Covid-19 vaccination during the third trimester of pregnancy: rate of vaccination and maternal and neonatal outcomes, a multicentre retrospective cohort study.

OBJECTIVE: To evaluate the impact of Covid-19 vaccination (Pfizer-BioNTech BNT162b2) during the third trimester of pregnancy on maternal and neonatal outcomes. DESIGN: A multicentre, retrospective computerised database. POPULATION: Women who gave birth at >24 weeks of gestation in Israel, between January and April 2021, with full records of Covid-19 disease and vaccination status. METHODS: Women who received two doses of the vaccine were compared with unvaccinated women. Women who were recorded as having disease or a positive Covid-19 polymerase chain reaction (PCR) swab during pregnancy or delivery were excluded from both study groups. Univariate analysis was followed by multivariate logistic regression. MAIN OUTCOME MEASURES: Composite adverse maternal outcomes. Secondary outcomes were vaccination rate and composite adverse neonatal outcomes. RESULTS: The overall uptake of one or both vaccines was 40.2%; 712 women who received two doses of the Covid-19 vaccine were compared with 1063 unvaccinated women. Maternal composite outcomes were comparable between the groups; however, women who received the vaccine had higher rates of elective caesarean deliveries (CDs) and lower rates of vacuum deliveries. An adjusted multivariable logistic regression analysis demonstrated that Covid-19 vaccination was not associated with maternal composite adverse outcome (aOR 0.8, 95% CI 0.61-1.03); a significant reduction in the risk for neonatal composite adverse outcomes was observed (aOR 0.5, 95% CI 0.36-0.74). CONCLUSIONS: In a motivated population covered by a National Health Insurance Plan, we found a 40.2% rate of vaccination for the Covid-19 vaccine during the third trimester of pregnancy, which was not associated with adverse maternal outcomes and, moreover, decreased the risk for neonatal adverse outcomes. TWEETABLE ABSTRACT: Covid-19 vaccine during pregnancy is safe for both mother and fetus.

Protease-activated receptors (PARs) in cancer: Novel biased signaling and targets for therapy.

Despite the fact that G protein-coupled receptors (GPCRs) mediate numerous physiological processes and represent targets for therapeutics for a vast array of diseases, their role in tumor biology is under appreciated. Protease-activated receptors (PARs) form a family which belongs to GPCR class A. PAR1&2 emerge with a central role in epithelial malignancies. Although the part of PAR1&2 in cancer is on the rise, their underlying signaling events are poorly understood. We review hereby past, present, and future cancer-associated PAR biology. Mainly, their role in physiological (placenta-cytotophobalst) and patho-physiological invasion processes. The identification and characterization of signal pleckstrin homology (PH)-domain-binding motifs established critical sites for breast cancer growth in PAR1&2. Among the proteins found to harbor important PH-domains and are involved in PAR biology are Akt/PKB as also Etk/Bmx and Vav3. A point mutation in PAR2, H349A, but not R352A, abrogated PH-protein association and is sufficient to markedly reduce PAR2-instigated breast tumor growth in vivo as also placental extravillous trophoblast (EVT) invasion in vitro is markedly reduced. Similarly, the PAR1 mutant hPar1-7A, which is unable to bind PH-domain, inhibits mammary tumors and EVT invasion, endowing these motifs with physiological significance and underscoring the importance of these previously unknown PAR1 and PAR2 PH-domain-binding motifs in both pathological and physiological invasion processes.

PH motifs in PAR1&2 endow breast cancer growth.

Although emerging roles of protease-activated receptor1&2 (PAR1&2) in cancer are recognized, their underlying signalling events are poorly understood. Here we show signal-binding motifs in PAR1&2 that are critical for breast cancer growth. This occurs via the association of the pleckstrin homology (PH) domain with Akt/PKB as a key signalling event of PARs. Other PH-domain signal-proteins such as Etk/Bmx and Vav3 also associate with PAR1 and PAR2 through their PH domains. PAR1 and PAR2 bind with priority to Etk/Bmx. A point mutation in PAR2, H349A, but not in R352A, abrogates PH-protein association and is sufficient to markedly reduce PAR2-instigated breast tumour growth in vivo and placental extravillous trophoblast (EVT) invasion in vitro. Similarly, the PAR1 mutant hPar1-7A, which is unable to bind the PH domain, reduces mammary tumours and EVT invasion, endowing these motifs with physiological significance and underscoring the importance of these previously unknown PAR1 and PAR2 PH-domain-binding motifs in both pathological and physiological invasion processes.

