The role of neutrophil activation in determining the outcome of pregnancy and modulation by hormones and/or cytokines.

Neutrophils are often exclusively considered as a first-line innate immune defence, able to rapidly kill or trap pathogens and causing in case of over-activation tissue damage. In the female reproductive tract, however, the presence and activity of neutrophils seems to be tightly regulated. Major players in orchestrating this regulation are cyclical steroid sex hormones present during the menstrual cycle and pregnancy. This review describes the role of sex hormones in regulating directly or indirectly the functionality of neutrophils, the role of neutrophils during fertilization and pregnancy and in controlling viral, fungal and bacterial infection. This review also discusses the consequence of overt neutrophil activation in pregnancy pathologies.

Efficacy and safety of carbetocin given as an intravenous bolus compared with short infusion for Caesarean section - double-blind, double-dummy, randomized controlled non-inferiority trial.

BACKGROUND: Carbetocin is a synthetic oxytocin-analogue, which should be administered as bolus according to manufacturer's recommendations. A higher speed of oxytocin administration leads to increased cardiovascular side-effects. It is unclear whether carbetocin administration as short infusion has the same efficacy on uterine tone compared with bolus administration and whether haemodynamic parameters differ. METHODS: In this randomized, double-blind, non-inferiority trial, women undergoing planned or unplanned Caesarean section (CS) under regional anaesthesia received a bolus and a short infusion, only one of which contained carbetocin 100 mcg (double dummy). Obstetricians quantified uterine tone two, three, five and 10 min after cord-clamping by manual palpation using a linear analogue scale from 0 to 100. We evaluated whether the lower limit of the 95% CI of the difference in maximum uterine tone within the first five min after cord-clamping did not include the pre-specified non-inferiority limit of -10. RESULTS: Between December 2014 and November 2015, 69 patients were randomized to receive carbetocin as bolus and 71 to receive it as short infusion. Maximal uterine tone was 89 in the bolus and 88 in the short infusion group (mean difference -1.3, 95% CI -5.7 to 3.1). Bp, calculated blood loss, use of additional uterotonics, and side-effects were comparable. CONCLUSIONS: Administration of carbetocin as short infusion does not compromise uterine tone and has similar cardiovascular side-effects as a slow i.v. bolus. In accordance with current recommendations for oxytocin, carbetocin can safely be administered as short -infusion during planned or unplanned CS. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT02221531 and www.kofam.ch SNCTP000001197.

[Severe neonatal blood loss due to umbilical cord rupture in an underwater birth]. / Hämorrhagischer Schock eines Neugeborenen aufgrund Nabelschnurruptur während Unterwassergeburt.

BACKGROUND: We present the case of an intrapartum umbilical cord rupture in an underwater birth with severe neonatal blood loss. CASE REPORT: A healthy 25-year-old gravida I with an uneventful pregnancy had an underwater birth. A completed rupture of the umbilical cord was diagnosed immediately after the newborn surfaced from the water and was laid on the mother's chest. The newborn suffered from severe haemorrhage with bradycardia and respiratory distress. It was immediately resuscitated by the neonatologist. Intravenous donation of volume and red blood cell transfusion could stabilise the vital parameters. The newborn was discharged in a state of well-being 6 days postnatally. DISCUSSION: Cases of umbilical cord rupture are reported in relationship to land and water births. Common causes of a cord rupture include haematoma of the cord vessels, trauma from an operative vaginal delivery, funisitis with localised cord necrosis, velamentous cord insertions, tumours of the umbilical cord and a short umbilical cord. A suspicious foetal heart rate might be absent. In the case of a water birth complications bear serious consequences. Proper team work between obstetricians and neonatologists is essential. CONCLUSION: Although water birth is restricted to low risk patients, unforeseen complications may occur. Because of the special situation in an underwater birth complications may be diagnosed late and their management will be more difficult. Obstetricians should be aware of this risk.

Monitoring and treatment of anti-D in pregnancy.

