Outcome of twin-to-twin transfusion syndrome in monochorionic monoamniotic twin pregnancy: systematic review and meta-analysis.

OBJECTIVES: To explore the outcome of monochorionic monoamniotic (MCMA) twin pregnancies affected by twin-to-twin transfusion syndrome (TTTS). METHODS: MEDLINE and EMBASE databases were searched for studies reporting the outcome of MCMA twin pregnancies complicated by TTTS. The primary outcome was intrauterine death (IUD); secondary outcomes were miscarriage, single IUD, double IUD, neonatal death (NND), perinatal death (PND), survival of at least one twin, survival of both twins and preterm birth (PTB) before 32 weeks' gestation. Outcomes were assessed in MCMA twins affected by TTTS not undergoing intervention and in those treated with amniodrainage, laser therapy or cord occlusion. Subgroup analysis was performed including cases diagnosed before 24 weeks. Random-effects meta-analysis of proportions was used to analyze the data. RESULTS: Fifteen cohort studies, including 888 MCMA twin pregnancies, of which 44 were affected by TTTS, were included in the review. There was no randomized trial comparing the different management options in MCMA twin pregnancies complicated by TTTS. In cases not undergoing intervention, miscarriage occurred in 11.0% of fetuses, while the incidence of IUD, NND and PND was 25.2%, 12.2% and 31.2%, respectively. PTB complicated 50.5% of these pregnancies. In cases treated by laser surgery, the incidence of miscarriage, IUD, NND and PND was 19.6%, 27.4%, 7.4% and 35.9%, respectively, and the incidence of PTB before 32 weeks' gestation was 64.9%. In cases treated with amniodrainage, the incidence of IUD, NND and PND was 31.3%, 13.5% and 45.7% respectively, and PTB complicated 76.2% of these pregnancies. Analysis of cases undergoing cord occlusion was affected by the very small number of included cases. Miscarriage occurred in 19.2%, while there was no case of IUD or NND of the surviving twin. PTB before 32 weeks occurred in 50.0% of these cases. CONCLUSIONS: MCMA twin pregnancies complicated by TTTS are at high risk of perinatal mortality and PTB. Further studies are needed in order to elucidate the optimal type of prenatal treatment in these pregnancies. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Perinatal mortality, timing of delivery and prenatal management of monoamniotic twin pregnancy: systematic review and meta-analysis.

OBJECTIVE: To quantify the rate of perinatal mortality in monochorionic monoamniotic (MCMA) twin pregnancies, according to gestational age, and to ascertain the incidence of mortality in pregnancies managed as inpatients compared with those managed as outpatients. METHODS: MEDLINE, EMBASE and CINAHL databases were searched for studies on monoamniotic twin pregnancy. The primary outcomes explored were the incidence of intrauterine death (IUD), neonatal death (NND) and perinatal death (PND) in MCMA twins at different gestational-age windows (24-30, 31-32, 33-34, 35-36 and ≥ 37 weeks of gestation). The secondary outcomes were the incidence of IUD, NND and PND in MCMA twins according to the type of fetal monitoring (inpatient vs outpatient), and the incidence of delivery ahead of schedule. Random-effects model meta-analyses were used to analyze the data. RESULTS: Twenty-five studies (1628 non-anomalous twins reaching 24 weeks of gestation) were included. Single and double intrauterine deaths occurred in 2.5% (95% CI, 1.8-3.3%) and 3.8% (95% CI, 2.5-5.3%) of cases, respectively. IUD occurred in 4.3% (95% CI, 2.8-6.2%) of twins at 24-30 weeks, in 1.0% (95% CI, 0.6-1.7%) at 31-32 weeks and in 2.2% (95% CI, 0.9-3.9%) at 33-34 weeks of gestation, while there was no case of IUD, either single or double, from 35 weeks of gestation. In MCMA twin pregnancies managed mainly as inpatients, the incidence of IUD was 3.0% (95% CI, 1.4-5.2%), while the corresponding figure for those managed mainly as outpatients was 7.4% (95% CI, 4.4-11.1%). Finally, 37.8% (95% CI, 28.0-48.2%) of MCMA pregnancies were delivered before the scheduled time, due mainly to spontaneous preterm labor or abnormal cardiotocographic findings. CONCLUSIONS: MCMA twins are at high risk of perinatal loss during the third trimester of pregnancy, with the large majority of such losses occurring as apparently unexpected events. Inpatient management seems to be associated with a lower rate of mortality, although further studies are needed in order to establish the appropriate type and timing of prenatal assessment in these pregnancies. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Inactivation of human coagulation factor X by a protease of the pathogen Capnocytophaga canimorsus.

