Low titer group O whole blood and risk of RhD alloimmunization: Rationale for use in Finland.

BACKGROUND: Prehospital low-titer group O whole blood (LTOWB) used for patients with life-threatening hemorrhage is often RhD positive. The most important complication following RhD alloimmunization is hemolytic disease of the fetus and newborn (HDFN). Preceding clinical use of RhD positive LTOWB, we estimated the risk of HDFN due to LTOWB prehospital transfusion in the Finnish population. STUDY DESIGN AND METHODS: We collected data on prehospital transfusions in Tampere and Helsinki University Hospital areas. Using the mean of reported alloimmunization rates in trauma studies (24%) and a higher reported rate representing trauma patients of 13-50 years old (42.7%), we estimated the risk of HDFN and extrapolated it to the whole of Finland. RESULTS: We estimated that in Finland, with the current prehospital transfusion rate we would see 1-3 cases of severe HDFN due to prehospital LTOWB transfusions every 10 years, and fetal death due to HDFN caused by LTOWB transfusion less than once in 100 years. DISCUSSION: The estimated risk of serious HDFN due to prehospital LTOWB transfusion in the Finnish population is similar to previous estimates. As Finland routinely screens expectant mothers for red blood cell antibodies and as the contemporary treatment of HDFN is very effective, we support the prehospital use of RhD positive LTOWB in all patient groups.

Use of O RhD-negative red blood cells: A nationwide, prospective audit.

BACKGROUND AND OBJECTIVES: Despite declining transfusion rates, overuse of O RhD-negative red blood cells (RBCs) risks the secure supply of this limited resource. A nationwide prospective audit was performed in Finland to understand the clinical use and inventory management of O RhD-negative units. Our aim was to identify areas where policy changes could help alleviate the shortage of O RhD-negative RBCs. MATERIALS AND METHODS: The use of every O RhD-negative unit in Finland during a period of 1 month was reviewed. For each issued unit (n = 1105), unit age, urgency of transfusion, hospital and patient demographics, and specific reasons for issuing O RhD-negative units were recorded. RESULTS: Almost half of the O RhD-negative units (n = 529, 47.9%) were issued to non-O RhD-negative patients. Only 22.3% (n = 118) were issued for females under the age of 50. Of the units for ABO-nonidentical transfusion, one-third (32.5%, n = 172) were issued for emergency transfusion, two-thirds (67.5%, n = 357) for non-urgent transfusions. The most common reason for issuing an O RhD-negative unit was inventory management (n = 172, 48.2% of units issued for non-urgent transfusion). Most of these units were issued close to the unit expiry date. CONCLUSION: This nationwide audit revealed that a significant proportion of O RhD-negative RBCs are used inappropriately. Clinicians should be educated on the appropriate use of O RhD-negative RBCs, and blood banks should develop strategies for inventory management to avoid issuing O RhD-negative units purely to prevent outdating.

Combined oral contraceptives containing estradiol valerate vs ethinylestradiol on coagulation: A randomized clinical trial.

