Miroslaw Wielgos

Intrapartum GBS screening and antibiotic prophylaxis: a European consensus conference

Abstract Group B streptococcus (GBS) remains worldwide a leading cause of severe neonatal disease. Since the end of the 1990s, various strategies for prevention of the early onset neonatal disease have been implemented and have evolved. When a universal antenatal GBS screening-based strategy is used to identify women who are given an intrapartum antimicrobial prophylaxis, a substantial reduction of incidence up to 80% has been reported in the USA as in other countries including European countries. However recommendations are still a matter of debate due to challenges and controversies on how best to identify candidates for prophylaxis and to drawbacks of intrapartum administration of antibiotics. In Europe, some countries recommend either antenatal GBS screening or risk-based strategies, or any combination, and others do not have national or any other kind of guidelines for prevention of GBS perinatal disease. Furthermore, accurate population-based data of incidence of GBS neonatal disease are not available in some countries and hamper good effectiveness evaluation of prevention strategies. To facilitate a consensus towards European guidelines for the management of pregnant women in labor and during pregnancy for the prevention of GBS perinatal disease, a conference was organized in 2013 with a group of experts in neonatology, gynecology-obstetrics and clinical microbiology coming from European representative countries. The group reviewed available data, identified areas where results were suboptimal, where revised procedures and new technologies could improve current practices for prevention of perinatal GBS disease. The key decision issued after the conference is to recommend intrapartum antimicrobial prophylaxis based on a universal intrapartum GBS screening strategy using a rapid real time testing.

Low oxygen atmosphere facilitates proliferation and maintains undifferentiated state of umbilical cord mesenchymal stem cells in an hypoxia inducible factor-dependent manner

BACKGROUND AIMS As we approach the era of mesenchymal stem cell (MSC) application in the medical clinic, the standarization of their culture conditions are of the particular importance. We re-evaluated the influences of oxygens concentration on proliferation, stemness and differentiation of human umbilical cord Wharton Jelly-derived MSCs (WJ-MSCs). METHODS Primary cultures growing in 21% oxygen were either transferred into 5% O2 or continued to grow under standard 21% oxygen conditions. Cell expansion was estimated by WST1/enzyme-linked immunosorbent assay or cell counting. After 2 or 4 weeks of culture, cell phenotypes were evaluated using microscopic, immunocytochemical, fluorescence-activated cell-sorting and molecular methods. Genes and proteins typical of mesenchymal cells, committed neural cells or more primitive stem/progenitors (Oct4A, Nanog, Rex1, Sox2) and hypoxia inducible factor (HIF)-1α-3α were evaluated. RESULTS Lowering O2 concentration from 21% to the physiologically relevant 5% level substantially affected cell characteristics, with induction of stemness-related-transcription-factor and stimulation of cell proliferative capacity, with increased colony-forming unit fibroblasts (CFU-F) centers exerting OCT4A, NANOG and HIF-1α and HIF-2α immunoreactivity. Moreover, the spontaneous and time-dependent ability of WJ-MSCs to differentiate into neural lineage under 21% O2 culture was blocked in the reduced oxygen condition. Importantly, treatment with trichostatin A (TSA, a histone deacetylase inhibitor) suppressed HIF-1α and HIF-2α expression, in addition to blockading the cellular effects of reduced oxygen concentration. CONCLUSIONS A physiologically relevant microenvironment of 5% O2 rejuvenates WJ-MSC culture toward less-differentiated, more primitive and faster-growing phenotypes with involvement of HIF-1α and HIF-2α-mediated and TSA-sensitive chromatin modification mechanisms. These observations add to the understanding of MSC responses to defined culture conditions, which is the most critical issue for adult stem cells translational applications.

Counseling for non-invasive prenatal testing (NIPT): what pregnant women may want to know