Essentials Capnocytophaga canimorsus causes severe dog bite related blood stream infections. We investigated if C. canimorsus contributes to bleeding abnormalities during infection. The C. canimorsus protease CcDPP7 causes factor X dysfunction by N-terminal cleavage. CcDPP7 inhibits coagulation in vivo, which could promote immune evasion and trigger hemorrhage. SUMMARY: Background Capnocytophaga canimorsus is a Gram-negative bacterium that is present in the oral flora of dogs and causes fulminant sepsis in humans who have been bitten, licked, or scratched. In patients, bleeding abnormalities, such as petechiae, purpura fulminans, or disseminated intravascular coagulation (DIC), occur frequently. Objective To investigate whether C. canimorsus could actively contribute to these bleeding abnormalities. Methods Calibrated automated thrombogram and clotting time assays were performed to assess the anticoagulant activity of C. canimorsus 5 (Cc5), a strain isolated from a fatal human infection. Clotting factor activities were measured with factor-deficient plasma. Factor X cleavage was monitored with the radiolabeled zymogen and western blotting. Mutagenesis of Cc5 genes encoding putative serine proteases was performed to identify the protease that cleaves FX. Protein purification was performed with affinity chromatography. Edman degradation allowed the detection of N-terminal cleavage of FX. Tail bleeding times were measured in mice. Results We found that Cc5 inhibited thrombin generation and increased the prothrombin time and the activated partial thromboplastin time of human plasma via FX cleavage. A mutant that was unable to synthesize a type 7 dipeptidyl peptidase (DPP7) of the S46 serine protease family failed to proteolyse FX. The purified protease (CcDPP7) cleaved FX heavy and light chains from the N-terminus, and was active in vivo after intravenous injection. Conclusions This is, to our knowledge, the first study demonstrating a detailed mechanism for FX inactivation by a bacterial protease, and it is the first functional study associating DPP7 proteases with a potentially pathogenic outcome.

Ultrasonographic prediction of birth weight discordance in twin pregnancies.

OBJECTIVE: This study aimed to assess the accuracy of the ultrasonographic prediction of intertwin birth weight discordance based on crown-rump length, estimated fetal weight (EFW) and abdominal circumference. METHOD: We retrospectively studied variables of prenatal surveillance of 281 twin pregnancies at the University Medical Centre Utrecht, between 2008 and 2011. RESULTS: Fifteen per cent of twins had a birth weight discordance of ≥20%. One twin more commonly had intrauterine growth restriction in the birth weight discordance group compared with the concordantly grown group (69% vs 20%, respectively). Sonographically, EFW discrepancy and increased abdominal circumference ratio were significantly correlated with birth weight discordance. The negative predictive values were high (92% and 87%, respectively). The best prediction of weight discordance was given by EFW discordance at the last ultrasound before delivery. CONCLUSION: Intertwin birth weight discordance is best predicted by an intertwin EFW discordance at the last ultrasound. If discordance is not suspected by ultrasound, the vast majority had no birth weight discordance. In case of birth weight discordance, the presence of at least one growth-restricted twin is very likely. However, because around 20% of concordantly grown twin pairs comprise at least one intrauterine growth restriction infant, one cannot rely on weight discordance alone.

Wnt5a inhibits the CpG oligodeoxynucleotide-triggered activation of human plasmacytoid dendritic cells.

Plasmacytoid dendritic cells (pDCs) fulfil multiple roles in immunity, and can secrete large amounts of interferon (IFN)-α. However, the available evidence suggests that they may actually counteract efficient antitumour immunity. Thus in melanoma, pDCs are abundant, but they are anergic and deficient in IFN-α secretion. pDC anergy is thought to be caused by immunosuppressive factors secreted by melanoma cells. One factor strongly expressed by melanoma is Wnt5a, which is implicated in cancer tissue invasion. In this paper, we show that Wnt5a is able to block the upregulation of the activation markers CD80 and CD86 on naive human pDCs stimulated by CpG oligodeoxynucleotide, and CpG-triggered secretion of IFN-α by pDCs. Our results suggest that Wnt5a may not only initiate cancer invasion, but could also regulate activation of pDC. These data provide a clear rationale to investigate a role for Wnt5a in immune regulation.

Perinatal mortality and mode of delivery in monochorionic diamniotic twin pregnancies ≥ 32 weeks of gestation: a multicentre retrospective cohort study.

