Changes in preterm birth and stillbirth during COVID-19 lockdowns in 26 countries.

Preterm birth (PTB) is the leading cause of infant mortality worldwide. Changes in PTB rates, ranging from -90% to +30%, were reported in many countries following early COVID-19 pandemic response measures ('lockdowns'). It is unclear whether this variation reflects real differences in lockdown impacts, or perhaps differences in stillbirth rates and/or study designs. Here we present interrupted time series and meta-analyses using harmonized data from 52 million births in 26 countries, 18 of which had representative population-based data, with overall PTB rates ranging from 6% to 12% and stillbirth ranging from 2.5 to 10.5 per 1,000 births. We show small reductions in PTB in the first (odds ratio 0.96, 95% confidence interval 0.95-0.98, P value <0.0001), second (0.96, 0.92-0.99, 0.03) and third (0.97, 0.94-1.00, 0.09) months of lockdown, but not in the fourth month of lockdown (0.99, 0.96-1.01, 0.34), although there were some between-country differences after the first month. For high-income countries in this study, we did not observe an association between lockdown and stillbirths in the second (1.00, 0.88-1.14, 0.98), third (0.99, 0.88-1.12, 0.89) and fourth (1.01, 0.87-1.18, 0.86) months of lockdown, although we have imprecise estimates due to stillbirths being a relatively rare event. We did, however, find evidence of increased risk of stillbirth in the first month of lockdown in high-income countries (1.14, 1.02-1.29, 0.02) and, in Brazil, we found evidence for an association between lockdown and stillbirth in the second (1.09, 1.03-1.15, 0.002), third (1.10, 1.03-1.17, 0.003) and fourth (1.12, 1.05-1.19, <0.001) months of lockdown. With an estimated 14.8 million PTB annually worldwide, the modest reductions observed during early pandemic lockdowns translate into large numbers of PTB averted globally and warrant further research into causal pathways.

Evolution of maternal and neonatal outcomes before and after the adoption of the IADPSG/WHO guidelines in Belgium: A descriptive study of 444,228 pregnancies.

Objectives: To appraise adverse pregnancy outcomes after the adoption of IADPSG/WHO guidelines in Belgium. Methods: A retrospective study of the Center for Perinatal Epidemiology registry was conducted. Demographic changes and adverse pregnancy outcomes were compared between a pre- and post-guideline period in women with and without hyperglycemia in pregnancy (HIP). Adjusted odds ratios with a 95% confidence interval (CI) were used to compare maternal and neonatal outcomes controlling for potential confounders (maternal age, body mass index (BMI), hypertension, parity, and multiple births). Results: The prevalence of HIP increased (6.0%-9.2%). In the overall population regardless of glycemic status, gestational weight gain (12.3 ± 5.7 vs 11.9 ± 5.8; p < 0.001), hypertension (0.92; 95% CI, 0.89-0.94; p < 0.001), and neonatal intensive care unit/special care nursery (0.89; 95% CI, 0.87-0.91; p < 0.001) decreased despite increasing maternal age and pre-pregnancy BMI. Emergency cesarean section rates (1.07; 95% CI, 1.05-1.09; p < 0.001) increased, but not in the HIP population (1.02; 95% CI, 0.95-1.10; ns). The overall incidence of preterm birth (1.09; 95% CI, 1.06-1.12; p < 0.001), stillbirth (1.10; 95% CI, 1.01-1.21; p < 0.05), and perinatal mortality (1.10; 95% CI, 1.01-1.19; p < 0.05) increased, except in the HIP population (1.03; 95% CI, 0.95-1.11; ns), (1.04; 95% CI, 0.74-1.47; ns) and (1.09; 95% CI, 0.80-1.49; ns), respectively. The overall incidence of small- for-gestational-age remained unchanged (0.99; 95%CI, 0.97-1.01; ns) regardless of glycemic status. In the HIP population, large-for-gestational age (0.90; 95% CI, 0.84-0.95; p < 0.001) and macrosomia (0.84; 95% CI, 0.78-0.92; p < 0.001) decreased. Conclusion: After the implementation of IADPSG/WHO guidelines, the prevalence of HIP increased by 53.7% and the incidence of major HIP-related pregnancy complications appears to be lower. However, we cannot conclude that the reduction of LGA-macrosomia is due to a better management of diabetes or due to greater recruitment of women with mild HIP associated with a lower risk of obstetrical complications.

