Factors influencing the choice-of-care pathway and survival in the fetus with hypoplastic left heart syndrome in New Zealand: a population-based cohort study.

OBJECTIVES: To better understand the relative influence of fetal and maternal factors in determining the choice-of-care pathway (CCP) and outcome in the fetus with hypoplastic left heart syndrome (HLHS). DESIGN: A retrospective, population-based study of fetuses with HLHS from a national dataset with near-complete case ascertainment from 20 weeks' gestation. Fetal cardiac and non-cardiac factors were recorded from the patient record and maternal factors from the national maternity dataset. The primary endpoint was a prenatal decision for active treatment after birth (intention-to-treat). Factors associated with a delayed diagnosis (≥24 weeks' gestation) were also reviewed. Secondary endpoints included proceeding to surgical treatment, and 30-day postoperative mortality in liveborns with an intention-to-treat. SETTING: New Zealand population-wide. PARTICIPANTS: Fetuses with a prenatal diagnosis of HLHS between 2006 and 2015. RESULTS: Of 105 fetuses, the CCP was intention-to-treat in 43 (41%), and pregnancy termination or comfort care in 62 (59%). Factors associated with intention-to-treat by multivariable analysis included a delay in diagnosis (OR: 7.8, 95% CI: 3.0 to 20.6, p<0.001) and domicile in the maternal fetal medicine (MFM) region with the most widely dispersed population (OR: 5.3, 95% CI: 1.4 to 20.3, p=0.02). Delay in diagnosis was associated with Maori maternal ethnicity compared with European (OR: 12.9, 95% CI: 3.1 to 54, p<0.001) and greater distance from the MFM centre (OR: 3.1, 95% CI: 1.2 to 8.2, p=0.02). In those with a prenatal intention-to-treat, a decision not to proceed to surgery was associated with maternal ethnicity other than European (p=0.005) and the presence of major non-cardiac anomalies (p=0.01). Thirty-day postoperative mortality occurred in 5/32 (16%) and was more frequent when there were major non-cardiac anomalies (p=0.02). CONCLUSIONS: Factors associated with the prenatal CCP relate to healthcare access. Anatomic characteristics impact treatment decisions after birth and early postoperative mortality. The association of ethnicity with delayed prenatal diagnosis and postnatal decision-making suggests systemic inequity and requires further investigation.

The impact of in utero transfusions on perinatal outcomes in patients with alpha thalassemia major: the UCSF registry.

Alpha thalassemia major (ATM) is a hemoglobinopathy that usually results in perinatal demise if in utero transfusions (IUTs) are not performed. We established an international registry (NCT04872179) to evaluate the impact of IUTs on survival to discharge (primary outcome) as well as perinatal and neurodevelopmental secondary outcomes. Forty-nine patients were diagnosed prenatally, 11 were diagnosed postnatally, and all 11 spontaneous survivor genotypes had preserved embryonic zeta-globin levels. We compared 3 groups of patients; group 1, prenatally diagnosed and alive at hospital discharge (n = 14), group 2, prenatally diagnosed and deceased perinatally (n = 5), and group 3, postnatally diagnosed and alive at hospital discharge (n = 11). Group 1 had better outcomes than groups 2 and 3 in terms of the resolution of hydrops, delivery closer to term, shorter hospitalizations, and more frequent average or greater neurodevelopmental outcomes. Earlier IUT initiation was correlated with higher neurodevelopmental (Vineland-3) scores (r = -0.72, P = .02). Preterm delivery after IUT was seen in 3/16 (19%) patients who continued their pregnancy. When we combined our data with those from 2 published series, patients who received ≥2 IUTs had better outcomes than those with 0 to 1 IUT, including resolution of hydrops, delivery at ≥34 weeks gestation, and 5-minute appearance, pulse, grimace, activity, and respiration scores ≥7. Neurodevelopmental assessments were normal in 17/18 of the ≥2 IUT vs 5/13 of the 0 to 1 IUT group (OR 2.74; P = .01). Thus, fetal transfusions enable the survival of patients with ATM and normal neurodevelopment, even in those patients presenting with hydrops. Nondirective prenatal counseling for expectant parents should include the option of IUTs.