OBJECTIVE: To study perinatal mortality rates in a cohort of 465 monochorionic (MC) twins without twin-twin transfusion syndrome (TTS) born at 32 weeks of gestation or later since reported interauterine fetal death (IUFD) rates >32 weeks of gestations in the literature vary, leading to varying recommendations on the optimal timing of delivery, and to investigate the relation between perinatal mortality and mode of delivery. DESIGN: Multicentre retrospective cohort study. SETTING: Ten perinatal referral centres in the Netherlands. POPULATION: All MC twin pregnancies without TTTS delivered at ≥ 32 weeks of gestation between January 2000 and December 2005. METHODS: The medical records of all MC twin pregnancies without TTTS delivered at the ten perinatal referral centres in the Netherlands between January 2000 and December 2005 were reviewed. MAIN OUTCOME MEASURES: Perinatal mortality in relation to gestational age and mode of delivery at ≥ 32 weeks of gestation. RESULTS: After 32 weeks of gestation, five out of 930 fetuses died in utero and there were six neonatal deaths (6 per 1000 infants). In women who delivered ≥ 37 weeks, perinatal mortality was 7 per 1000 infants. Trial of labour was attempted in 376 women and was successful in 77%. There were three deaths in deliveries with a trial of labour (8 per 1000 deliveries), of which two were related to mode of delivery. Infants born by caesarean section without labour had an increased risk of neonatal morbidity and respiratory distress syndrome. CONCLUSIONS: In MC twin pregnancies the incidence of intrauterine fetal death is low ≥ 32 weeks of gestation. Therefore, planned preterm delivery before 36 weeks does not seem to be justified. The risk of intrapartum death is also low, at least in tertiary centres.

A comparative cohort study on transfusion practice and outcome in two Dutch tertiary neonatal centres.

The objective of this study was to investigate how a red blood cell transfusion volume of 15 or 20 mL kg(-1) body weight affects the total number of administered transfusions and neonatal complications in premature infants born before 32 gestational weeks. In this observational study, we analysed clinical data from two cohorts of 218 and 241 premature infants admitted to two neonatal centres which used the same transfusion guideline and product, but different transfusion volumes. Outcome parameters were the number of administered transfusions and the composite outcome of bronchopulmonary dysplasia, retinopathy of prematurity, intraventricular haemorrhage and mortality. The proportion of transfused infants was significantly lower (59 vs. 77%) in the centre using a lower transfusion volume of 15 mL kg(-1). In infants born between a gestational age of 24 0/7 weeks and 27 6/7 weeks. a similar proportion received transfusions in both centres, with an equal number of transfusions per infant. In infants born between a gestational age of 28 0/7 weeks and 31 6/7 weeks, the proportion of transfused infants (49 vs. 74%) was significantly higher in the centre using a larger transfusion volume. In these infants, transfusion with 20 mL kg(-1) resulted, however, in a mean reduction of one transfusion episode per infant. The higher proportion of transfused infants was associated with a higher pre-transfusion haematocrit in less ill infants, suggesting the use of different triggers based on clinical grounds. Composite clinical complications were similar in both cohorts. Clinical neonatal outcome was similar disregard of a higher proportion of transfused patients and a higher total amount of RBC transfused in one of the centres. A larger transfusion volume of 20 mL kg(-1) prolonged the interval until next transfusion and can reduce donor exposure in infants born between a gestational age of 28 0/7 weeks and 31 6/7 weeks.

Placental characteristics of monoamniotic twin pregnancies in relation to perinatal outcome.

OBJECTIVE: To study placental characteristics in relation to perinatal outcome in 55 pairs of monochorionic monoamniotic (MA) twins. METHODS: Between January 1998 and May 2008 55 pairs of MA twins were delivered in 4 tertiary care centers and analysed for mortality, birth weight discordancy and twin-to-twin transfusion syndrome (TTTS) in relation to type of anastomoses, type and distance between cord insertions and placental sharing. Five acardiac twins, 2 conjoined twins, 4 higher order multiples and one early termination of pregnancy were excluded, leaving 43 MA placentas for analysis. Of these 43, one placenta could not be analysed for placental vascular anastomoses due to severe maceration after single intra-uterine demise leaving 42 placentas for analysis of anastomoses. RESULTS: Arterio-arterial (AA), venovenous (VV) and arteriovenous (AV) anastomoses were detected in 98%, 43% and 91% of MA placentas, respectively. Velamentous cord insertion was found in 4% of cases. Small distance between both umbilical cord insertions (<5 cm) was present in 53% of MA placentas. Overall perinatal loss rate was 22% (19/86). We found no association between mortality and type of anastomoses, type and distance between cord insertions and placental sharing. The incidence of TTTS was low (2%) and occurred in the only pregnancy with absent AA-anastomoses. CONCLUSION: Perinatal mortality in MA twins was not related to placental vascular anatomy. The almost ubiquitous presence of compensating AA-anastomoses in MA placentas appears to prevent occurrence of TTTS.