Prophylactic anti-D is a very safe and effective therapy for the suppression of anti-D immunization and thus prevention of haemolytic disease of the foetus and newborn. However, migration from countries with low health standards and substantial cuts in public health expenses have increased the incidence of anti-D immunization in many "developed" countries. Therefore, this forum focuses on prenatal monitoring standards and treatment strategies in pregnancies with anti-D alloimmunization. The following questions were addressed, and a response was obtained from 12 centres, mainly from Europe.

Georg Schmorl on trophoblasts in the maternal circulation.

Trafficking of cells between the fetus and its mother provides indirect clues to the underlying pathophysiology of pregnancy. Georg Schmorl first documented the presence of fetal cells in the maternal body and emphasized the importance of the placenta in eclampsia. Although his classic paper, written in 1893, is widely cited today, few investigators have actually read the paper, as it was published in German [Schmorl G., Pathologisch-anatomische Untersuchungen über Puerperal-Eklampsie. Verlag FCW Vogel, Leipzig; 1893]. Our goal was to translate the paper into English and critically re-evaluate its conclusions from a 21st century perspective. Schmorl was remarkably astute in his assessment of the pathologic changes that were seen in the 17 women on whom he performed complete autopsies. He found similar severe changes in all of the women, implying a common pathogenesis. This was in direct contrast to the then current doctrine. He was the first to observe the presence of thrombi containing multinucleated syncytial giant cells in the lungs of the women and speculated that they were of placental origin. To support his hypothesis he performed animal experiments. He also recognized that feto-maternal trafficking occurred in normal gestations but was increased in pregnancies affected by eclampsia. Using sophisticated molecular techniques we can now precisely confirm what Schmorl so elegantly described.

Oral misoprostol vs. intravenous oxytocin in reducing blood loss after emergency cesarean delivery.

OBJECTIVE: To compare the effectiveness of oral misoprostol and intravenous oxytocin in reducing blood loss in women undergoing indicated or elective cesarean delivery (CD) under spinal anesthesia. METHODS: In this prospective, double-blind pilot study, 56 parturients who received 5 IU of intravenous oxytocin after cord clamping were randomized to further receive either misoprostol orally and a placebo infusion intravenously or placebo orally and an oxytocin infusion intravenously. RESULTS: After adjustment was made for the sonographically estimated amniotic fluid volume, there was no statistical difference in blood loss between the 2 groups (mean+/-S.D., 1083+/-920 mL in the oxytocin group vs. 970+/-560 mL in the misoprostol group; P=.59). CONCLUSION: Oxytocin followed by oral misoprostol is as effective as an oxytocin injection followed by an oxytocin infusion in reducing postoperative blood loss after CD, and the protocol may be a safe, valuable, and cost-effective alternative to oxytocin alone. Visual estimation of intraoperative blood loss undervalues the effective value of misoprostol use by 30%.

[Recent advances in prenatal diagnostics]. / Neue Möglichkeiten in der pränatalen Diagnostik.

During the last years, technical improvements have increased the possibilities in prenatal ultrasound. During the eighties and nineties, fetal malformations were increasingly detected and specified. Since a few years, the measurement of the fetal nuchal translucency between 11 and 14 weeks of gestation has been implemented to calculate the individual risk, in combination with most recent biochemical markers. Today, the sonographic measurement of the nuchal translucency is regarded as a valuable screening tool for chromosomal anomalies in prenatal medicine. Beside standardized examinations, a profound information and counseling of the pregnant women should be emphasized. With the improvement of the specific maternal risk calculation, using the sonographic measurement of the nuchal translucency, the biochemical markers and the maternal age, unnecessary invasive examinations may be prevented and their overall number can significantly be reduced. The same trend is seen in the whole field of prenatal medicine, illustrated by the detection of the fetal rhesus D status from the maternal blood and the use of Doppler ultrasound in the management of fetal anemia.

[Antidepressants and pregnancy]. / Antidepressiva in der Schwangerschaft.