Newborn pulse oximetry screening in the context of a high antenatal detection rate of critical congenital heart disease.

AIM: Assess the potential additional benefit from pulse oximetry screening in the early detection of critical congenital heart disease in a country with a well-developed antenatal ultrasound screening programme. METHODS: Live-born infants, pregnancy terminations and stillbirths from 20 weeks' gestational age, between 2013 and 2015, with critical cardiac defects defined as primary or secondary targets of pulse oximetry screening were identified. Critical defects were those resulting in the death of a fetus or an infant in the first 28 days after birth, or a defect requiring intervention in the first 28 days. RESULTS: Two hundred and sixty-eight infants and Fetuses were identified. Antenatal detection rates improved from 69% to 77% over the study period. An associated co-morbidity improved antenatal detection rates. Twenty-seven live-born infants were diagnosed after discharge: 15 aortic arch obstruction (AAO); 10 d-loop transposition of the great arteries (d-TGA), and two total anomalous pulmonary venous drainage (TAPVD). Of these, five with AAO, nine with d-TGA and likely both with TAPVD could potentially have been detected with oximetry screening. CONCLUSION: The antenatal detection of critical cardiac anomalies continues to improve in New Zealand. Despite high antenatal detection rates for most lesions, universal postnatal oximetry screening has the potential to improve early detection.

Antenatal Detection of Treatable Critical Congenital Heart Disease Is Associated with Lower Morbidity and Mortality.

OBJECTIVE: To establish the impact that timing of diagnosis and place of birth have on neonatal outcomes in those with readily treatable critical congenital heart disease. STUDY DESIGN: This was a population-based study with a complete national cohort of live-born infants with transposition of the great arteries and aortic arch obstruction in New Zealand between 2006 and 2014. Timing of diagnosis, place of birth, survival to surgery, in-hospital events, and neonatal mortality were reviewed. Live births with a gestation of ≥35 weeks and without associated major extracardiac anomalies were included for analysis. RESULTS: A total of 166 live-born infants with transposition of the great arteries and 87 with aortic arch obstruction were included. Antenatal detection increased from 32% in the first 3 years to 47% in the last 3 years (P = .05). During the same period, neonatal mortality decreased from 9% to 1% (P = .02). No deaths occurred after surgical intervention. An antenatal diagnosis was associated with decreased mortality (1/97 [1%] vs 11/156 [7%]; P = .03) and birth outside the surgical center was associated with increased risk of mortality (11/147 [7%] vs 1/106 [1%]; P = .02). Those with an antenatal diagnosis required fewer hours of mechanical ventilation (P = .02) and had shorter durations of hospital stay (P = .05) compared with those diagnosed >48 hours after birth. CONCLUSIONS: The mortality risk for transposition of the great arteries and critical aortic arch obstruction is greatest before cardiac surgery. Improved antenatal detection allowing delivery at a surgical center is associated with reduced mortality.

Maternal lipid profile and the relation with spontaneous preterm delivery: a systematic review.

BACKGROUND: It is unknown whether an unfavorable (atherogenic) lipid profile and homocysteine level, which could supersede clinical cardiovascular disease, is also associated with an increased risk of spontaneous preterm delivery (sPTD). A systematic review of studies assessing the lipid profile and homocysteine value of women with sPTD compared to women with term delivery in pre-pregnancy and during pregnancy. METHODS: A systematic search of peer-reviewed articles published between January 1980 and May 2014 was performed using MEDLINE, EMBASE and the Cochrane database. We included case-control and cohort studies that examined triglycerides, high/low density lipoprotein cholesterol, total cholesterol and homocysteine in women with sPTD. Articles were subdivided in pre-pregnancy, first, second and third trimester. Of 708 articles reviewed for eligibility, 14 met our inclusion criteria. RESULTS AND CONCLUSION: Nine cohort studies and five case-control studies were analyzed, reporting on 1466 cases with sPTD and 11296 controls with term delivery. The studies suggest a possible elevated risk of sPTD in woman with high TG levels, no association of high and low density lipoprotein cholesterol with the risk of sPTD was found. High homocysteine levels are associated with sPTD in the second trimester. The role of triglycerides and homocysteine in sPTD should be explored further.