Placental characteristics of monochorionic diamniotic twin pregnancies in relation to perinatal outcome.

To study placental characteristics in relation to perinatal outcome in 150 pairs of monochorionic diamniotic (MCDA) twins. Between January 1998 and January 2007 150 pairs of MCDA twins were delivered in the University Medical Center, Utrecht, The Netherlands. Mortality, neonatal morbidity and birth weight discordancy were studied in relation to type of anastomoses, type and distance between cord insertions and placental sharing. From 14 weeks onwards, there were 45 (15.0%) perinatal deaths. We found no clear relationship between perinatal mortality and type of anastomoses, distance between cord insertions and placental sharing. Perinatal mortality was significantly increased in the presence of velamentous cord insertion (OR 3.65, 95% CI 1.83-7.28). Data concerning neonatal morbidity were similar. TTTS occurred predominantly in the presence of AV-anastomoses without compensating superficial AA-anastomoses (p=0.005) and occurred more frequently in the presence of velamentous cord insertion (OR 1.79, 95% CI 0.94-3.44). Twins with unequal shared placentas had significantly more often severe birth weight discordancy, although only in the presence of AA-anastomoses (OR 4.09, 95% CI 1.74-9.63). If AA-anastomoses were absent in the unequally shared placenta, there was no relation between severe birth weight discordancy and unequal sharing of the placenta (OR 1.06, 95% CI 0.08-13.52). In MCDA twins, placental characteristics determine perinatal outcome, occurrence of TTTS and fetal growth. Prenatal identification of these characteristics by ultrasound may alter counselling and intensity of pregnancy surveillance.

Pathology of twin placentas with special attention to monochorionic twin placentas.

The risk of perinatal morbidity and mortality in twins is 3-7 times higher than in singletons. In comparison to dichorionic twins, monochorionic twins are at increased risk for perinatal mortality and serious morbidity. In both type of twins growth discordance can occur. Discordant growth of dichorionic twins could be due to differences in placental mass or differences in placental parenchymal lesions, whereas birth weight discordancy in monochorionic twins is caused by placental vascular anastomoses. In this review the different types of complications (acardiac twins, acute and chronic twin-twin transfusion syndrome) due to different combinations of vascular anastomoses are discussed in relation to a computer model developed to gain more insight into the development of the twin-twin transfusion syndrome. The angioarchitecture of 395 monochorionic twin placentas was studied. Mortality was highest in the absence of an arterio-arterial anastomosis (42%) and lowest in the presence of an arterio-arterial anastomosis (15%). If mortality occurred, pregnancies with double mortality usually had an arterio-arterial anastomosis. If pregnancies were complicated by one death, a veno-venous anastomosis is more likely to be present. In conclusion, monochorionic twin pregnancies are a high risk pregnancy with a high chance of both mortality and morbidity; placental characteristics are a major contributor to adverse outcome in these pregnancies.

[Need for blood transfusion in premature infants in 2 Dutch perinatology centres particularly determined by blood sampling for diagnosis]. / Bloedtransfusiebehoefte bij prematuren in 2 Nederlandse perinatologische centra sterk bepaald door bloedafname voor diagnostiek.

OBJECTIVE: Determination of factors related to the need for transfusion in premature infants. DESIGN: Descriptive. METHOD: The need for transfusion in premature infants was determined in 2 academic centres: University Medical Center Utrecht and Leiden University Medical Center, The Netherlands. The data had been acquired in another study. The factors under study were: hospital, pregnancy duration, birth weight, gender, time of clamping of the umbilical cord, total volume of blood sampled for diagnostic purposes, number of days of mechanical ventilation, total duration of admission and duration of the admission to the Neonatal Intensive care unit. Both hospitals followed the national interdisciplinary practice guideline 'Blood transfusion'. RESULTS: The total volume ofsampled blood for diagnosis, the duration of the mechanical ventilation and the admission period were related to a greater need for transfusion. On the other hand, the chance of transfusions diminished with longer pregnancy duration or increased birth weight. The difference in need for blood transfusion between both centres was significant. The total volume of transfused erythrocytes showed a strong correlation with the volume sampled for diagnostic procedures. CONCLUSION: Anaemia in neonates is strongly related to the amount of blood taken for diagnostic procedures. Alternatives for blood transfusions in premature infants, and consequently for the reduction of the number of donors per child, are to be sought in delayed clamping of the umbilical cord, use of erythropoietin and use ofautologous umbilical cord blood.

