Eleonor Tiblad

Lower-dose intravenous immunoglobulins for the treatment of fetal and neonatal alloimmune thrombocytopenia: a cohort study.

Intravenous immunoglobulins (IVIGs) are the cornerstone in the treatment of pregnancies at risk for fetal and neonatal alloimmune thrombocytopenia (FNAIT). The most commonly used dose is 1.0 g/kg/week, not based on any dose‐finding study. IVIG is an expensive multidonor human blood product with dose‐related side effects. Our aim was to describe the amount of severe thrombocytopenia according to two different doses of IVIG.

Pharmacokinetics of 250 μg anti‐D IgG in the third trimester of pregnancy: An observational study

Objective. We present a pharmacokinetic study evaluating a single intramuscular dose of 250 μg anti‐D immunoglobulin in the third trimester of pregnancy. The aim of the study was to determine the kinetic profile and duration of detectable levels of anti‐D. Design. Prospective observational study. Setting. Antenatal outpatient clinic. Population. Healthy Rhesus D (RhD)‐negative pregnant women with an RHD‐positive fetus. Methods. Serial plasma anti‐D quantitations following antenatal administration of anti‐D immunoglobulin were performed using flow cytometry. Kinetic profiles for anti‐D levels were generated from the concentration values at predetermined sampling time points. The half‐lives were calculated by linear regression analysis. Main outcome measures. Time vs. concentration profile, half‐life and anti‐D concentration ≥1 ng/mL close to term. Results. The maximal plasma concentration of anti‐D was usually seen at 3–10 days postinjection, with a median value of 25 ng/mL. The half‐life varied between individuals, with a median of 23 days. We found detectable levels of anti‐D IgG within two weeks of parturition in 11 of 12 women. Conclusions. The preparation of anti‐D immunoglobulin used in the present study, if administrated in pregnancy week 28–30, is associated with detectable levels of anti‐D in most women at the time of delivery. Although the half‐time is 23 days, it is uncertain whether all mothers have adequate anti‐D concentrations at term. Alternative strategies may be evaluated in the future, with repeated administration of antenatal prophylaxis at term rather than conventional postpartum administration of anti‐D.

MAIT cells accumulate in placental intervillous space and display a highly cytotoxic phenotype upon bacterial stimulation

During pregnancy, the maternal immune system must tolerate the developing foetus, and yet retain a potent antimicrobial response to prevent infections. Mucosal associated invariant T (MAIT) cells recognize microbial-derived vitamin B metabolites presented on the MR1 molecule, but their presence and function at the foetal-maternal interface is not known. We here isolated mononuclear cells from paired samples of peripheral blood (PB), intervillous blood (IVB), and decidua parietalis (DP) following uncomplicated term pregnancies. Interestingly, MAIT cells were highly enriched in IVB compared to PB and DP. The activation status of IVB MAIT cells was similar to that of PB MAIT cells, except for a lower expression of PD-1. Both IVB MAIT cells and conventional T cells were more dominated by an effector memory phenotype compared to PB MAIT cells and T cells. IVB MAIT cells also responded more vigorously with expression of IFN-γ, granzyme B, and perforin in response to Escherichia coli stimulation compared to PB. MR1 was not expressed in syncytiotrophoblasts, but in placental villous and decidual macrophages. These data indicate that maternal MAIT cells accumulate in the intervillous space of the placenta and that they are highly armed to quickly respond if bacteria are encountered at the foetal-maternal interface.

Establishing a national program for fetoscopic guided laser occlusion for twin-to-twin transfusion syndrome in Sweden.

Objective. To describe the establishment of the fetoscopic guided laser occlusion (FLOC) technique for treatment of twin‐to‐twin transfusion syndrome (TTTS) and the initial results in a Swedish national center. Design. Retrospective, descriptive study. Setting. Tertiary level university hospital. Population. All referred and treated cases suffering significant TTTS. Methods. The present study includes all cases of FLOC for TTTS at the Center of Fetal Medicine at Karolinska University Hospital, Stockholm, Sweden from October 2001 until December 2009. Patients were referred from all over Sweden and a few from other Nordic countries. The patients were evaluated with ultrasound examination between gestational ages of 18 and 26 weeks. Data from patients were extracted from our electronic medical record system and, in addition, families were contacted and medical records requested from referring hospitals. Main outcome measures. Pregnancies with one or more surviving infants after FLOC treatment categorized according to stage of TTTS. Results. In 75% of pregnancies, one or more infant was born alive. At stage I, both infants survived in one pregnancy and one survived in the second. There was no significant difference between cases at stage II or III, i.e. 73 vs. 78% of pregnancies resulted in one or more surviving infant. At stage IV, 66% of pregnancies ended with one or more surviving infant. Conclusions. Treatment of TTTS is feasible in a rather small country like Sweden, with comparable results to other centers. There are strong arguments for centralization and further improvement of this kind of highly specialized treatment.