Midtrimester preterm prelabour rupture of membranes (PPROM): expectant management or amnioinfusion for improving perinatal outcomes (PPROMEXIL - III trial).

BACKGROUND: Babies born after midtrimester preterm prelabour rupture of membranes (PPROM) are at risk to develop neonatal pulmonary hypoplasia. Perinatal mortality and morbidity after this complication is high. Oligohydramnios in the midtrimester following PPROM is considered to cause a delay in lung development. Repeated transabdominal amnioinfusion with the objective to alleviate oligohydramnios might prevent this complication and might improve neonatal outcome. METHODS/DESIGN: Women with PPROM and persisting oligohydramnios between 16 and 24 weeks gestational age will be asked to participate in a multi-centre randomised controlled trial. INTERVENTION: random allocation to (repeated) abdominal amnioinfusion (intervention) or expectant management (control). The primary outcome is perinatal mortality. Secondary outcomes are lethal pulmonary hypoplasia, non-lethal pulmonary hypoplasia, survival till discharge from NICU, neonatal mortality, chronic lung disease (CLD), number of days ventilatory support, necrotizing enterocolitis (NEC), periventricular leucomalacia (PVL) more than grade I, severe intraventricular hemorrhage (IVH) more than grade II, proven neonatal sepsis, gestational age at delivery, time to delivery, indication for delivery, successful amnioinfusion, placental abruption, cord prolapse, chorioamnionitis, fetal trauma due to puncture. The study will be evaluated according to intention to treat. To show a decrease in perinatal mortality from 70% to 35%, we need to randomise two groups of 28 women (two sided test, ß-error 0.2 and α-error 0.05). DISCUSSION: This study will answer the question if (repeated) abdominal amnioinfusion after midtrimester PPROM with associated oligohydramnios improves perinatal survival and prevents pulmonary hypoplasia and other neonatal morbidities. Moreover, it will assess the risks associated with this procedure. TRIAL REGISTRATION: NTR3492 Dutch Trial Register (http://www.trialregister.nl).

[Perinatal policy in cases of extreme prematurity; an investigation into the implementation of the guidelines]. / Perinataal beleid bij extreme vroeggeboorte; een onderzoek naar de implementatie van de richtlijn.

OBJECTIVE: To determine to what extent the recommendations to actively treat preterm infants with a gestational age of 24 weeks upwards laid down in the guidelines 'Perinatal policy in cases of extreme prematurity' have influenced policy in Dutch perinatal centres in the first year after publication, and what the health outcomes were. DESIGN: Retrospective, descriptive study. METHOD: Our study population included all pregnant women who were admitted to a perinatal centre at 23 5/7 to 26 weeks gestation with a diagnosis of 'threatened preterm labour', and their preterm infants. We collected both obstetric data and data on survival and morbidity of the infants from the medical files. RESULTS: Of a total of 192 preterm infants 185 (96%) were born alive; 92% of these infants were admitted to the neonatal intensive care unit. Survival rates were 43% and 61% at 24 weeks and 25 weeks gestation, respectively. Short-term morbidity (bronchopulmonary dysplasia, retinopathy of the newborn, severe intraventricular haemorrhage, necrotising enterocolitis and persistent ductus arteriosus) occurred in 79% and 71% of the infants born at 24 weeks and 25 weeks gestation, respectively. CONCLUSIONS: The recommendations from these guidelines have been implemented swiftly in Dutch perinatal centres, and survival of extremely preterm infants has increased. This has imposed a considerable burden on the capacity of these centres. Little is yet known about the long-term (up to school-age) health and survival of these infants.