INTRODUCTION: Contraceptives containing ethinylestradiol (EE) induce changes in the coagulation system and are associated with a risk of venous thromboembolism. However, studies comparing the effects of combined oral contraceptives containing EE and low-potency estrogens (ie, estradiol [E2 ] and estradiol valerate [EV]) on coagulation biomarkers are limited. This study represents secondary outcomes of a randomized trial comparing combined oral contraceptives containing EV + dienogest (DNG), EE + DNG, and DNG alone on selected coagulation biomarkers. We could compare the specific effects of the different estrogen components owing to the inclusion of preparations containing the same progestin. MATERIAL AND METHODS: We enrolled 59 healthy, 18- to 35-year-old, non-smoking women, of whom three discontinued. The participants were randomly allocated to 9 weeks of continuous treatment with EV 2 mg + DNG 2-3 mg (n = 20), EE 0.03 mg + DNG 2 mg (n = 20), or DNG 2 mg (n = 19). Blood samples were collected at baseline and after 9 weeks. We assessed coagulation in vitro by thrombin generation using the Calibrated Automated Thrombogram. Thrombin generation was evaluated by lag time, time to thrombin peak, thrombin peak, and endogenous thrombin potential in response to tissue factor (1 pm). In vivo coagulation assessment was based on levels of prothrombin fragment 1 + 2 (F1 + 2) (thrombin generation) and D-dimer (fibrin turnover). CLINICAL TRIAL REGISTRATION: NCT02352090. RESULTS: Lag time and time to thrombin peak remained unaltered after exposure to EV + DNG, whereas EE + DNG shortened both lag time (mean percentage change -24%, 95% confidence interval [CI] -32% to -15%; p < 0.01) and time to thrombin peak (-26%, 95% CI -37% to -16%; p < 0.01). EV + DNG induced lower thrombin peak and endogenous thrombin potential than EE + DNG (peak; +45%, 95% CI 22%-67% vs +147%,95% CI 96%-198%; p < 0.01, and endogenous thrombin potential; +26%, 95% CI 15%-38% vs +64%, 95% CI 51%-76%; p < 0.01). Median F1 + 2 levels remained unchanged with EV + DNG (p = 0.22) but increased within normal ranges with EE + DNG (from 152 pmol/L, 95% CI 127-206] pmol/L to 194 pmol/L, 95% CI 149-250 pmol/L, p = 0.04). The within-group change in D-dimer levels was not significant in any of the groups. DNG alone did not affect these biomarkers. CONCLUSIONS: Both in vitro and in vivo thrombin generation was lower after exposure to EV + DNG compared with EE + DNG. The lower thrombin generation measures after treatment with EV + DNG indicate less enhancement of coagulation potential and suggest that EV may be favorable to EE as a component of combined oral contraceptives.

Rh Blood Group D Antigen Genotyping Using a Portable Nanopore-based Sequencing Device: Proof of Principle.

BACKGROUND: Nanopore sequencing is direct sequencing of a single-stranded DNA molecule using biological pores. A portable nanopore-based sequencing device from Oxford Nanopore Technologies (MinION) depends on driving a DNA molecule through nanopores embedded in a membrane using a voltage. Changes in current are then measured by a sensor, thousands of times per second and translated to nucleobases. METHODS: Genomic DNA (gDNA) samples (n = 13) were tested for Rh blood group D antigen (RHD) gene zygosity using droplet digital PCR. The RHD gene was amplified in 6 overlapping amplicons using long-range PCR. Amplicons were purified, and the sequencing library was prepared following the 1D Native barcoding gDNA protocol. Sequencing was carried out with 1D flow cells R9 version. Data analysis included basecalling, aligning to the RHD reference sequence, and calling variants. Variants detected were compared to the results acquired previously by the Ion Personal Genome Machine (Ion PGM). RESULTS: Up to 500× sequence coverage across the RHD gene allowed accurate variant calling. Exonic changes in the RHD gene allowed RHD allele determination for all samples sequenced except 1 RHD homozygous sample, where 2 heterozygous RHD variant alleles are suspected. There were 3 known variant RHD alleles (RHD*01W.02, RHD*11, and RHD*15) and 6 novel RHD variant alleles, as previously seen in Ion PGM sequencing data for these samples. CONCLUSIONS: MinION was effective in blood group genotyping, provided enough sequencing data to achieve high coverage of the RHD gene, and enabled confident calling of variants and RHD allele determination.

Time points and risk factors for RhD immunizations after the implementation of targeted routine antenatal anti-D prophylaxis: A retrospective nationwide cohort study.