Noninvasive prenatal screening for RHD: the Stockholm study

The non‐invasive technique to determine fetal RHD status opens the opportunity to change the antenatal screening and Rh‐prophylaxis programs. During the period September 2009 to December 2011, we performed a study in the Stockholm area with approximately 27000 pregnancies per year. The study included routine cell free fetal DNA (cffDNA) RHD genotyping in early pregnancy followed by targeted RAADP in gestational week 29 to all RhD negative pregnant women carrying an RHD positive fetus. The new approach in our strategy, compared to previous studies, was that fetal RHD screening was done in early pregnancy at the first antenatal visit and based on a single‐exon 4 assay. The implementation of this new screening program in a routine clinical setting is described. The final results of the study are still under analysis. The conclusion until now is that fetal RHD screening in early pregnancy is feasible and accurate with a high sensitivity and specificity, provided samples before gestational week eight were excluded.

Ultrasound in Prenatal Diagnostics and Its Impact on the Epidemiology of Spina Bifida in a National Cohort from Denmark with a Comparison to Sweden

Objectives The aim of this study was to assess the incidence, the prenatal detection rate by ultrasound, and the pregnancy outcome of spina bifida (SB) in Denmark (DK) in 2008–2015 and to compare results to national data from Sweden. Methods Data were retrieved from the Danish Fetal Medicine Database, which includes International Classification of Diseases- (ICD-) 10 codes for pre- or postnatally diagnoses and pregnancy outcome. Missing data were obtained from the National Patient Register. Livebirth data with myelomeningocele (MMC) in Sweden were obtained from different databases. Results There were 234 cases with SB in DK in 2008–2015. The incidence of SB was 4.9u2009:u200910,000; 89% were detected with ultrasound prior to week 22; 90% of these pregnancies were terminated (ToP); 91% were isolated malformations of which 11% showed abnormal karyotype. The incidence of newborns with MMC was 1.3u2009:u200910,000 in Sweden. Conclusions Ultrasound screening has a major impact on the epidemiology of SB. The prenatal detection rate of SB was high, and most SB cases were isolated and had a normal karyotype. Among women with a prenatal fetal diagnosis of SB, 90% chose to have ToP. The incidence of newborns with SB was higher in Sweden than in DK.

Postponing Early intrauterine Transfusion with Intravenous immunoglobulin Treatment; the PETIT study on severe hemolytic disease of the fetus and newborn

BACKGROUND: Intrauterine transfusion for severe alloimmunization in pregnancy performed <20 weeks’ gestation is associated with a higher fetal death rate. Intravenous immunoglobulins may prevent hemolysis and could therefore be a noninvasive alternative for early transfusions. OBJECTIVE: We evaluated whether maternal treatment with intravenous immunoglobulins defers the development of severe fetal anemia and its consequences in a retrospective cohort to which 12 fetal therapy centers contributed. STUDY DESIGN: We included consecutive pregnancies of alloimmunized women with a history of severe hemolytic disease and by propensity analysis compared index pregnancies treated with intravenous immunoglobulins (n = 24) with pregnancies managed without intravenous immunoglobulins (n = 28). RESULTS: In index pregnancies with intravenous immunoglobulin treatment, fetal anemia developed on average 15 days later compared to previous pregnancies (8% less often <20 weeks’ gestation). In pregnancies without intravenous immunoglobulin treatment anemia developed 9 days earlier compared to previous pregnancies (10% more <20 weeks), an adjusted 4‐day between‐group difference in favor of the immunoglobulin group (95% confidence interval, –10 to +18; P = .564). In the subcohort in which immunoglobulin treatment was started <13 weeks, anemia developed 25 days later and 31% less <20 weeks’ gestation (54% compared to 23%) than in the previous pregnancy. Fetal hydrops occurred in 4% of immunoglobulin‐treated pregnancies and in 24% of those without intravenous immunoglobulin treatment (odds ratio, 0.03; 95% confidence interval, 0–0.5; P = .011). Exchange transfusions were given to 9% of neonates born from pregnancies with and in 37% without immunoglobulin treatment (odds ratio, 0.1; 95% confidence interval, 0–0.5; P = .009). CONCLUSION: Intravenous immunoglobulin treatment in mothers pregnant with a fetus at risk for hemolytic disease seems to have a potential clinically relevant, beneficial effect on the course and severity of the disease. Confirmation in a multicenter randomized trial is needed.

Maternal Adaptive Immune Cells in Decidua Parietalis Display a More Activated and Coinhibitory Phenotype Compared to Decidua Basalis

The maternal part of the placenta, the decidua, consists of maternal immune cells, decidual stromal cells, and extravillous fetal trophoblasts. In a successful pregnancy, these cell compartments interact to provide an intricate balance between fetal tolerance and antimicrobial defense. These processes are still poorly characterized in the two anatomically different decidual tissues, basalis and parietalis. We examined immune cells from decidua basalis and parietalis from term placentas (n = 15) with flow cytometry. By using multivariate discriminant analysis, we found a clear separation between the two decidual compartments based on the 81 investigated parameters. Decidua parietalis lymphocytes displayed a more activated phenotype with a higher expression of coinhibitory markers than those isolated from basalis and contained higher frequencies of T regulatory cells. Decidua basalis contained higher proportions of monocytes, B cells, and mucosal-associated invariant T (MAIT) cells. The basalis B cells were more immature, and parietalis MAIT cells showed a more activated phenotype. Conventional T cells, NK cells, and MAIT cells from both compartments potently responded with the production of interferon-γ and/or cytotoxic molecules in response to stimulation. To conclude, leukocytes in decidua basalis and parietalis displayed remarkable phenotypic disparities, indicating that the corresponding stromal microenvironments provide different immunoregulatory signals.