Successful management of a severe anti-M alloimmunization during pregnancy.

We report the successful outcome of a patient with anti-M antibodies with a previous history of severe hemolysis of erythrocytes. Serial plasma exchange from the first trimester combined with ultrasound monitoring of the fetal middle cerebral artery blood velocity was implemented. This management allowed a favorable pregnancy outcome of an infant born by an elective caesarean section at 32 weeks 6/7 with a normal Apgar score at 8/9/10. The other therapeutic alternatives such as intravenous immunoglobulin and in utero fetal blood transfusions are discussed.

"Serpentine-like syndrome"-A very rare multiple malformation syndrome characterised by brachioesophagus and vertebral anomalies.

"Serpentine-like syndrome" is a severe and rare association of multiple congenital malformations, characterised by brachioesophagus, secondary intrathoracic stomach, and vertebral anomalies. Other associated anomalies have been described, such as malposition and herniation of abdominal organs. We report the natural history of a baby girl born at 29 weeks of gestation with intra uterine growth restriction, short neck, large rachischisis from cervical to thoracic spine, a very short oesophagus, thoracic stomach associated with a midline diaphragmatic hernia, malrotated gut and median cleft lip. Most of these anomalies were detected antenatally. Molecular karyotype was normal. She died at age 12 days. To our knowledge, the present patient represents the 8th report of a case of "Serpentine-like syndrome". Brachioesophagus and congenital vertebral anomalies, in particular rachischisis, are the cardinal features of this condition. All reported cases have been sporadic and the cause is still unknown. We believe that the specificity of the presentation as well as the similarities between available descriptions of patients suggests a common, yet to identify, molecular cause, possibly involving a developmental "toolkit"/homeobox gene or related pathways.

An unusual cause of fetal hypomobility:congenital central hypoventilation syndrome associated with hirschsprung disease.

Co-occurrence of congenital central hypoventilation syndrome and Hirschsprung disease is known as Haddad syndrome. Affected patients develop with variable expressivity a dysfunction of the autonomic nervous system. We report the natural history of a full-term newborn infant presenting multiple features of autonomic system dysfunction that were already noted antenatally. The presence of a nonpolyalanine repeat expansion mutation in the PHOX2B gene confirmed postnatally the diagnosis of Haddad syndrome. This case suggests that patients presenting with autonomic system dysfunction may already present signs of the disease during the fetal period. Furthermore, antenatal presentations may correlate with a more severe presentation of the disease. In conclusion, antenatal signs of dysautonomy should stimulate multidisciplinary prenatal approach to orientate proper postnatal intervention and facilitate treatment strategies.

Efficacy and safety of a parenteral amino acid solution containing alanyl-glutamine versus standard solution in infants: a first-in-man randomized double-blind trial.

BACKGROUND & AIMS: Efforts are directed at reaching the optimal composition of pediatric amino acids (AA) infusions. The goal was to demonstrate the safety and efficacy of a newly developed parenteral AA solution containing alanyl-glutamine (GLN-AA) compared to Standard-AA. METHODS: This is a randomized (2:1), double-blind, multicentre clinical pilot trial. Infants after surgical interventions were allocated to receive GLN-AA or Standard-AA over a minimum of 5 days to maximum of 10 days. AA profiles in blood samples obtained at baseline, day 7, and end of treatment were compared to normal ranges. Data regarding safety, and efficacy were also collected. RESULTS: Infants were comparable for (safety population) gestational age at birth (36 vs 38 weeks), birth weight (2460 vs 2955 g), and day of life during start intervention (1 vs 2 days). Plasma AA profiles in infants treated with GLN-AA (n = 13) were closer the normal ranges than those in infants treated with Standard-AA (n = 6). There were no clinical or statistical differences in adverse events, safety and efficacy parameters between both groups. CONCLUSION: This first-in-man study shows that GLN-AA is safe in infants after surgical interventions, and is well tolerated. Compared to reference values, GLN-AA better reflects the amino acid requirements of the infant.

Twin-to-twin transfusion syndrome: perinatal outcome and recipient heart disease according to treatment strategy.