INTRODUCTION: Targeted routine antenatal anti-D prophylaxis was introduced to the national prophylaxis program in Finland in late 2013. The aim of this study was to assess the incidence, time-points, and risk factors for Rhesus D immunization after the implementation of routine antenatal anti-D prophylaxis, in all women in Finland with antenatal anti-D antibodies detected in 2014-2017. MATERIAL AND METHODS: In a nationwide population-based retrospective cohort study, the incidence, time-points, and risk factors of anti-D immunizations were analyzed. Information on antenatal screening was obtained from the Finnish Red Cross Blood Service database, and obstetric data from hospital records and the Finnish Medical Birth Register. RESULTS: The study included a total of 228 women (197 with complete data for all pregnancies). After the implementation of routine antenatal anti-D prophylaxis, the prevalence of pregnancies with anti-D antibodies decreased from 1.52% in 2014 to 0.88% in 2017, and the corresponding incidence of new immunizations decreased from 0.33% to 0.10%. Time-points for detection of new anti-D antibodies before and after 2014 were the first screening sample at 8-12 weeks of gestation in 52% vs 19%, the second sample at 24-26 weeks in 20% vs 50%, and the third screening at 36 weeks in 28% vs 32%. CONCLUSIONS: The incidence of new anti-D immunizations decreased as expected after the implementation of routine antenatal anti-D prophylaxis. True failures are rare and they mainly occur when the prophylaxis is not given appropriately, suggesting a need for constant education of healthcare professionals on the subject.

Intrapartal cardiotocographic patterns and hypoxia-related perinatal outcomes in pregnancies complicated by gestational diabetes mellitus.

AIMS: In previous reports, cardiotocographic (CTG) fetal heart rate (FHR) monitoring has shown only limited benefits in decreasing adverse perinatal outcomes in pregnancies complicated by gestational diabetes mellitus (GDM). The aim of the present study was to evaluate whether an association exists between the recently reported ZigZag pattern (FHR baseline amplitude changes of > 25 bpm with a duration of 2-30 min) and asphyxia-related neonatal outcomes in GDM pregnancies. METHODS: Intrapartal CTGs were recorded in a one-year cohort of 5150 singleton childbirths. The following CTG changes were evaluated: ZigZag pattern, saltatory pattern, late decelerations, episodes of tachycardia and bradycardia, reduced variability, and uterine tachysystole. The cohort was divided into three groups: women with GDM, women with normal oral glucose tolerance test (OGTT), and women with no OGTT performed. Umbilical artery (UA) blood gases, Apgar scores, neonatal respiratory distress, and neonatal encephalopathy were used as outcome variables. RESULTS: GDM was diagnosed in 624 (12.1%), OGTT was normal in 4115 (79.9%), and OGTT was not performed in 411 (8.0%) women. Hypoxia-related ZigZag patterns (OR 1.94, 95% CI 1.64-2.34) and late decelerations (OR 1.65, 95% CI 1.27-2.13) of FHR, as well as a greater risk of fetal asphyxia (UA pH < 7.10 and/or UA BE < -12.0 meq/L and/or Apgar scores < 7 at 5-min) (OR 6.64, 95% CI 1.84-12.03) were observed in those with GDM compared with those without GDM. CONCLUSIONS: GDM is associated with intrapartal ZigZag pattern and late decelerations, cord blood acidemia and low 5-min Apgar scores at birth indicating increased occurrence of fetal hypoxia in GDM pregnancies.

Maternal health care utilization and the obstetric outcomes of undocumented women in Finland - a retrospective register-based study.

BACKGROUND: Undocumented pregnant women constitute a vulnerable group of people who lack equal access to pregnancy care. Previous research has shown that undocumented migrants encounter difficulties in accessing health services, the onset of prenatal care is delayed, and women have an increased risk for infectious diseases. The aim of this study was to describe the use of maternal health care services and the obstetric outcomes of undocumented women in Helsinki, capital city of Finland, in addition to comparing the results with all pregnant women in Finland. METHODS: The study was a retrospective register-based study consisting of data collected between 2014 to 2018 from the electronic medical records of the public maternity clinic and maternity hospital in Helsinki, Finland. The study population consists of 62 individual pregnancies of undocumented women. The results of the study were compared with national data on parturients and deliveries (N = 47,274 women) and with prenatal screening tests for infectious diseases (N = 51,447 [HIV, HBV], N = 51,446 [syphilis]). RESULTS: The majority (91%) of the undocumented women attended public prenatal care. However, four women received no prenatal care and three women were denied access to care. Undocumented women entered prenatal care later and had fewer visits compared with all pregnant women. The majority (71%) of the undocumented women received inadequate prenatal care as the number of visits was less than eight. Of the study population, 5% (3/59) tested positive for HIV, 3% (2/59) for HBV, and 2% (1/57) for syphilis. The prevalence of HIV (p-value < 0.001) and HBV (p-value = 0.007) was significantly higher amongst undocumented women compared with all pregnant women. CONCLUSIONS: Undocumented women entered prenatal care later than recommended. Most women received inadequate prenatal care and some of them did not receive prenatal care at all. The prevalence of infectious diseases was significantly higher and the coverage of prenatal screenings deficient amongst undocumented pregnant women.