Severe heart disease complicating pregnancy does not preclude a favourable pregnancy outcome: 15 years' experience in a single centre.

Heart disease (HD) in pregnancy remains a major cause of non-obstetric maternal and neonatal mortality and morbidity. This study describes the outcome in 164 pregnant women with HD (158 deliveries in women in New York Heart Association (NYHA) Classes 1 and 2; 17 in NYHA Classes 3 and 4) who received good antenatal care and benefitted from a specific protocol and experience of a dedicated staff. There were no maternal or neonatal deaths; 46 women were diagnosed peripartum. Based on a sub-division into NYHA categories, and when sub-divided by HD, there were no statistically significant differences between groups with regard to maternal age, gestational age at admission or at delivery, birth weight, 5 min Apgar scores, mode of delivery (caesarean delivery), senior obstetric/anaesthesiology staff in attendance or delivery during day/working hours. There was a higher incidence of pre-term deliveries in women with rheumatic heart disease and Marfan syndrome (p = 0.06) relative to others. Babies of women with coronary heart disease had prolonged postpartum course in the NICU (p = 0.0001) and longer total hospital stays for the mother. In conclusion, well-managed, motivated mothers with HD who benefit from comprehensive antenatal care, and are managed primarily by their obstetric and anaesthesia teams, can aspire to a good outcome for themselves and their babies.

Peripartum anesthetic management of a patient with brittle cornea syndrome.

Brittle cornea syndrome (BCS) is a rare autosomal recessive disease that affects the connective tissue. The syndrome is caused by genetic changes in the 4.7-Mb interval between the D16S3423 and D16S3425 markers on the 16q24 chromosome and mutations in the Zinc-Finger 469 gene (ZNF469). BCS is characterized by thin and fragile cornea that tends to perforate spontaneously or as a result of minor trauma to the eye. In addition, the patient usually suffers from hearing loss, mental retardation, hyperextensibility of skin and joints, as well as varying degrees of scoliosis. This phenotypical expression presents an interesting challenge to anesthetic care. We briefly present the perioperative management of a patient with BCS who underwent three cesarean sections.

Perinatal outcome following fetal chest shunt insertion for pleural effusion.

OBJECTIVE: To evaluate perinatal outcome of fetuses with primary pleural effusions following pleuroamniotic shunting. METHODS: This was a retrospective study of 88 fetuses with large pleural effusions referred to a tertiary fetal medicine unit between 1991 and 2008 which, after a thorough work-up, underwent pleuroamniotic shunting. RESULTS: At presentation, 59 (67.0%) fetuses were hydropic and 67 (76.1%) had bilateral effusions. In 17 (19.3%) fetuses, pleural fluid was aspirated prior to shunting and in 71 (80.7%), shunts were inserted directly as the first procedure. Mean gestational age at shunting was 27.6 (range, 18-37) weeks and at delivery 34.2 (range, 19-42) weeks. Seventy-four (84.1%) babies were born alive, of whom 52 (70.3%) survived the neonatal period. Of 59 hydropic fetuses, 10 (16.9%) died @ in utero and 18 neonates (30.5%) died, resulting in perinatal survival of 52.5%, whereas of 29 non-hydropic fetuses, perinatal survival was 72.4%. Hydrops resolved following shunting in 28 fetuses, of whom 71% survived, compared to 35% survival in 31 fetuses where hydrops persisted (P = 0.006). Of 22 neonatal deaths, seven were related to pulmonary hypoplasia, five to genetic syndromes, two to aneuploidy and one to a congenital anomaly (truncus arteriosus). Overall 13 (14.8%) were diagnosed with a chromosomal, genetic or other condition, several of which could not have been diagnosed antenatally. CONCLUSION: Carefully selected fetuses with primary pleural effusions can benefit from pleuroamniotic shunting, allowing hydrops to resolve with a survival rate of almost 60%.