The value of umbilical artery Doppler velocimetry in the antenatal surveillance of uncomplicated monochorionic twin pregnancies.

OBJECTIVES: To investigate the predictive value of abnormal umbilical artery Doppler findings on outcome in uncomplicated monochorionic (MC) twin pregnancies. METHODS: Sixty-seven MC twin pregnancies, with antenatal care and delivery at the University Medical Center, Utrecht, The Netherlands, between 1999 and 2004, were studied. Pregnancies with antenatal signs of twin-to-twin transfusion syndrome were excluded. We analyzed the data according to both the last Doppler measurement of the umbilical artery before delivery and the presence of any abnormal Doppler measurement during the course of pregnancy. Risks of mortality and total neonatal morbidity were stratified according to the Doppler findings in one or both fetuses at the time of each standard ultrasound assessment in order to estimate the risk associated with an abnormal Doppler finding at or before that specific gestational age. RESULTS: Mortality rates were similar in the normal and abnormal Doppler groups. Using both group definitions, total neonatal morbidity was higher in the abnormal Doppler group; this was significant at > 32 weeks' gestation, and was due to lower birth weight and earlier gestational age at delivery. There was no mortality at > or = 36 weeks in the abnormal Doppler group, but there were four perinatal deaths in the normal Doppler group. Gestational age at delivery was significantly lower when one or more abnormal Doppler findings had been present (median, 34 + 1 weeks vs. 36 + 3 weeks) and infants with abnormal Doppler findings weighed on average 261 g (95% CI, 21-502 g) less than those with normal findings. CONCLUSIONS: In MC twins, abnormal Doppler flow of the umbilical artery identifies a subgroup at risk for preterm delivery, low birth weight and neonatal morbidity, but with a similar mortality risk to those with normal Doppler flow. At term, mortality occurred only in the group with normal Doppler findings, suggesting that fetal surveillance is insufficient in uncomplicated term MC twin pregnancies.

Increased perinatal mortality and morbidity in monochorionic versus dichorionic twin pregnancies: clinical implications of a large Dutch cohort study.

OBJECTIVE: To evaluate mortality and morbidity in a large cohort of twin pregnancies according to chorionicity. We aimed to estimate the optimal time of delivery. DESIGN: Historical cohort design. Setting Two teaching hospitals. POPULATION: Twin pregnancies delivered in the University Medical Centre, Utrecht, and the St Elisabeth Hospital, Tilburg (1995-2004), The Netherlands (n = 1407). METHODS: Pregnancy outcomes were documented according to chorionicity. Mortality >/=32 weeks was reviewed carefully with special attention to antenatal fetal monitoring, autopsy and placental histopathology to find an explanation for adverse outcome. MAIN OUTCOME MEASURES: Perinatal mortality and morbidity in monochorionic (MC) and dichorionic (DC) twins. RESULTS: Perinatal mortality was 11.6% in MC twin pregnancies and 5.0% in DC twin pregnancies. After 32 weeks, the risk of intrauterine death (IUD) was significantly higher in MC twins than in DC twins (hazard ratio 8.8, 95% CI 2.7-28.9). In most of these cases of IUD, no antenatal signs of impaired fetal condition had been present. Median gestational age was 1 week longer in DC twins than in MC twins, and the mean birthweight was 221 g higher. Severe birthweight discordancy (>20%) occurred more often in MC twins than in DC twins (OR 1.23, 95% CI 0.97-1.55). The incidence of necrotising enterocolitis (NEC) was higher in MC twins, after adjustment for age and weight at birth (OR 4.05, 95% CI 1.97-8.35). There was a trend towards higher neuromorbidity in MC twins. CONCLUSIONS: This is the largest cohort study of twin pregnancies evaluating outcome according to chorionicity thus far. MC twins are at increased risk for fetal death (even at term), NEC and neuromorbidity. Current antenatal care is insufficient to predict and prevent this excess perinatal mortality and morbidity. Planned delivery at or even before 37 weeks of gestation seems to be justified for MC twins.