Factors associated with intrapartum ZigZag pattern of fetal heart rate: A retrospective one-year cohort study of 5150 singleton childbirths.

OBJECTIVES: Recent studies suggest that intrapartum ZigZag pattern of fetal heart rate (FHR) is significantly associated with cord blood acidaemia and neonatal complications. For the clinical significance of this pattern, it is mandatory that ZigZag episodes in cardiotocographic (CTG) recording are correctly identified. The aim of the present study was to examine maternal, fetal and delivery-related factors that could explain the occurrence of ZigZag pattern of FHR during the last 2 h of labour in a large obstetric cohort. STUDY DESIGN: CTG recordings from 5150 singleton childbirths at ≥33 weeks of gestation during one year were evaluated retrospectively and blinded to pregnancy and neonatal outcomes in a university hospital in Helsinki, Finland. All women in the cohort were in the active phase of labour with regular uterine contractions. ZigZag FHR pattern was defined as FHR baseline amplitude changes of >25 bpm with a duration of 2-30 min. The following maternal, fetal and labour/delivery-related variables were determined: maternal age, obesity (prepregnancy BMI ≥ 30.0 kg/m2), parity, preeclampsia, maternal fever ≥38.0 °C, smoking, gestational age at delivery, fetal sex, birth weight z-score, mode of delivery, and type of onset of labour. RESULTS: ZigZag pattern occurred in 582/5150 (11.3 %) cases, and only in childbirths after 37 weeks of gestation. Fetal male gender (OR 3.29; 95 % CI 2.70-4.02), nulliparous pregnancy (OR 2.60; 95 % CI 2.15-3.15) and post-term gestational age (≥42 weeks) (OR 1.92; 95 % CI 1.47-2.48) were independently associated with the occurrence of ZigZag pattern. Among the three significant risk factors, clustering of two or three factors was associated with an increase of the ZigZag pattern occurrence risk to 5.0-16.4-fold (95 % CI 3.16-31.60). CONCLUSIONS: ZigZag pattern occurred in term pregnancies after 37 weeks of gestation only. Fetal male gender, nulliparity and post-term pregnancy are significantly associated with ZigZag FHR pattern during the last two hours of labour. Identification of maternal, fetal and delivery-related variables are imperative in order to interpret correctly the findings of CTG and to prevent adverse neonatal outcome.

Afucosylated IgG characterizes enveloped viral responses and correlates with COVID-19 severity.

Immunoglobulin G (IgG) antibodies are crucial for protection against invading pathogens. A highly conserved N-linked glycan within the IgG-Fc tail, which is essential for IgG function, shows variable composition in humans. Afucosylated IgG variants are already used in anticancer therapeutic antibodies for their increased activity through Fc receptors (FcγRIIIa). Here, we report that afucosylated IgG (approximately 6% of total IgG in humans) are specifically formed against enveloped viruses but generally not against other antigens. This mediates stronger FcγRIIIa responses but also amplifies brewing cytokine storms and immune-mediated pathologies. Critically ill COVID-19 patients, but not those with mild symptoms, had high concentrations of afucosylated IgG antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), amplifying proinflammatory cytokine release and acute phase responses. Thus, antibody glycosylation plays a critical role in immune responses to enveloped viruses, including COVID-19.

Intrapartum zigzag pattern of fetal heart rate is an early sign of fetal hypoxia: A large obstetric retrospective cohort study.