The clinical and molecular relations between idiopathic preterm labor and maternal congenital heart defects.

Preterm labor (PTL) is an important cause of preterm delivery. The trigger initiating the process toward overt labor and parturition is poorly understood and the molecular basis remains an enigma. It recently emerged that the overall occurrence of PTL in pregnant women with congenital heart disease (CHD) is increased. In this review, we present data on pregnancy in women with CHD and the opportunities this provides for research on the initiating mechanisms of inappropriately premature contractions. This may provide means for early detection of women at high risk of PTL in the general population, with models using cervical length, novel biomarkers, and maternal factors. We discuss human embryonic development of the heart and the uterus and the molecular pathways shared by the cardio- and uteromyocytes. We propose 2 hypotheses for the co-occurrence of maternal CHD and PTL; one based on a shared genetic origin and the other on a shared epigenetic origin.

Associations between cardiovascular parameters and uteroplacental Doppler (blood) flow patterns during pregnancy in women with congenital heart disease: Rationale and design of the Zwangerschap bij Aangeboren Hartafwijking (ZAHARA) II study.

BACKGROUND: Previous research has shown that women with congenital heart disease (CHD) are more susceptible to cardiovascular, obstetric, and offspring events. The causative pathophysiologic mechanisms are incompletely understood. Inadequate uteroplacental circulation is an important denominator in adverse obstetric events and offspring outcome. The relation between cardiac function and uteroplacental perfusion has not been investigated in women with CHD. Moreover, the effects of physiologic changes on pregnancy-related events are unknown. In addition, long-term effects of pregnancy on cardiac function and exercise capacity are scarce. METHODS: Zwangerschap bij Aangeboren Hartafwijking (ZAHARA) II, a prospective multicenter cohort study, investigates changes in and relations between cardiovascular parameters and uteroplacental Doppler flow patterns during pregnancy in women with CHD compared to matched healthy controls. The relation between cardiovascular parameters and uteroplacental Doppler flow patterns and the occurrence of cardiac, obstetric, and offspring events will be investigated. At 20 and 32 weeks of gestation, clinical, neurohumoral, and echocardiographic evaluation and fetal growth together with Doppler flow measurements in fetal and maternal circulation are performed. Maternal evaluation is repeated 1 year postpartum. IMPLICATIONS: By identifying the factors responsible for pregnancy-related events in women with CHD, risk stratification can be refined, which may lead to better pre-pregnancy counseling and eventually improve treatment of these women.

[Practice guideline 'Perinatal management of extremely preterm delivery']. / Richtlijn 'Perinataal beleid bij extreme vroeggeboorte'.

At the request of the State Secretary of the Dutch Ministry of Health, Welfare and Sport a national multidisciplinary workgroup developed an evidence-based practice guideline for the management of pregnant women with an imminent preterm delivery after a pregnancy of less than 26 weeks duration and for extremely preterm neonates. Active care measures are advised for neonates from a gestational age of 24 0/7 weeks onwards, unless there are serious arguments that justify a conservative management. In cases of imminent preterm delivery, intrauterine transport to a perinatological care centre is advised from a gestational age of 23 4/7 weeks onwards. In cases of imminent preterm delivery, glucocorticoids to enhance fetal lung maturity should be administered from a gestational age of 23 5/7 weeks onwards. From a gestational age of 24 0/7 weeks onwards a caesarean section may be considered if the fetal condition during spontaneous labour justifies this.

Hypercoiling of the umbilical cord and placental maturation defect: associated pathology?

