Multi-fetal pregnancy reduction (MFPR) to twins or singleton - medical justification and ethical slippery slope.

Multi-fetal pregnancy reduction (MFPR) is an ethically acceptable procedure aimed to increase survival and well-being of the remaining fetuses from high-order multiple gestations. In most cases we offer the procedure to triplets or quadruplets and opt to preserve twins; lately, the option to maintain a single fetus was suggested. We examined the outcomes of 140 pregnancies that underwent MFPR in our center and were followed to delivery - 105 were reduced to twins and 35 to singletons. The rate of procedure-related pregnancy loss was identical (2.9%). Leaving only one fetus was associated with a higher gestational age at delivery (35.4±2.4 weeks vs. 37.7±2.1 weeks, P<0.0001), with heavier neonates (2222 g vs. 3017 g, P<0.0001) and with a reduction in the cesarean section (CS) rate (76% in twins vs. 51.4% in singletons, P=0.02). Six pregnancies reduced to twins (5.8%) ended before 32 weeks as compared to one pregnancy reduced to a singleton. We conclude that reduction of triplets to singletons is medically and ethically acceptable, after thorough counseling of patients. However, considering the pregnancy loss risk of MFPR and the relatively good outcome of twin gestations, reduction of twins to singletons is ethically acceptable only in extraordinary maternal or fetal conditions.

Glucose tolerance in singleton, twin and triplet pregnancies.

BACKGROUND: Data regarding the effects of multifetal pregnancy on the incidence of gestational diabetes mellitus (GDM) are inconsistent and even conflicting. Twin pregnancies have been associated with no increase, a marginal increase or a higher incidence of gestational diabetes. In triplet pregnancies, these effects have not been investigated yet. OBJECTIVES: To analyze the results of the glucose challenge and tolerance tests in singleton, twin and triplet pregnancies. STUDY DESIGN: A retrospective database analysis of pregnant women with singletons, twins or triplets who had complete results of the 50 g glucose challenge test (GCT) and the 100 g oral glucose tolerance test (OGTT). The cohort included 12,382 singletons, 515 twins and 39 triplets. RESULTS: There were significantly higher rates of abnormal GCTs in twins and triplets compared to singletons (45.4% and 33.3%, respectively vs. 13.7%, P<0.001 and P<0.05). Significantly higher rates of gestational diabetes in twins (10.1% vs. 2.9 %, P<0.001) and triplets (12.8% vs. 2.9%, P<0.05) compared to singletons were observed. Mean glucose levels after the GCT were higher in twins compared to singletons, and even more in triplets (108 mg/dL in singletons vs. 120 mg/dL in twins vs. 129 mg/dL in triplets, P<0.001). CONCLUSIONS: Glucose intolerance is aggravated in multifetal pregnancies. The likelihood of an abnormal GCT and gestational diabetes is higher in twins and triplets compared to singletons.

Accuracy of ultrasound in estimating fetal weight and growth discordancy in triplet pregnancies.

AIMS: Sonographic estimation of fetal weight is a fundamental part of the routine obstetrical practice and may affect management decisions particularly in multiple gestations. The data available on the accuracy of sonographic estimation of fetal weight in triplets are very limited. In the present study we investigated the accuracy of sonographic fetal weight estimation and discordancy in triplet gestations. METHODS: We analyzed the sonographic data of 33 sets of triplets born at one medical center between January 2001 and March 2013. Estimated fetal weight was calculated from biometric measurements and compared with actual neonatal weights following delivery. The Pearson correlation coefficient, linear regression analyses, and Bland-Altman method were used for statistical comparisons. RESULTS: The differences between predicted and actual birth weights (ABW) were <10% in 69 newborns (70%), 10%-20% in 19 newborns (19%), and more than 20% in 11 newborns (11%). There was a good correlation between predicted and ABW (correlation coefficient=0.928, r2=0.86, P<0.0001). CONCLUSIONS: Weight assessment in triplets does not fall behind that of singletons or twins, and decisions based upon these examinations are reliable in the majority of cases.