INTRODUCTION: The aim of the present study was to identify possible associations of fetal heart rate (FHR) patterns during the last 2 hours of labor with fetal asphyxia expressed by umbilical artery acidemia at birth and with neonatal complications in a large obstetric cohort. MATERIAL AND METHODS: Cardiotocographic recordings from 4988 singleton term childbirths over 1 year were evaluated retrospectively and blinded to the pregnancy and neonatal outcomes in a university teaching hospital in Helsinki, Finland. Umbilical artery pH, base excess and pO2 , low Apgar scores at 5 minutes, need for intubation and resuscitation, early neonatal hypoglycemia, and neonatal encephalopathy were used as outcome variables. According to the severity of the neonatal complications at birth, the cohort was divided into three groups: no complications (Group 1), moderate complications (Group 2) and severe complications (Group 3). RESULTS: Of the 4988 deliveries, the ZigZag pattern (FHR baseline amplitude changes of >25 bpm with a duration of 2-30 minutes) occurred in 11.7%, late decelerations in 41.0%, bradycardia episodes in 52.9%, reduced variability in 36.7%, tachycardia episodes in 13.9% and uterine tachysystole in 4.6%. No case of saltatory pattern (baseline amplitude changes of >25 bpm with a duration of >30 minutes) was observed. The presence of the ZigZag pattern or late decelerations, or both, was associated with cord blood acidemia (odds ratio [OR] 3.3, 95% confidence interval [CI] 2.3-4.7) and severe neonatal complications (Group 3) (OR 3.3, 95% CI 2.4-4.9). In contrast, no significant associations existed between the other FHR patterns and severe neonatal complications. ZigZag pattern preceded late decelerations in 88.7% of the cases. A normal FHR preceded the ZigZag pattern in 90.4% of the cases, whereas after ZigZag episodes, a normal FHR pattern was observed in only 0.9%. CONCLUSIONS: ZigZag pattern and late decelerations during the last 2 hours of labor are significantly associated with cord blood acidemia at birth and neonatal complications. The ZigZag pattern precedes late decelerations, and the fact that normal FHR pattern precedes the ZigZag pattern in the majority of the cases suggests that the ZigZag pattern is an early sign of fetal hypoxia, which emphasizes its clinical importance.

Next-generation sequencing of 35 RHD variants in 16 253 serologically D- pregnant women in the Finnish population.

Fetal RHD screening for targeted routine antenatal anti-D prophylaxis has been implemented in many countries, including Finland, since the 2010s. Comprehensive knowledge of the RHD polymorphism in the population is essential for the performance and safety of the anti-D prophylaxis program. During the first 3 years of the national screening program in Finland, over 16 000 samples from RhD- women were screened for fetal RHD; among them, 79 samples (0.5%) containing a maternal variant allele were detected. Of the detected maternal variants, 35 cases remained inconclusive using the traditional genotyping methods and required further analysis by next-generation sequencing (NGS) of the whole RHD gene to uncover the variant allele. In addition to the 13 RHD variants that have been previously reported in different populations, 8 novel variants were also detected, indicating that there is more variation of RHD in the RhD- Finnish population than has been previously known. Three of the novel alleles were identified in multiple samples; thus, they are likely specific to the original Finnish population. National screening has thus provided new information about the diversity of RHD variants in the Finnish population. The results show that NGS is a powerful method for genotyping the highly polymorphic RHD gene compared with traditional methods that rely on the detection of specific nucleotides by polymerase chain reaction amplification.

Saltatory Pattern of Fetal Heart Rate during Labor Is a Sign of Fetal Hypoxia.