Depressive disorders in women are not uncommon during the reproductive period. Identifying women at risk for the development of depression, early detection of depressive symptoms and an adequate treatment are important issues in preventing severe chronic depressive disorders. Do psychotherapeutic interventions not show any sufficient benefits, the use of antidepressants is indicated. In the meantime sufficient data are available concerning the use of anti-depressants during pregnancy to exclude any serious damage to the fetus or newborn. As a basic principle, a monotherapy should be favoured and the drug applicated in the lowest efficient dose. Due to the SSRI's side effect profile the choice of the antidepressant should be done in favour of serotonin reuptake inhibitors rather than tri- and tetracyclic antidepressants. For both substance groups there is no hint for any teratogenic potential. Benzodiazepine should be prescribed with caution. Negative long term effects to the newborn cannot be excluded. Based on few available data, indeed, there exists no reservation against the use of St. John's wort during pregnancy and breastfeeding. A profound ultrasound screening of the organs should be performed in case of lithium exposition, whereas newer studies showed no increase in risk for Ebstein anomaly. A multidisciplinary approach, including psychiatry, obstetrics and neonatology should be always aimed at in case of depressive disorders during pregnancy.

miR455 is linked to hypoxia signaling and is deregulated in preeclampsia.

Preeclampsia is a severe pregnancy-related disorder and a leading cause of maternal and fetal mortality worldwide. Early identification of patients with an increased risk for preeclampsia is thus one of the most important goals in obstetrics. Here we identify two related human microRNAs as potential biomarkers to detect at-risk pregnancies. We demonstrate that miR455-3P and miR455-5P are significantly downregulated in placentas from preeclampsia patients, whereas other placenta-specific microRNAs remain unaffected. microRNA target prediction and validation revealed a potential link of miR455-3P to hypoxia signaling. Together with our observation that expression levels of miR455-3P and miR455-5P are upregulated during trophoblast differentiation, our results suggest a model in which miR455-3P represses a hypoxia response that might otherwise prevent cytotrophoblasts from syncytiotrophoblast differentiation. In summary, our work reveals aberrant hypoxia signaling in preeclampsia that can be explained by deregulated expression of miR455. As miR455 has been found in circulating blood, the development of noninvasive prenatal tests enabling early diagnosis of preeclampsia may be possible.

Cell-free nucleic acids as potential markers for preeclampsia.

Preeclampsia is one of the leading causes of maternal and fetal/neonatal mortality and morbidity worldwide. Therefore, widely applicable and affordable tests are needed to make an early diagnosis before the occurrence of the clinical symptoms. Circulating cell-free nucleic acids in plasma and serum are novel biomarkers with promising clinical applications in different medical fields, including prenatal diagnosis. Quantitative changes of cell-free fetal (cff)DNA in maternal plasma as an indicator for impending preeclampsia have been reported in different studies, using real-time quantitative PCR for the male-specific SRY or DYS 14 loci. In case of early onset preeclampsia, elevated levels may be already seen in the first trimester. The increased levels of cffDNA before the onset of symptoms may be due to hypoxia/reoxygenation within the intervillous space leading to tissue oxidative stress and increased placental apoptosis and necrosis. In addition to the evidence for increased shedding of cffDNA into the maternal circulation, there is also evidence for reduced renal clearance of cffDNA in preeclampsia. As the amount of fetal DNA is currently determined by quantifying Y-chromosome specific sequences, alternative approaches such as the measurement of total cell-free DNA or the use of gender-independent fetal epigenetic markers, such as DNA methylation, offer a promising alternative. Cell-free RNA of placental origin might be another potentially useful biomarker for screening and diagnosis of preeclampsia in clinical practice. Fetal RNA is associated with subcellular placental particles that protect it from degradation. Its levels are ten-fold higher in pregnant women with preeclampsia compared to controls. In conclusion, through the use of gender-independent sequences, the universal incorporation of fetal nucleic acids into routine obstetric care and into screening or diagnostic settings using combined markers may soon become a reality. Effort has now to be put into the establishment of standardized and simplified protocols for the analysis of these biomarkers in a clinical setting.

Pregenesys pre-eclampsia markers consensus meeting: What do we require from markers, risk assessment and model systems to tailor preventive strategies?