Sequencing of cell-free fetal and maternal DNA fragments (cfDNA) in maternal plasma can be used to test for fetal chromosomal abnormalities. In particular, prediction of the presence or absence of fetal trisomy 21, the most common fetal chromosomal abnormality, has been proved to be highly accurate. The first studies, showing > 99% accuracy, were done in selected high-risk groups1,2. More recent studies in average-risk populations of pregnant women confirm, as was expected biologically, that the test works equally well in the general population3–7. Not surprisingly, this safe and accurate test, commonly referred to as non-invasive prenatal testing (NIPT), increasingly is being offered by clinicians and requested by pregnant women who want to be informed about the possibility of trisomy 21 in their unborn child. With the first studies suggesting very high accuracy of trisomy 21 detection, there was hope that after decades of searching for this ‘Holy Grail’, a safe blood test could replace chorionic villus sampling and amniocentesis, eliminating (fear of) procedure-related miscarriages. From larger follow-up studies, we now know that while an NIPT result positive for trisomy 21 often means that the fetus is affected, this is not always the case, and therefore confirmation using an invasive test remains necessary, at least when the woman is considering an irreversible decision. Furthermore, sensitivity for detection of trisomy 21 is > 99% in practically all studies, but some missed cases have been reported. Thus, although highly accurate, NIPT is not perfect. In the not-so-distant past, the use of maternal age alone to select women to undergo invasive testing was replaced by various forms of measuring maternal serum markers with or without nuchal translucency (NT) measurement. In countries in which this was implemented well, unnecessary invasive tests (and related miscarriages) significantly decreased, with concomitant improved detection, thus improving women’s reproductive choices8. Still, the vast majority of invasive tests following screening for trisomy reveal a normal result, while the screening test is falsely reassuring in at least one in 10 pregnancies with a trisomy 21 fetus. The use of NIPT enables us to further improve the quality of prenatal testing for fetal abnormalities. The aim of counseling a pregnant woman before she chooses to undergo any test which can have major consequences is to provide sufficient understanding of the test characteristics, limitations and risks for her to make what we call an ‘informed choice’ regarding whether she wants to undergo this test, another one or no test at all. The introduction of NIPT does not change this general principle. We have been counseling women of advanced maternal age on invasive testing for decades, and we are used to discussing serumand NT-based screening, which, when all aspects of the various tests are to be explained, is quite a complex task. Following the first publications on NIPT for trisomy 21, clinicians for a while were under the impression that pretest counseling would become an easier, if not almost superfluous, task. A simple message (‘If you want to know about trisomy 21, we take a tube of blood and let you know in a week or so whether your baby is affected.’) was thought, at least by some, to be capable of replacing the complex explanation involving serum markers, the meaning of this rim of fluid in the baby’s neck, an algorithm including the age of the mother and not so easy-to-understand reasons behind the cut-off between high and low risk. However, with the increasing use of NIPT in clinical practice, there is a rising awareness among professionals and policy makers that adequate pre-test counseling is still important, even for NIPT, in order to prevent misconceptions, disappointments and, in some cases, inappropriate selection of this test by women or doctors. In this Opinion paper, we describe what pregnant women may want to know about NIPT before consenting to undergo this test, and summarize useful aspects, which could be included in various forms of patient information (websites, guidelines, booklets or by personal contact in the clinic).

Menstrual Function in Female Liver Transplant Recipients of Reproductive Age

BACKGROUND AND AIM End-stage liver failure is associated with severe abnormalities in menstrual and reproductive function. These abnormalities may be reversed by successful orthotopic liver transplantation (OLT). The aim of the study was to investigate menstrual patterns and sex hormone profiles among female liver transplant recipients of reproductive age. METHODS The study group consisted of 24 women of reproductive age with end-stage liver failure who underwent successful OLT. Menstrual patterns and sex hormone profiles were analyzed before as well as 3 and 12 months after OLT. Twenty-seven healthy women of reproductive age served as controls. Biochemical parameters of liver function were assessed before and after OLT. RESULTS Amenorrhea was the most commonly observed abnormality of menstrual cycle in women with end-stage liver failure (71% of patients). The recurrence of regular menstrual cycles was observed in 35% of patients 3 months after OLT. The percentage increased to 70% at 1 year after grafting and was clearly associated with stabilization of liver function. Similar levels of follicle stimulation hormone (FSH), luteinizing hormone (LH), prolactine (PRL), and testosterone (T) as well as lower levels of estradiol (E(2)), dehydroepiandrostendione sulphate (DHEA-S), and progesterone, (P) were observed in patients with liver failure compared with healthy women. We observed normalization of E(2) and DHEA-S levels after OLT. CONCLUSIONS Amenorrhea, the most common menstrual disturbance in women with end-stage liver failure, may be reversed by OLT. One year after OLT menstrual bleedings were noted in 74% of patients of reproductive age. The recurrence of reproductive function indicated the need for effective and safe family planning methods in that group of patients.

Successful Pregnancy Outcome after In Vitro Fertilization in a Kidney Graft Recipient: A Case Report and Literature Review

BACKGROUND Successful spontaneous pregnancy in a kidney graft recipient is regarded as a sign of full recovery. The crucial factors determining positive outcome are optimizing time of conception and multidisciplinary team care. However, there are only a few reports dealing with in vitro fertilization (IVF) outcomes in organ recipients. CASE REPORT A 34-year-old living donor kidney recipient with primary infertility due to bilateral tubal obstruction was referred to our clinic. Transfer of 2 embryos was conducted after a long stimulation protocol with GnRH and rFSH, and a viable singleton pregnancy was confirmed by subsequent ultrasound examination. Pregnancy complications were: chronic hypertension, fetal intrauterine growth restriction, and severe anemia requiring blood transfusions and erythropoietin treatment. In the 34th week of gestation the patient presented with worsening of blood pressure control. A male newborn, 1810 grams weight and 10 points Apgar score was delivered by cesarean section. Although our patient was qualified for the IVF program with signs of suboptimal graft function, it was stable during the ovarian stimulation protocol. Fortunately, in the second half of the pregnancy only mild creatinine rise and proteinuria <1 g/day were observed. CONCLUSIONS IVF may be a good treatment option in female kidney graft recipients. It does not necessarily lead to graft function deterioration and it provides multidisciplinary specialized care, allowing for delivery of a healthy newborn.