Fetal reduction in triplet gestations: twins still fare better.

BACKGROUND: Reduction of fetal number has been offered in high order multiple gestations but is still controversial in triplets. Since recent advances in neonatal and obstetric care have greatly improved outcome, the benefits of multifetal pregnancy reduction (MFPR) may no longer exist in triplet gestations. OBJECTIVES: To evaluate if fetal reduction of triplets to twins improves outcome. METHODS: We analyzed the outcome of 80 triplet gestations cared for at Rambam Health Care Campus in the last decade; 34 families decided to continue the pregnancy as triplets and 46 opted for MFPR to twins. RESULTS: The mean gestational age at delivery was 32.3 weeks for triplets and 35.6 weeks for twins after MFPR. Severe prematurity (delivery before 32 gestational weeks) occurred in 37.5% and 7% of twins. Consequently, the rate of severe neonatal morbidity (respiratory distress syndrome, bronchopulmonary dysplasia, intraventricular hemorrhage) and of neonatal death was significantly higher in unreduced triplets, as was the length of hospitalization in the neonatal intensive care unit (31.4 vs. 15.7, respectively). Overall, the likelihood of a family with triplets to take home all three neonates was 80%; the likelihood to take home three healthy babies was 71.5%. CONCLUSIONS: MFPR reduces the risk of severe prematurity and the neonatal morbidity of triplets. A secondary benefit is the reduction of cost of care per survivor. Our results indicate that MFPR should be offered in triplet gestations.

SERKAL syndrome: an autosomal-recessive disorder caused by a loss-of-function mutation in WNT4.

The WNT-signaling pathway plays a major role during mammalian embryogenesis. We report a novel autosomal-recessive syndrome that consists of female to male sex reversal and renal, adrenal, and lung dysgenesis and is associated with additional developmental defects. Using a candidate-gene approach, we identified a disease-causing homozygous missense mutation in the human WNT4 gene. The mutation was found to result in markedly reduced WNT4 mRNA levels in vivo and in vitro and to downregulate WNT4-dependent inhibition of beta-catenin degradation. Taken together with previous observations in animal models, the present data attribute a pivotal role to WNT4 signaling during organogenesis in humans.

Optimizing outcome of twins by routine cesarean section beyond 37 weeks.

The appropriate time and the optimal mode of delivery of twins are still controversial. We assessed the effect of gestational age and the mode of elective delivery of twins on the occurrence of neonatal respiratory morbidity (NRM) and of maternal morbidity. This study included twins born beyond 35 weeks' gestation. NRM was defined as respiratory distress syndrome (RDS) and transient tachypnea of the newborn (TTN). Additionally, maternal complications related to the different modes of delivery were taken into account. Of 711 twin pregnancies (1422 liveborn neonates) included, 74 (5.2%) experienced NRM. Maternal age > 25 years, delivery at an earlier gestational age, and delivery by emergency cesarean section maintained statistical significance with NRM. From the maternal point of view, increased length of hospitalization ( P = 0.045) and the need for postoperative antibiotics ( P = 0.0065) were significantly higher following an emergency cesarean section than after an elective cesarean birth. The risk of NRM in twins born beyond 37 weeks' gestation is rather low. We suggest considering elective cesarean delivery at completion of 37 weeks. This can be performed safely in regard to NRM, the trade-off being reduced maternal morbidity associated with elective cesarean delivery.

The effects of oxytocin and atosiban on the modulation of heart rate in pregnant women.