Prostanoid DP receptor (PTGDR) variants in mothers with post-coital associated preterm births: preliminary observations.

OBJECTIVE: To describe prostanoid DP receptor (PTGDR) variants in women with preterm births who admitted to coital activity (CA) within 24 h of labor. STUDY DESIGN: To achieve >80% statistical power, a pilot case-control study compared 24 premature births from mothers with CA (Group 1), 30 mothers of premature infants who did not have CA (Group 2 non-coital activity) and 95 non-coital activity mothers with term births (Group 3 controls). Four functional PTDGR single nucleotide polymorphisms (SNPs) were evaluated: T-549C, C-441/T, T-197C and G+1044A. PHASE 2.0.2 and SAS 9.2 were used for analysis. RESULT: All SNPs were in Hardy-Weinberg equilibrium in controls. The C-441/T genotype frequency was significantly increased among Group 1 women relative to Group 2 and 3 women (odds ratio (OR): 30.1, 95% confidence interval (CI) 6.9-191 and 25.7 95%CI 25.7-not computible, respectively). Of the possible haplotypes among the groups, the TCTG haplotype (T-549C, C-441/T, T-197C and G+1044A) was significantly more frequent in Group 1 women compared with the control groups (OR 53.4, 95%CI 10.3-554.8). CONCLUSIONS: A differential genomic pattern of PTGDR polymorphisms was identified in a sub-set of mothers which was associated with an increased risk of post-coital preterm birth.

Anesthetic management of a patient with cleidocranial dysplasia undergoing various obstetric procedures.

Patients with cleidocranial dysplasia, a rare autosomal dominant genetic syndrome, possess abnormal anatomical features of the head, mouth, neck and spinal column. These features may result in perioperative problems such as difficult airway and complicated regional anesthesia. We report the anesthetic management of a young woman with cleidocranial dysplasia undergoing four caesarean sections, one vaginal delivery and a dilatation and curettage, employing different modes of anesthesia. Anesthetic management in this disorder presents challenges for both general and neuraxial anesthesia.

Peripartum anesthetic management of patients with aortic valve stenosis: a retrospective study and literature review.

BACKGROUND: Anesthetic management of parturients with aortic stenosis is controversial. Early studies suggest maternal mortality was related to cardiac condition and anesthetic care. In this report, management of parturients with moderate or severe aortic stenosis in two institutions is compared, and published cases are reviewed. METHODS: Peripartum anesthetic management of all parturients with moderate or severe aortic stenosis who gave birth between 1990 and 2005 at our institutions, is described. Patients with mild or non-valvular aortic stenosis were excluded. RESULTS: There were 12 parturients, six with moderate and six with severe aortic stenosis. Two patients with moderate aortic stenosis were New York Heart Association (NYHA) classification II, the others were asymptomatic. Five patients with severe aortic stenosis were symptomatic (NYHA classification II or III). Two patients with moderate and three with severe aortic stenosis underwent cesarean delivery; epidural anesthesia was used for two. Two patients with moderate and all with serious aortic stenosis were observed postpartum for 24 to 48 h in a high-dependency unit. There were no severe maternal or neonatal complications. CONCLUSIONS: Carefully titrated regional analgesia is usually well tolerated in patients undergoing vaginal or cesarean delivery even in the presence of severe aortic stenosis. Standard monitoring is usually adequate for vaginal delivery, but invasive monitoring may facilitate management in some patients. An arterial line allows close monitoring of systemic blood pressure. Facilities for close 24-48-h post-partum observation should be available. A multidisciplinary approach is needed.

Perioperative anaesthetic management of high-order repeat caesarean section: audit of practice in a university-affiliated medical centre.