AIM: The aims of the study were to compare perinatal outcome and assess recipient cardiac disease according to treatment strategy (amnioreduction (AR), laser or selective feticide). METHODS: We retrospectively reviewed 81 consecutive cases of twin-to-twin transfusion syndrome diagnosed before 28 weeks between 1993 and 2007. RESULTS: Although fetuses treated by laser were younger at diagnosis (median 20.4 vs. 22.4 weeks, P = 0.01), they were significantly older at birth (median 33.6 vs. 28.5 weeks, P = 0.004) than those treated by AR. Neonatal morbidity was globally lower after laser than AR, and cardiac insufficiency tended to be less frequent (31% vs. 57%, P = 0.09). There was a trend towards increased perinatal survival after laser treatment (68% vs. 49%, P = 0.1). Heart failure was the cause of death in half (23/46) of the recipients. Fetal heart failure leading to death was 2.7 times more frequent after AR than after laser (n = 11 vs. n = 4), and all four neonatal cardiac deaths occurred after AR. Compared with laser, selective feticide did not further improve the outcome. CONCLUSIONS: Heart failure was an important cause of perinatal morbidity and death. However, laser therapy resulted in a longer diagnosis-delivery interval and lower global neonatal morbidity than AR, with a trend towards increased perinatal survival. Improved outcome after laser treatment compared with AR might be related to its impact on recipient heart disease.

Pregnancy and neonatal outcome following an antenatal diagnosis of cleft lip and palate.

AIM: To identify the significance of associated antenatal ultrasound findings on long-term prognosis following the antenatal diagnosis of cleft lip/palate [CL(P)]. PATIENTS AND METHODS: Retrospective case note analysis of patients seen at a single tertiary referral centre with a diagnosis of CL(P). The patients were classified as those with unilateral or bilateral clefts and then further subdivided according to the presence of associated anomalies, and these were related to pregnancy and neonatal outcome. RESULTS: A total of 125 singleton pregnancies were seen at the antenatal diagnostic unit, 14 of which were subsequently lost to follow-up. Eighty-two (65.6%) had a diagnosis of unilateral CL(P) and 43 (34.4%) a bilateral CL(P). Seventy-five foetuses (67.5%) had no other anomalies detected on antenatal ultrasound. Seventeen patients (15%) underwent a termination of pregnancy. A normal postnatal outcome was seen in 79% of liveborn infants overall. Only 50% of foetuses diagnosed with a single minor anomaly and 4% of the foetuses in whom more than two minor anomalies or one major anomaly had been detected on ultrasound had a normal postnatal outcome. Infants with bilateral CL(P) had a significantly reduced incidence of a normal postnatal course (60% vs. 87.5%, P<0.01). CONCLUSION: In cases of CL(P), there is a high incidence of associated anomalies detected on antenatal ultrasound and these significantly increase the risk of poor neonatal outcome.

Pulmonary effects of prolonged oligohydramnios following mid-trimester rupture of the membranes--antenatal and postnatal management.

Mid-trimester, preterm prelabour rupture of the membranes (PPROM) with prolonged oligohydramnios remains a challenge for both obstetricians and neonatologists. Although survival rates have improved, morbidity remains common particularly due to pulmonary insufficiency and pulmonary hypertension. The aetiology of abnormal lung development is unknown but may depend critically on pulmonary vascular development. Antenatal evaluation of at-risk foetuses by three-dimensional ultrasound and MRI is possible but the techniques need to be further assessed. Antenatal corticosteroids given in cases of PPROM reduce the incidence of neonatal death, respiratory distress syndrome, intraventricular haemorrhage and necrotising enterocolitis without increasing maternal or neonatal infection. The true risk-benefit ratio of antibiotics, tocolysis and strategies to normalise amniotic fluid volume remains less clear. There is no consensus regarding the optimal ventilation strategy to support infants with pulmonary insufficiency following PPROM, and further work is required to determine whether and which pulmonary vasodilators improve long-term outcome in these infants.

Multiorgan developmental anomalies presenting as a variation of the serpentine-like syndrome: cervical fusion and brachioesophagus with intrathoracic stomach and malposition of duodenopancreas and spleen.