BACKGROUND: While late decelerations and major bradycardia episodes in intrapartum cardiotocography (CTG) recordings are known to correlate with fetal distress,little is known of the importance of the saltatory pattern. OBJECTIVE: The aim of the study was to examine whether the fetal heart rate (FHR) saltatory pattern in intrapartum CTG registration is associated with fetal hypoxia during the last 2 h of labor. DESIGN: The study group consisted of CTG recordings from 194 births with a 1-min Apgar score of <8 (birth weight 3,614 ± 512 g; gestational age 40.6 ± 0.7 weeks). The comparison group included 51 infants with a 1-min Apgar score of ≥9 (birth weight 3,624 ± 400 g; gestational age 40.5 ± 0.4 weeks). FHR patterns were evaluated blindly by 2 experienced perinatologists. The pH, base excess (BE), pO2 and erythropoietin (EPO) were measured from umbilical cord blood at birth as outcome variables. RESULTS: Saltatory pattern occurred in 31/194 (16.0%) of the study group and in 1/51 (2.0%) of the comparison group. Umbilical artery pH, BE, and pO2 were lower and umbilical vein (UV) EPO higher in the study group than in the comparison group. In the study group, UV EPO level was significantly higher in cases where the saltatory pattern was present (median 241 mU/mL, 95% CI 39.4-16,484), than in those without the saltatory pattern (median 39.4 mU/mL, 95% CI 11-282) (p < 0.0001, for difference). In the study group, no differences in EPO levels were found in cases where episodes of bradycardia, tachycardia, reduced variability, or uterine tachysystole were present or absent. In the study group, saltatory pattern preceded late decelerations in 82.8%. CONCLUSION: Saltatory pattern in an intrapartum FHR recording is an early sign of fetal hypoxia.

Targeted antenatal anti-D prophylaxis program for RhD-negative pregnant women - outcome of the first two years of a national program in Finland.

INTRODUCTION: The aim of this study was to assess the accuracy of the non-invasive fetal RHD test at 24-26 weeks of gestation as part of the national antenatal screening program to target routine antenatal anti-D prophylaxis (RAADP) at 28-30 weeks at women carrying an RhD-positive fetus. MATERIAL AND METHODS: A prospective cohort study involving all maternity care centers and delivery hospitals in Finland between February 2014 and January 2016. Fetal RHD genotyping using cell-free fetal DNA in maternal plasma was performed with real-time polymerase chain reaction in a centralized setting. The results were systematically compared with the serological newborn RhD typing. The main outcome measure was the accuracy of the fetal RHD assay; the secondary variable was compliance with the newly introduced RAADP program. RESULTS: Fetal RHD was screened from 10 814 women. For the detection of fetal RHD, sensitivity was 99.99% [95% confidence interval (CI) 99.92-99.99] and specificity 99.81% (95% CI 99.60-99.92). One false-negative and seven false-positive results were reported by the delivery hospitals in two years. The negative predictive value of the test was 99.97% (95% CI 99.81-99.99). At the end of the study period, over 98% of the RhD-negative women participated in the new screening program. CONCLUSIONS: The targeted RAAPD program was implemented effectively in the national maternity care program in Finland. An accurate fetal RHD screening test allows discontinuation of newborn testing without risking the postnatal prophylaxis program. In the future, the main area to investigate will be the clinical effect of RAADP on subsequent pregnancies.

Maternal HLA genotyping is not useful for predicting severity of fetal and neonatal alloimmune thrombocytopenia.

Lack of reliable laboratory parameters is the main challenge in the management of fetal and neonatal alloimmune thrombocytopenia (FNAIT). Despite the long-known association between the HLA-DRB3*01:01 allele and human platelet antigen 1a (HPA-1a) alloimmunisation, maternal human leucocyte antigen (HLA) typing has been of little clinical value. Recently, other DRB3 allele variants have been suggested to predict the severity of FNAIT. In this nationwide population-based retrospective cohort study, we performed extensive HLA typing of 96 women, accounting for 87% of our cohort of 110 families with confirmed or possible HPA-1a-immunisation. The HLA type was compared with anti-HPA-1a levels, severity of neonatal disease and responsiveness to maternally administrated intravenous gammaglobulin (IVIG). HLA haplotypes were constructed to investigate further HLA associations. Despite significantly lower anti-HPA-1a levels in DRB3*01:01-negative women, the carrier status of this particular allele could not be used to confirm or rule out FNAIT in the absence of detectable antibodies. In the haplotype analysis, the DRB3*01:01 allele was the actual factor associated with FNAIT. No other HLA allele was shown to be of additional value as a predictor of severe FNAIT or non-responsiveness to IVIG treatment. Thus, HLA genotyping was not found useful in differentiating high- and low-risk pregnancies or in guiding antenatal treatment in affected families.