Our objective was to determine whether there is an association between hypercoiling of the umbilical cord and placental maturation defect. From a database comprising 1147 cases, containing data on all placentas examined at our institution during the study period, we selected all cases with a gestational age of at least 37 weeks that exhibited hypercoiling of the umbilical cord (coiling density above the 90th percentile, n = 42); we also examined 2 matched controls for each case, one with hypocoiling and one with normocoiling. The mean number of syncytiocapillary membranes (SCM) per terminal villus was calculated. Presence of a placental maturation defect was defined as the mean number of SCM below the 10th percentile. Correlations were assessed using Spearman's rho. Relations between dichotomous variables were tested using logistic regression. Mean number of SCM per terminal villus (+/-standard deviation) was 1.25 +/- 0.65. Difference in mean between hypo- and hypercoiled cords was 0.37 (95% confidence interval [CI], 0.07 to 0.67). The correlation coefficient between mean number of SCM and umbilical coiling index (UCI, coils/cm) was -0.28 (P = 0.002). The odds ratio (OR) for placental maturation defect in presence of hypercoiling was 2.61 (95% CI, 0.75 to 9.12). The OR for fetal death was 132 (95% CI, 13.2 to 1315) in the presence of a placental maturation defect and 5.49 (95% CI, 1.02 to 29.6) in the presence of hypercoiling. The OR for indication of fetal hypoxia/ischemia was 12.3 (95% CI, 3.0 to 50.3) in the presence of a placental maturation defect and 3.2 (95% CI, 0.95 to 10.9) in the presence of hypercoiling. We found a trend toward placental maturation defect in the presence of hypercoiling and an inverse relationship between the mean number of SCM in the terminal villi and the UCI. We confirmed associations between fetal death and both a maturation defect and hypercoiling and found an association between histological indication of fetal hypoxia/ischemia and a placental maturation defect.

The Roach muscle bundle and umbilical cord coiling.

OBJECTIVE: To determine if presence of the Roach muscle, a small muscle bundle lying just beside the umbilical artery, contributes to umbilical cord coiling. METHODS: 251 umbilical cords were examined. The umbilical coiling index (UCI) was calculated as the number of coils divided by the cord length in cm. Cords were classified as hypocoiled (UCIp90). On microscopic examination of a cross section of the cord, absence or presence of a Roach muscle was determined. The t-test for independent samples and logistic regression were used for statistical analysis. RESULTS: A Roach muscle was observed in 101 cords. The mean UCI was higher in cords with the muscle bundle (0.23 coils/cm) than in cords without a muscle (0.18 coils/cm). Difference in mean: 0.05 coils/cm (95% C.I. 0.01-0.09). OR for hypercoiling in presence of the muscle was 2.98 (95% C.I. 1.57-5.64). OR for hypocoiling in the presence of the muscle was 1.49 (95% C.I. 0.79-2.81). CONCLUSIONS: Our results suggest that presence of a Roach muscle bundle contributes to umbilical cord coiling. Given the divergence in umbilical cord coiling within subgroups with or without this muscle, other factors must play a more dominant role.

The umbilical coiling index in complicated pregnancy.

OBJECTIVE: To evaluate umbilical cord coiling in pregnancies with adverse outcome. STUDY DESIGN: Umbilical cords and hospital records of 565 consecutive cases with an indication for histological examination of the placenta were studied. The umbilical coiling index (UCI) was determined as the number of complete coils divided by the length of the cord in centimeters, by an observer blinded for pregnancy outcome. Data on obstetric history and pregnancy outcome of each case were obtained from the hospital records. We calculated odds ratios and their 95% confidence interval to evaluate the strength of associations between pregnancy outcome and abnormal cord coiling. RESULTS: Fetal death (OR 4.09, 95% CI 2.22-7.55), chorioamnionitis (OR 1.77, 95% CI 1.09-2.88), fetal structural or chromosomal abnormalities (OR 1.78, 95% CI 1.08-2.95), and lower Apgar score at 5 min (p=0.03) were associated with undercoiling (UCI below the 10th percentile, using reference values from uncomplicated pregnancies). Fetal death (OR 3.74, 95% CI 1.89-7.40), iatrogenic preterm delivery (OR 1.91, 95% CI 1.04-3.49), umbilical arterial pH<7.05 (OR 3.63, 95% CI 1.44-9.17), fetal structural or chromosomal abnormalities (OR 1.79, 95% CI 1.01-3.16), thrombosis in fetal placental vessels (OR 2.64, 95% CI 1.37-5.06), chronic fetal hypoxia/ischemia (OR 1.82, 95% CI 1.09-3.05), and lower weight for gestational age (p=0.01) were associated with overcoiling (UCI above the 90th percentile). CONCLUSIONS: Our findings confirm that adverse perinatal outcome is associated with both undercoiling and overcoiling of the umbilical cord.

