficult, such as in cases of unexplained intrauterine fetal growth restriction or death. These conditions, along with perinatal hypoxic risk and in utero ischemic damage, are frequently found in multiple gestations. In this context, a myocardial damage could be expected more frequently in multiple than in singleton births. We hypothesized that cord blood cardiac troponin T and troponin I, markers of myocardial damage, could be different between singleton and multiple pregnancies and, among twins, between the first- and the second-born twin. Troponins T and I and creatine kinase MB concentrations were not increased in twins at birth and were not different between the first- and the second-born twin. These data suggest that myocardial damage, evaluated by cardiac troponin T, troponin I, and creatine kinase MB measurements, does not seem to be a relevant problem in multiple-gestation neonates.

Genetic polymorphisms associated with thrombophilia and vascular disease in women with unexplained late intrauterine fetal death: a multicenter study.

We determined whether gene polymorphisms associated with thrombophilia and vascular disease as etiologic factors were involved in the pathogenesis of pregnancy-associated complications. We conducted a multicenter case-control study in which we studied 94 women with late unexplained intrauterine fetal death (IUFD) and 94 healthy women with at least one uncomplicated full-term pregnancy and no history of IUFD. We obtained blood samples from all subjects and analyzed their DNA for 12 common polymorphisms of thrombophilic and vascular genes (factor V Leiden, factor V H1299R, prothrombin G20210A, factor XIII V34L, MTHFR C677T, MTHFR A1298C, beta-fibrinogen-455 G to A, PAI-1 4G/5G, GPIIIa L33P, HFE C282Y, apolipoprotein B R3500Q, and apolipoprotein E2/E3/E4). We found no significant association between any of the polymorphisms investigated and IUFD. Subgroup analyses involving various combinations of polymorphisms and in which gestational age and fetal weight were corrected for also showed no significant results. Our data represent the largest study to date with respect to thrombophilic and vascular gene polymorphisms in IUFD. In accordance with others, we challenge the importance of thrombophilic and vascular gene polymorphisms in the pathogenesis of this condition.

Placental Pathology in Women with Type 1 Diabetes and in a Control Group with Normal and Large-for-Gestational-Age Infants

Unexplained intra-uterine fetal death is still a problem in diabetic pregnancies, especially in those with an LGA-infant. We hypothesized that in these pregnancies impaired placental function, in terms of abnormal placental weight and/or abnormal placental histology, may account for this phenomenon. To test this hypothesis, we assessed the relative placental weight and scored several histological abnormalities in 34 AGA- and 24 LGA-placentae of type 1 diabetic women and in 22 AGA- and 16 LGA-placentae of control women. Relative placental weight was comparable in the LGA-diabetic cases and in the control groups, but was significantly higher in the AGA-diabetic subgroup. Histological abnormalities such as the presence of nucleated fetal red blood cells, fibrinoid necrosis, villous immaturity and chorangiosis were observed more often in the diabetic placentae compared with the control placentae. These differences in histology were particularly observed when we compared both AGA-groups. LGA-control placentae showed a high incidence of histological abnormalities, almost comparable to the diabetic placentae. Only fibrinoid necrosis was significantly more common in the LGA-diabetic placentae. Three of the four cases of perinatal death/asphyxia in the diabetic group concerned an LGA-infant with a relative low placental weight. In conclusion, placentae of women with type 1 diabetes showed several abnormalities that can be associated with impaired functioning. The difference between AGA- and LGA-diabetic placentae was related to relative placental weight and our data suggest that an increase in relative weight may protect the fetus from asphyxia. Placentae from LGA-non-diabetic women showed several similarities to those of women with diabetes.