At what age does the risk for adverse maternal and infant outcomes increase? Nationwide register-based study on first births in Finland in 2005-2014.

INTRODUCTION: It is poorly understood if there are specific ages at which adverse outcomes during pregnancy and childbirth start to increase (threshold-ages). The purpose of this study was to examine at which maternal ages the use of maternity care and the risks for adverse maternal and infant outcomes increase. MATERIAL AND METHODS: National data from the Finnish Medical Birth Register including all first-time mothers aged 20 years or over with singleton pregnancies in 2005-2014 were analyzed (n = 228 348). Odds ratios for each outcome at different ages were calculated by logistic regression, using women aged 20-24 (n = 56 282) as the reference and adjusting for socioeconomic position and urbanity of residence. The threshold-age was defined as the first significant adjusted odds ratio after which the risk remained significant. RESULTS: The threshold-ages for use of maternity care varied from 25 years for cesarean section (OR 1.08, 95% CI 1.03-1.14) to 38 years for having 16 or more antenatal visits (1.13, 1.04-1.21). Four threshold-ages were found for maternal health outcomes: 25 years for gestational diabetes (OR 1.15, 1.09-1.23), 27 years for placenta previa (OR 1.75, 1.11-2.75), 33 years for gestational hypertension (1.14, 1.03-1.27), and 38 years for preeclampsia (OR 1.48, 1.12-1.96). The threshold-ages for infant health outcomes varied from 28 years for preterm birth (37 weeks, OR 1.10, 1.02-1.19) to 36 years for perinatal mortality (OR 2.10, 1.44-3.07). CONCLUSIONS: Different threshold-ages were identified. Most adverse outcomes occurred earlier than the traditional cut-off ages for high risk pregnancy, which have been set at 35 or 40 years.

Glycosylation pattern of anti-platelet IgG is stable during pregnancy and predicts clinical outcome in alloimmune thrombocytopenia.

Fetal or neonatal alloimmune thrombocytopenia (FNAIT) is a potentially life-threatening disease where fetal platelets are destroyed by maternal anti-platelet IgG alloantibodies. The clinical outcome varies from asymptomatic, to petechiae or intracranial haemorrhage, but no marker has shown reliable correlation with severity, making screening for FNAIT impractical and highly inefficient. We recently found IgG Fc-glycosylation towards platelet and red blood cell antigens to be skewed towards decreased fucosylation, increased galactosylation and sialylation. The lowered core-fucosylation increases the affinity of the pathogenic antibodies to FcγRIIIa and FcγRIIIb, and hence platelet destruction. Here we analysed the N-linked glycans of human platelet antigen (HPA)-1a specific IgG1 with mass spectrometry in large series of FNAIT cases (n = 166) including longitudinal samples (n = 26). Besides a significant decrease in Fc-fucosylation after the first pregnancy (P = 0·0124), Fc-glycosylation levels remained stable during and after pregnancy and in subsequent pregnancies. Multiple logistic regression analysis identified anti-HPA-1a -fucosylation (P = 0·006) combined with galactosylation (P = 0·021) and antibody level (P = 0·038) correlated with bleeding severity, making these parameters a feasible marker in screening for severe cases of FNAIT.

[Where to find a suitable red cell product, if the patient has a rare blood group?]. / Mistä sopiva punasoluvalmiste, jos potilaalla on harvinainen veriryhmä?

A rare blood group and the associated anti-red cell antibody against a very common blood group factor make it significantly more difficult to find suitable red cell products, possibly endangering the additional treatment of the patient. The need of rare blood should be anticipated early enough. The availability of red cells is secured by extensive blood group studies among blood donors, by donor registers, freezing of rare red cells and through international collaboration. The determination of rare blood groups by genotyping provides a longed-for addition to the investigational repertoire of both patients and blood donors. Systematic freezing of red cells was started in Finland in 2010.