Umbilical coiling index in normal and complicated pregnancies.

OBJECTIVE: To estimate the relation between undercoiling and overcoiling of the umbilical cord and adverse pregnancy outcome. METHODS: Umbilical cords and hospital records of 885 patients were studied in a cross-sectional study design. The umbilical coiling index was determined as the number of complete coils divided by the length of the cord in centimeters, blinded for pregnancy outcome. Obstetric history and pregnancy outcome of each patient were obtained from hospital records, blinded for the umbilical coiling index. Odds ratios and their 95% confidence intervals were calculated to evaluate associations between undercoiling and overcoiling and adverse pregnancy outcome, using multiple logistic regression. RESULTS: Undercoiling (umbilical coiling index below the 10th percentile, using references values from uncomplicated pregnancies) was associated with fetal death (odds ratio [OR] 3.35, 95% confidence interval [CI] 1.48-7.63), spontaneous preterm delivery (OR 2.16, 95% CI 1.34-3.48), trisomies (OR 5.79, 95% CI 2.07-16.24), low Apgar score at 5 minutes (OR 3.14, 95% CI 1.47-6.70), velamentous cord insertion (OR 3.00, 95% CI 1.16-7.76), single umbilical artery (OR 3.68, 95% CI 1.26-10.79), and dextral coiling (OR 1.80, 95% CI 1.02-3.17). Overcoiling (umbilical coiling index above the 90th percentile) was associated with asphyxia (OR 4.16, 95% CI 1.30-13.36), umbilical arterial pH < 7.05 (OR 2.91, 95% CI 1.05-8.09), small for gestational age infants (OR 2.10, 95% CI 1.01-4.36), trisomies (OR 9.26, 95% CI 2.84-30.2), single umbilical artery (OR 8.25, 95% CI 2.60-26.12), and sinistral coiling (OR 4.30, 95% CI 1.52-12.2). CONCLUSION: Undercoiling and overcoiling of the umbilical cord are associated with increased risk for adverse perinatal outcome.

The umbilical coiling index, a review of the literature.

Our aim was to review the literature on umbilical cord coiling. Relevant articles in English published between 1966 and 2003 were retrieved by a Medline search and cross-referencing. The normal umbilical cord coiling index (UCI) is 0.17 (+/- 0.009) spirals completed per cm. Abnormal cord coiling, i.e. UCI <10th centile (<0.07) or >90th centile (>0.30) is associated with adverse pregnancy outcome. Hypocoiling of the cord is associated with increased incidence of fetal demise, intrapartum fetal heart rate decelerations, operative delivery for fetal distress, anatomic-karyotypic abnormalities and chorio-amnionitis. Hypercoiling of the cord is associated with increased incidence of fetal growth restriction, intrapartum fetal heart rate decelerations, vascular thrombosis and cord stenosis. It is not clear whether abnormal coiling is actually a cause of pathology, or merely one of the sequelae, or both. We discuss the theories involving the cause of cord coiling, and the consequences of the degree of cord coiling on blood flow through the umbilical vessels. In the future ultrasonographic evaluation of the umbilical cord and the UCI may become an integral part of fetal assessment in high-risk pregnancies.