Prevalence of high-risk human papillomavirus cervical infection in female kidney graft recipients: an observational study

BackgroundImmunosuppressive therapy protects the transplanted organ but predisposes the recipient to chronic infections and malignancies. Transplant patients are at risk of cervical intraepithelial neoplasia (CIN) and cervical cancer resulting from an impaired immune response in the case of primary infection or of reactivation of a latent infection with human papillomavirus of high oncogenic potential (HR-HPV).MethodsThe aim of this study was to assess the prevalence of HR-HPV cervical infections and CIN in 60 female kidney graft recipients of reproductive age in comparison to that in healthy controls. Cervical swabs were analyzed for the presence of HR-HPV DNA. HR-HPV-positive women remained under strict observation and were re-examined after 24 months for the presence of transforming HR-HPV infection by testing for HR-HPV E6/E7 mRNA. All the HR-HPV-positive patients were scheduled for further diagnostic tests including exfoliative cytology, colposcopy and cervical biopsy.ResultsThe prevalence of HR-HPV did not differ significantly between the study group and the healthy controls (18% vs 25%, p = 0.37). There was no correlation between HR-HPV presence and the immunosuppresive regimen, underlying disease, graft function or time interval from transplantation. A higher prevalence of HR-HPV was observed in females who had had ≥2 sexual partners in the past. Among HR-HPV-positive patients, two cases of CIN2+ were diagnosed in each group. In the course of follow-up, transforming HR-HPV infections were detected in two kidney recipients and in one healthy female. Histologic examination confirmed another two cases of CIN2+ developing in the cervical canal.ConclusionsFemale kidney graft recipients of reproductive age are as exposed to HR-HPV infection as are healthy individuals. Tests detecting the presence of HR-HPV E6/E7 mRNA offer a novel diagnostic opportunity in those patients, especially in those cases where lesions have developed in the cervical canal.

Pregnancy risk in female kidney and liver recipients: a retrospective comparative study.

Objective: To determine and compare maternal, neonatal and graft outcomes in pregnant women after kidney or liver transplantation, who had delivered from 1 January 2005 to 1 February 2010. Methods: A retrospective, single-center study provided in Warsaw, Poland. Results: Complete data were collected in 38 deliveries in 37 women. Preexisting hypertension was present in 15 of 19 (79%) pregnant kidney recipients and in 2 of 19 (10.5%) women after liver transplantation (p < 0.000). The incidence of preeclampsia was also more often in pregnant kidney recipients (p = 0.04). Mean gestational age at labor was lower in the kidney group (34.9 ± 3.56 vs. 37.5 ± 1.62, p = 0.000). A similar relation was observed in the frequency of preterm deliveries before 37 weeks of gestation (42% vs. 11%, respectively, p = 0.02) and neonates small for gestational age (47% vs. 11%, respectively, p = 0.008). Cesarean sections were performed in approximately 79% (15/19) and 95% (18/19) liver and kidney posttransplant pregnancies, respectively. Four of 38 infants presented structural malformations. Conclusions: Pregnancies after kidney transplantation are complicated with a higher prevalence of prematurity and worse neonatal prognosis, which depends mainly on the underlying condition.

Intrauterine Hypotrophy and Premature Births in Neonates Delivered by Female Renal and Liver Transplant Recipients

BACKGROUND Neonates born to mothers, who underwent organ transplantation require close medical monitoring. It is unknown how chronically diseased mothers organs or immunosuppressive drugs affect fetal growth and development; some immunosuppressants are teratogenic and contraindicated during pregnancy. The aim of this study was to determine the prevalence of prematurity and intrauterine growth restriction in neonates born to women who have undergone renal or liver transplantation. METHODS Our retrospective analysis identified 53 (25 renal and 28 liver) cases of neonates delivered by female graft recipients between January 2005 and December 2009. Hypotrophy was defined as a birth weight<10th percentile for gestational age. We excluded newborns diagnosed with severe hypotrophy (<5th percentile). RESULTS Neonates born prematurely were predominate in the renal (16/25, 64%), but less than half of the liver cohort (13/28, 46%). Hypotrophy less than the 10th percentile was noted significantly more often among renal than liver recipients; 36% versus 14% (P<.05). Severe hypotrophy was also observed significantly more often among renal than liver transplant neonates: 28% versus 3.6% (P<.001). CONCLUSIONS Compared with liver insufficiency, chronic kidney diseases have stronger effects on the fetus, leading to adverse neonatal complications. A greater prevalence of preterm births, as well as hypotrophic newborns, especially less than the 5th percentile, was observed among neonates delivered by mothers after kidney transplantation.

Potential first trimester metabolomic biomarkers of abnormal birth weight in healthy pregnancies

Macrosomia and low birth weight (LBW) can be associated with pregnancy complications and may affect the long‐term health of the child. The aim of this study was to evaluate the metabolomic serum profiles of healthy pregnant women to identify early biomarkers of macrosomia and LBW and to understand mechanisms leading to abnormal fetal growth not related to mothers body mass index or presence of gestational diabetes.

Pregnancy complications after liver transplantation

To review complications in pregnancy after liver transplantation and assess the time interval since transplantation on fetal development and preterm birth rate.