BACKGROUND: High-order (five or more) repeat caesarean sections (HORCS) are associated with increased rates of placenta praevia, placenta accreta and peripartum hysterectomy and prolonged surgical time secondary to intra-abdominal adhesions. This study summarizes our experience in the anaesthetic management of HORCS. METHODS: The files of all parturients undergoing HORCS between January 1995 and August 2007 were reviewed to determine surgical times, rates and causes of conversion from neuraxial to general anaesthesia and the need to supplement neuraxial anaesthesia with intravenous sedation. RESULTS: Parturients (n=108) were 35+/-4.5 years old with a gestational age of 37.5+/-1.5 weeks, weighed 88+/-20 kg and had undergone 6+/-1 caesarean sections. Eighty-six (80%) were elective. Initial anaesthetic techniques included spinal (n=80, 74%), epidural (n=9, 8%), combined spinal-epidural (n=6, 6%) and general anaesthesia (n=13, 12%). Surgery lasted 38+/-19 min (median 34, range 9-120). Fourteen parturients (13%) underwent intraoperative manipulations other than caesarean section, including three hysterectomies for haemorrhage (two placenta accreta, one praevia). There were no ruptures or dehiscences of the uterine scar, intraoperative bladder/ bowel injuries or re-explorations. Apgar scores <9 at 1 (n=9, 13%) and 5 (n=6, 5%) min were related to non-anaesthetic causes. Anaesthesia was converted from neuraxial to general in five cases (5/95, 5%) but only two were due to haemorrhage. No epidural top-up doses or intravenous sedatives/analgesics were required for spinal anaesthesia. CONCLUSION: HORCS is not necessarily an indication for general anaesthesia provided uterine and placental abnormalities are sought preoperatively. In our practice single-shot spinal anaesthesia sufficed for uncomplicated HORCS.

Congenital diaphragmatic hernia: review of the literature in reflection of unresolved dilemmas.

BACKGROUND: Congenital diaphragmatic hernia (CDH) is a rare but clinically and scientifically challenging condition. The introduction of ultrasound has enabled early prenatal detection and consequently, hope of early therapeutic intervention. AIM: We undertook the task to review the recent developments in understanding the pathology of CDH as well as the history and current management strategies to aid perinatologists in consultations with parents of CDH-affected foetuses. STUDY DESIGN: A Medline search was undertaken of all reports and reviews published between 1980 and 2008 using MeSH search terms 'diaphragmatic hernia', 'congenital' and 'newborn'. RESULTS: The true incidence of CDH is still difficult to estimate because of the high incidence of hidden mortality of CDH. Complete case ascertainment also poses difficulties in assessment of the impact of new therapeutic modalities on overall survival. Recent improvements in prenatal detection are a milestone in affording time for re-assessments and parental counselling. The true benefit of antenatal therapy is circumscribed and should be offered only in selected cases of isolated severe CDH as defined by existing guidelines. Postnatal intensive respiratory supportive therapy and innovative surgical techniques within specialized tertiary centres has had a major impact on survival of babies with CDH. CONCLUSION: The high survival of 'selected cases' that are live births and benefit from optimal care will be difficult to improve by antenatal interventions. The multidisciplinary approach to basic research and randomized clinical trials will further define the best approach to the foetus and neonate with CDH.

Peripartum anesthetic management of patients with Takayasu's arteritis: case series and review.

Takayasu or pulseless disease is a rare, chronic progressive inflammatory disease that causes thrombosis and occlusion of systemic and pulmonary arteries. Almost 80% of patients are women in their childbearing years. We present three patients with Takayasu's disease who between them had six pregnancies and discuss them in the context of a review of previously published cases. Assessment of the parturient with Takayasu's disease should include an evaluation of the extent of disease, including organ ischemia such as cardiac, renal, cerebral and limb. A multidisciplinary approach should be taken to optimize the parturient's status and formulate a plan for delivery. Peripartum anesthetic management should include optimization of intravascular volume and appropriate monitoring, which may be difficult in the pulseless patient. A regional anesthetic technique may be preferred over general anesthesia to allow monitoring of the cerebral circulation. A slowly titrated regional technique may prevent hemodynamic instability. Patients should be closely monitored postpartum with attention to hypertensive or end organ complications.

PAPP-A levels as an early marker of idiopathic preterm birth: a pilot study.