Congenital brachioesophagus with secondary intrathoracic stomach is an extremely rare condition. In association with rachischisis, the latter condition has been described recently as "serpentine-like syndrome." We report here a unique case of a male infant with normal karyotype from healthy nonconsanguinous parents, presenting with a complex malformative syndrome combining ultrashort brachioesophagus with intrathoracic stomach, duodenum, pancreas, and spleen associated with short neck because of posterior fusion and scoliosis. This case report details aspects of diagnostic and management of this unusual clinical presentation and includes a review of the literature.

Sporadic in utero generalized edema caused by mutations in the lymphangiogenic genes VEGFR3 and FOXC2.

OBJECTIVES: To investigate the genetic causes of idiopathic sporadic prenatal generalized edema. STUDY DESIGN: In a series of 12 patients, in whom in utero generalized skin edema or hydrops fetalis had been diagnosed, we screened 3 lymphangiogenic genes, VEGFR3, FOXC2, and SOX18. RESULTS: In 3 of the patients, we identified a mutation: 2 in VEGFR3 and 1 in FOXC2. Two of the mutations were de novo and one was either de novo or nonpenetrant inherited. In these patients, the generalized edema resorbed spontaneously, either in utero or after birth. In the 2 individuals with a VEGFR3 mutation, edema remained limited to lower limbs. CONCLUSIONS: Mutations in the VEGFR3 and FOXC2 genes account for a subset of patients with unexplained in utero generalized subcutaneous edema and hydrops fetalis without family history of lymphedema. Lymphangiogenic genes should be screened for mutations in sporadic patients diagnosed with fetal edema.

Congenital erosive and vesicular dermatosis with reticulated scarring in a newborn: an innovative treatment using a silicone dressing.

Congenital erosive and vesicular dermatosis healing with reticulated supple scarring is a rare entity presenting in the newborn with crusted erosions and vesicles that heal relatively rapidly, forming unique reticulated scars. We report the case of a premature baby 31 weeks old. Diagnosis was confirmed by skin biopsies, and the clinical improvement was excellent, with complete healing observed within 7 weeks. This report highlights clinical and histopathologic features, and a new successful treatment approach using a silicone dressing.

Pyloric obstruction, duodenal dilatation, and extrahepatic cholestasis: a neonatal triad suggesting multiple intestinal atresias.

Whereas physiologic jaundice constitutes a common finding in neonates, a few cases present with cholestatic jaundice owing to various pathologic conditions, including extrahepatic biliary obstruction. We report the case of a 2-day-old female neonate presenting with neonatal cholestasis, nonbilious vomiting with pyloric obstruction, and multiple intestinal atresias. A pathognomonic clinicoradiologic triad is described, based on clinical data, plain abdominal x-ray, and ultrasound examination.

Prophylactic ibuprofen in premature infants: a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Ibuprofen is used for treatment and prevention of patent ductus arteriosus in low-birthweight infants. Its effects on regional circulations differ from those of indometacin. Because prophylactic indometacin reduces the frequency of severe intraventricular haemorrhage and patent ductus arteriosus, we aimed to study the efficacy of early ibuprofen in reducing these outcomes in a double-blind, multicentre trial. METHODS: Within 6 h after birth, 415 low-birthweight infants (gestational age <31 weeks) were randomly allocated ibuprofen-lysine (10 mg/kg then two doses of 5 mg/kg after 24 h and 48 h) or placebo intravenously. The primary outcome was occurrence of severe intraventricular haemorrhage; secondary outcomes were occurrence of patent ductus arteriosus and possible adverse effects of ibuprofen. Analysis was by intention to treat. FINDINGS: 17 (8%) of 205 infants assigned ibuprofen and 18 (9%) of 210 assigned placebo developed severe intraventricular haemorrhage (relative risk 0.97 [95% CI 0.51-1.82]). In 172 (84%) infants of the ibuprofen group, the ductus was closed on day 3 compared with 126 (60%) of the placebo group (relative risk 1.40 [1.23-1.59]). No important differences in other outcomes or side-effects were noted; however, urine production was significantly lower on day 1 and concentration of creatinine in serum was significantly higher on day 3 after ibuprofen. INTERPRETATION: Ibuprofen prophylaxis in preterm infants does not reduce the frequency of intraventricular haemorrhage, but does decrease occurrence of patent ductus arteriosus.

The EPIBEL study: outcomes to discharge from hospital for extremely preterm infants in Belgium.

OBJECTIVE: To determine mortality and morbidity at discharge from the hospital of a large population-based cohort of infants who were born at