OBJECTIVE: To evaluate autonomic modulation of heart rate in pregnant women treated with oxytocin to induce labor and with atosiban (an oxytocin antagonist) to arrest preterm labor. METHODS: A prospective study with two cohorts: 14 pregnant women treated with atosiban for premature uterine contractions, and 28 women undergoing induction of labor with oxytocin. Computerized analyses of the electrocardiogram were performed with spectral and nonlinear dynamic analyses. RESULTS: Atosiban did not alter any of the variables associated with heart rate variability, whereas oxytocin showed a dose-dependent decrease in heart rate (p < 0.05) and a significant increase in all spectral variables studied (p < 0.01). CONCLUSIONS: Atosiban has no adverse effects on the cardiovascular system or the modulation of heart rate. Oxytocin, on the other hand, can cause a dose-dependent bradycardic effect and an increase in the spectral power, thus should be used with caution in certain pregnant women.

[Prenatal diagnosis of chorioangioma].

Chorioangioma is a benign tumor ot aberrant vessels originated from the chorion. This is a case study of a 22 year-old woman presented at 22 weeks of her first gestation with polyhydramnios and a sonographic finding consistent with placental chorioangioma. The fetus developed hydrops two weeks later. After three more days the patient was admitted due to abdominal pain and vaginal bleeding. The membranes ruptured spontaneously. Five hours from admission she delivered spontaneously a dead 1450 grams male abortus. Uterine revision was performed due to incomplete placental expulsion. A solid mass was removed during the procedure. The mass was sent to pathology and was diagnosed as placental chorioangioma. Large chorioangioma require careful follow-up due to the possibility of rapid deterioration in fetal condition.

Episiotomy: beliefs, practice and the impact of educational intervention.

OBJECTIVE: To assess the potential effect of educational intervention on episiotomy practice. STUDY DESIGN: A survey of the attitude of obstetrical caregivers toward episiotomy was conducted among obstetricians and midwives in the three public hospitals in Haifa. Data regarding episiotomy rates was collected for the years 2001-2003. At the beginning of 2002, lectures on the risks and benefits of episiotomy were given in two hospitals. Episiotomy rates before and after the lecture were compared. RESULTS: A significant and lasting reduction in episiotomy rates was observed in the two hospitals where lectures were given. There were no clinically significant and consistent changes in the episiotomy practices in the third hospital. CONCLUSION: Education may play an important role in changing common medical practices, as in episiotomy. It was clearly shown that our beliefs are not always up to date. We call for periodic reassessment of all medical procedures, as common and accepted as they are.

[Malformed pygopagus conjoined twins in a spontaneous triplet pregnancy].

This is a case study of malformed conjoined twins in a spontaneous triplet pregnancy. A 20-year-old primigravida spontaneously delivered at 22 weeks gestation a normal 425-gram male newborn followed by a delivery of a 525 grams pygopagus conjoined male twins. One twin had omphalocele, missing ears, cleft palate and dysmorphic figures while the other had imperforated anus and dysmorphic figures. The Apgar scores were 2/0. The placenta was monochorionic/diamniotic with single umbilical artery supplying both conjoined twins. Conjoined twin in a triplet pregnancy may be diagnosed by ultrasound as early as the first trimester. Failure in diagnosis of the condition resulted in early delivery of three premature infants. All three infants died after delivery.

The circadian rhythm of "urgent" operative deliveries.

BACKGROUND: Even operative deliveries defined as "urgent" show marked diurnal variation with a significant increase during regular working hours. OBJECTIVE: To investigate the diurnal variation of urgent operative deliveries and its potential implications on the outcome of newborns. METHODS: We conducted a retrospective study of all deliveries in a public hospital from 1 January 1990 to 31 December 1998. Delivery mode variables analyzed were spontaneous vaginal delivery, urgent cesarean section and operative vaginal delivery. Deliveries were stratified hourly throughout the day. The rate of operative deliveries was calculated and the analysis was then performed according to the daily routine shifts of the medical staff. Birth weight and Apgar scores at 1 and 5 minutes were retrieved as outcome measures. RESULTS: The rate of urgent cesarean deliveries increased significantly between 8 a.m. and 2 p.m. (150%-230%) from that predicted. The lowest rate of urgent cesarean sections was found between 5 a.m. and 6 a.m. (5.3%). Mean birth weight in spontaneous deliveries was higher in the morning hours than during the night shift (3,293 +/- 520 g vs. 3,277 +/- 510 g, respectively, P < 0.005). Apgar scores of newborns delivered by urgent cesarean section during the morning were higher compared to those delivered during night shifts and the rate of low Apgar scores was lower in the morning than in evening and night shifts. CONCLUSIONS: Our results indicate a marked diurnal variation in urgent operative deliveries, caused perhaps by varying definition of "urgency" according to the time of day.