OBJECTIVE: To evaluate late PAPP-A levels as predictive of preterm birth in symptomatic women. STUDY DESIGN: Prospective cohort study of singleton gestations, 23 to 34 weeks, and symptoms of preterm labor. PAPP-A, IGF-I and IGF-III analysis were performed. Primary end point was delivery < or =7 days. Accuracy and optimally predictive PAPP-A values were based on receiver operator characteristic (ROC) curves. RESULT: In all, 26 women (51%) delivered < or =7 days post-admission (Group 1); 25 women (49%) >7 days (Group 2). Group 1 mean PAPP-A=38 000 vs 55 333 for Group 2 (P<0.04). Group 1 mean gestational age at delivery=29 weeks vs 37 weeks for Group 2 (P<0.00014). PAPP-A level < or =30,000 mU l(-1) had highest specificity (88%), sensitivity (50%), and positive predictive (81%) and negative predictive (62%) values for delivery < or =7 days. ROC area under curve=0.703. CONCLUSION: PAPP-A levels < or =30,000 mU l(-1) at admission was associated with increased risk for preterm birth < or =7 days, supporting active management and therapeutic approach in these women.

Temporizing treatment for the respiratory-compromised gravida: an observational study of maternal and neonatal outcome.

Acute lung disease may originate in pregnancy because of the pregnancy itself or because of an intercurrent etiology. The purpose of this study was to describe the effect of prolonged antepartum mechanical ventilatory support on the mother and the neonate when the strategy was to prolong the pregnancy rather than deliver preterm. Among 72 312 parturients over eight years, three gravidae required mechanical ventilation 12-48 h after admission for different conditions, 45-91 days before delivery. Gestational age at intubation was 21-28 weeks. Appropriate analgesia, broad-spectrum antibiotics, vasopressors and betamethsone for fetal lung maturity were used in all cases. None received tocolysis. Despite uterine distension, respiratory support provided adequate oxygenation and FiO2 could be maintained below critical levels, obviating the need for early delivery. All women survived, were weaned from ventilatory support, discharged, and delivered healthy neonates at term. Mode of delivery was dictated by obstetrical indicators only. All five infants (two sets of twins) are healthy at 12-36 months with appropriate developmental milestones. We conclude that when the maternal condition is amenable to therapy, and given the risks of labor induction and of prematurity, there is only limited benefit of delivery while on mechanical ventilation.

Emergency cesarean section in a patient with Fontan circulation using an indwelling epidural catheter.

Management of parturients with a history of Fontan procedure requires careful monitoring of cardiovascular parameters and anticipation of potential complications. We describe potential pitfalls in a parturient with atriopulmonary Fontan circulation, who received epidural analgesia for labor and who later required emergency cesarean section. Low-dose local anesthetic in combination with meperidine provided excellent perioperative epidural analgesia and cardiovascular stability. Epidural analgesia during labor offered optimal pain relief and facilitated conversion to surgical anesthesia for an emergency cesarean section.

Anesthesia for obstetric patients with Gaucher disease: survey and review.

Pregnancy and delivery in patients with non-neuronopathic Gaucher disease, whether treated with enzyme replacement or untreated, are usually uncomplicated. Various factors may influence mode of delivery, vaginal or cesarean section, as well as type of anesthesia, general or regional, used during delivery. This retrospective review was intended to highlight some of the practical issues relating to obstetric anesthetic management, based on a review of the literature and experiences from a large referral clinic for Gaucher disease. In the past decade, there were 16 deliveries in 11 women in our institution. There were five normal vaginal deliveries, two vacuum extractions, one placental extraction, and eight cesarean sections. Platelet counts were 27-215 x 10(9)/L. Two spontaneous deliveries and one vacuum extraction were performed under epidural anesthesia; two other women having vaginal deliveries and one vacuum extraction were given i.v. analgesia; the fifth was given i.v. patient-controlled analgesia. The placental extraction was performed under general anesthesia. Seven of the women having cesarean deliveries received spinal anesthesia; the breech presentation required general anesthesia. There were no anesthesia-related side effects or complications, although there were some instances of post-partum bleeding irrespective of enzyme therapy. Gaucher disease affects multiple organs and can be a challenge to the anesthesiologist. Based on this survey we suggest that anesthetic management requires particular attention to hematological parameters before delivery. A multidisciplinary approach and extensive communication among obstetrician, hematologist and anesthesiologist is required to anticipate the possibility of post-partum hemorrhage, and preclude skeletal damage.