The Pregenesys Consensus Meeting held in Cambridge on 13 July 2009 was organized by the Pregenesys Consortium to review and critically discuss current knowledge regarding early markers of preeclampsia, to identify priorities and opportunities for future research, to consider issues that may need to be addressed in future recommendations and to highlight key issues in cost effectiveness and national policies concerning prediction and early screening for the risk of developing preeclampsia. This report summarizes the outcome of the Consensus Meeting and draws attention to issues for further investigation with specific regard to single versus multiple markers, early versus late risk identification, and the long-term effects on both maternal and perinatal health and the need to include these in any future cost-benefit assessment.

Water birth: is the water an additional reservoir for group B streptococcus?

OBJECTIVE: Water birth became popular in the last years, despite the fact that many questions like the risk of infection for the newborn remain unanswered. Group B streptococcal (GBS) infections in the newborn remain a challenge in obstetrics and neonatology. METHOD: We conducted a prospective trial to study the impact of water birth on the colonization rate of the bath water and, more importantly, the GBS-colonization rate of the newborn. RESULT: After water birth the bath water was significantly more often colonized with GBS than after immersion followed by a delivery in bed. The newborns, however, showed no difference in GBS colonization and there was even a trend towards less GBS colonization of the newborn after a water delivery. CONCLUSION: Regarding GBS colonization of the newborn during water birth there might be a wash out effect, which protects the children during the delivery.

[Sonographic first trimester screening in Switzerland]. / Aktuelles zum geburtshilflichen Ultraschall: Sonographisches Ersttrimester-Screening in der Schweiz.

The sonographic measurement of the nuchal translucency is already regarded as the most valuable screening parameter for chromosomal anomalies. Beside standardised examinations profound information and counselling of the pregnant women should be emphasised. With the improvement of the specific maternal risk calculation using the sonographic measurement of the nuchal translucency, the biochemical markers and the maternal age, unnecessary invasive examinations may be prevented and their overall number can be reduced significantly.

Umbilical cord edema associated with patent urachus.

Umbilical cord anomalies can often be detected prenatally by ultrasound, but a definitive prenatal diagnosis is not always possible. We present a case with increasing edema of the Wharton's jelly followed by the development of pseudocysts in the proximal umbilical cord due to a patent urachus. The first abnormal findings were detected by ultrasound in the 14th week of gestation. Differential diagnoses and their influence on surveillance and birth management are discussed.

Lost intrauterine devices during pregnancy: maternal and fetal outcome after ultrasound-guided extraction. An analysis of 82 cases.

OBJECTIVES: It is generally agreed that intrauterine devices (IUDs) with visible strings in pregnancy should be removed because of the increased risk of miscarriage, septic complications and premature delivery. The precise management of pregnancies in association with so-called 'lost IUDs', and especially the technique of their removal, has remained controversial. We present our experience of the management of intrauterine pregnancies with a lost IUD. METHODS: Ultrasound-guided extraction of a lost IUD was performed in 82 intrauterine pregnancies. The subsequent outcome of the pregnancies is described. RESULTS: There were no intra- or post-procedure maternal complications. Although the miscarriage rate in the first 3 weeks after the procedure was higher than that in normal pregnancy, the complication rate approached that of normal pregnancy as the pregnancies progressed. The total miscarriage rate of 22% was comparable to that following extraction of IUDs with visible filaments. The rate of live births was 77.0%. Delivery before 37 weeks occurred in 13.5% of cases. CONCLUSIONS: Ultrasound-guided extraction is a minimally invasive and inexpensive procedure that is associated with few postoperative complications. It has a high success rate and is associated with a moderate miscarriage rate and no maternal complications.

Split hand and foot malformation: ultrasound detection in the first trimester.

The split hand split foot malformation is a rare disorder inherited in an autosomal dominant pattern with variable expression. In our case it was detected early by ultrasound in the twelfth week of gestation. To our knowledge, this is the earliest finding by ultrasound of this malformation. The sonographic findings were bilateral split hands and split foot. No other associated malformation was observed. The pathological findings were consistent with the diagnosis of split hand split foot malformation. Prenatal diagnosis, the genetic background, and the differential diagnosis are discussed.