[Prenatal imaging of the Meckel-Gruber syndrome].

A 32 years old woman, gravida 2 para 1, presented at 27 + 5 weeks' gestation with a large fetal head for the gestational age, an occipital encephalocele and ventriculomegaly. Both fetal kidneys were large, echogenic and multicystic, but oligohydramnion was not observed. Post-axial polydactyly of the fetal feet was demonstrated. The Meckel-Gruber syndrome was diagnosed, but termination of pregnancy was declined. Three weeks later, the patient spontaneously delivered an 1890 grams live-born female. The newborn died 2 days later in the neonate intensive care unit.

[Is there an association between PUPPP and preeclampsia, abruptio placentae and fetal death?].

This is a case study of a 28-year old woman, gravida 1 para 0, presented at 37+4 weeks gestation due to purpura and fetal death. A 3700 gram dead male fetus without gross malformation was delivered by forceps. Post delivery abruptio placentae, diffuse intravascular coagulation, fulminant preeclampsia and acute renal failure followed. Skin biopsy revealed pruritic urticarial papules and plaques of pregnancy. The patient fully recovered one week postpartum. This case report discusses a possible association between pruritic urticarial papules, plaques of pregnancy and severe preeclampsia with fetal death.

Triplet pregnancies--a three-decade perspective: do we fare better?

OBJECTIVES: To evaluate the impact of advances in perinatal and neonatal care in the past three decades on the outcome of triplet pregnancies. STUDY DESIGN: We compared the outcome of 29 sets of triplets born in our medical center during 1978-1987 with 34 sets of triplets born in the same medical center during 2001-2011. Data were extracted from maternal and neonatal medical records. RESULTS: There were no significant differences in mortality or morbidity in any of the studied outcome measures between the two epochs. Of the 34 women with triplet pregnancies in the present cohort only 28 (82%) took all three born babies home, not different from the 86% found in the early cohort. The overall take-home baby rate was 93% (95/102) in the present cohort, not different than the 86% (74/86) in the early cohort. CONCLUSIONS: Despite technological advances in perinatal and neonatal care, there was no significant improvement in the outcome of triplet pregnancies during the past three decades.

An assay to evaluate heparanase procoagulant activity.

BACKGROUND: Heparanase that was cloned from and is abundant in the placenta is implicated in cell invasion, tumor metastasis and angiogenesis. Recently, we demonstrated that heparanase is directly involved in the regulation of the hemostatic system. Heparanase was shown to form a complex and enhance tissue factor (TF) activity, resulting in increased factor Xa production (Nadir et al. Haematologica, 2010). The present work suggests a novel assay to evaluate heparanase procoagulant activity. METHODS: Heparanase procoagulant activity was studied using purified proteins of heparanase, TF, factor VIIa and factor X. The assay was verified in 55 plasma samples and compared to heparanase and tissue factor pathway inhibitor (TFPI) levels by ELISA and factor Xa, thrombin levels and antithrombin activity by chromogenic substrates. Thirty five samples were of third-trimester pregnant women (weeks 36-41) who were in labor or came for appointed elective cesarean section and 20 control samples were of non-pregnant healthy women. RESULTS: Heparanase procoagulant activity assay was shown to differentiate heparanase procoagulant effect from TF activity, in purified proteins. Heparanase procoagulant activity was significantly higher in the plasma of pregnant women compared to non-pregnant (p < 0.005). Heparanase relative contribution to the TF / heparanase complex activity was significantly higher in the plasma of pregnant women compared to non-pregnant (29% increase, p < 0.0001). Differences in heparanase procoagulant activity were more prominent than changes in heparanase levels by ELISA, TF activity, factor Xa, thrombin and free TFPI levels. CONCLUSIONS: Heparanase procoagulant activity can be determined by the suggested assay. The assay revealed a significant contribution of heparanase to the procoagulant state in late third-trimester pregnancy and at delivery.

Involvement of heparanase in vaginal and cesarean section deliveries.

BACKGROUND: Heparanase is an endo-ß-D-glucuronidase dominantly involved in cell invasion, tumor angiogenesis and metastasis. Recently, we demonstrated increased levels of heparanase, tissue factor pathway inhibitor (TFPI)-2 and vascular endothelial growth factor (VEGF)-A in early miscarriages (Nadir et al., Thromb Res, 2010). Herein, we investigated the role of heparanase in third trimester placentas, in correlation to tissue factor (TF), TFPI, TFPI-2, and VEGF-A. METHODS: Twenty five third-trimester placenta samples (weeks 36-41) were studied applying real time RTPCR and immunostaining. Ten cases were placentas of elective cesarean sections, 8 cases were of normal vaginal deliveries and 7 samples were placentas of intra-uterine growth restriction (IUGR) fetuses. Skin and lung tissues of heparanase over-expressing mice and heparanase knock-out mice were subjected to immunostaining. RESULTS: Sections obtained from vaginal and IUGR placentas revealed 2 folds increased levels of heparanase, TFPI-2 and VEGF-A compared to placentas from elective cesarean sections in maternal decidua as well as in fetal placenta elements. Interestingly, abundance of TFPI staining in the intra-villous blood was observed in placentas of vaginal and IUGR deliveries. Heparanase effect on TFPI release to the blood was supported by immunostaining of heparanase over-expressing and heparanase knock-out mice tissues. CONCLUSIONS: In regard to our previous data on early pregnancy losses, the present data strengthen the understanding that in placental vascular complications levels of heparanase, TFPI-2 and VEGF-A increase. In the process of delivery, heparanase may have a regulatory role on TFPI release to fetal circulation.

Congenital cervical teratoma, associated with agenesis of corpus callosum and a subarachnoid cyst.

Cervical teratoma is a neoplasm composed of embryonic tissues with representation of all three germ layers. We report an extremely rare case of fetal cervical teratoma presenting at 24 weeks of gestation. A submaxillary mass and agenesis of corpus callosum were identified on ultrasonography, associated with agenesis of corpus callosum and a subarachnoid cyst.

Hemivertebra: prenatal diagnosis, incidence and characteristics.

OBJECTIVE: Hemivertebra is a rare congenital spinal anomaly where only one side of the vertebral body develops, resulting in deformation of the spine, such as scoliosis, lordosis, or kyphosis. We aimed to determine the incidence and clinical characteristics of hemivertebra. PATIENTS AND METHODS: We present three fetuses with a prenatal ultrasonographic diagnosis of hemivertebra at 15-22 weeks' gestation, and we determine the incidence and clinical characteristics of hemivertebra among 78,500 live-born infants at a tertiary medical center in Israel. RESULTS: There were 26 cases of hemivertebra (0.33/1,000 live-born infants): male/female ratio 1/1, Jewish/Arab ratio 10/16, and ratio of single/multiple type of hemivertebrae 17/9. Twenty-three out of 26 infants (88.5%) with hemivertebra had additional congenital anomalies (cranial, cardiac, renal, intestinal, and skeletal). CONCLUSIONS: Hemivertebra is not an infrequent finding in fetuses and live-born infants. Comprehensive ultrasonographic screening of the fetus allows early prenatal diagnosis of hemivertebra, and provides parents with helpful information for their decision regarding the fate of pregnancy.