Diagnosis and treatment of severe hemolytic disease of the fetus and newborn: a 10-year nationwide retrospective study.

OBJECTIVE: Outcome after intrauterine transfusions due to severe hemolytic disease of the fetus and newborn. DESIGN: Nationwide population-based retrospective cohort study. SETTING: All women treated with intrauterine transfusions for hemolytic disease of the fetus and newborn in Finland in 2003-2012. POPULATION: 339 intrauterine transfusions, performed in 104 pregnancies of 84 women. METHODS: Information on antenatal screening of red cell antibodies and red cell units issued for intrauterine transfusion was obtained from the Finnish Red Cross Blood Service database, and obstetric and neonatal data from hospital records. MAIN OUTCOME MEASURES: Procedure-related complications, perinatal mortality, neonatal morbidity. RESULTS: Overall survival was 94.2% (95% confidence interval 89.7-98.7). There were four fetal and two neonatal deaths. Procedure-related fetal loss rate was 1.2% (95% confidence interval 0.04-2.4) per procedure and 3.8% (95% confidence interval 0.1-7.5) per pregnancy. Of the four procedure-related losses, three were due to technically difficult intrauterine transfusions causing infection and preterm birth. Of the live born infants, 19% (95% confidence interval 11.3-26.7) were born before 32 weeks' gestation. The incidence of severe neonatal morbidity (respiratory distress syndrome, severe cerebral injury, sepsis) was 22.2% (95% confidence interval 13.4-30.2). Poor outcome (death, severe neonatal morbidity) was negatively associated with gestational age at first transfusion (p = 0.001) and at birth (p = 0.00006). Follow-up of the infants was too incomplete to assess the neurodevelopmental outcome. CONCLUSIONS: Although overall survival is comparable with previous studies, our concern is procedure-related infections and preterm births. Close collaboration between the university hospitals is needed to ensure timely treatment, operator skills and systematic follow-up of the children.

Case report: Severe hemolytic disease of the fetus and newborn due to anti-C+G.

Anti-G is commonly present with anti-D and/or anti-C and can confuse serological investigations. in general, anti-G is not considered a likely cause of severe hemolytic disease of the fetus and newborn (HDFN), but it is important to differentiate it from anti-D in women who should be administered anti-D immunoglobulin prophylaxis. We report one woman with three pregnancies severely affected by anti-C+G requiring intrauterine treatment and a review of the literature. In our case, the identification of the correct antibody was delayed because the differentiation of anti-C+G and anti-D+C was not considered important during pregnancy since the father was D-. In addition, anti-C+G and anti-G titer levels were not found to be reliable as is generally considered in Rh immunization. Severe HDFN occurred at a maternal anti-C+G antibody titer of S and anti-G titer of 1 in comparison with the critical titer level of 16 or more in our laboratory. close collaboration between the immunohematology laboratory and the obstetric unit is essential. In previously affected families, early assessment for fetal anemia is required even when titers are low.

Fetal intracranial haemorrhages caused by fetal and neonatal alloimmune thrombocytopenia: an observational cohort study of 43 cases from an international multicentre registry.

OBJECTIVE: To characterise pregnancies where the fetus or neonate was diagnosed with fetal and neonatal alloimmune thrombocytopenia (FNAIT) and suffered from intracranial haemorrhage (ICH), with special focus on time of bleeding onset. DESIGN: Observational cohort study of all recorded cases of ICH caused by FNAIT from the international No IntraCranial Haemorrhage (NOICH) registry during the period 2001-2010. SETTING: 13 tertiary referral centres from nine countries across the world. PARTICIPANTS: 37 mothers and 43 children of FNAIT pregnancies complicated by fetal or neonatal ICH identified from the NOICH registry was included if FNAIT diagnosis and ICH was confirmed. PRIMARY AND SECONDARY OUTCOME MEASURES: Gestational age at onset of ICH, type of ICH and clinical outcome of ICH were the primary outcome measures. General maternal and neonatal characteristics of pregnancies complicated by fetal/neonatal ICH were secondary outcome measures. RESULTS: From a total of 592 FNAIT cases in the registry, 43 confirmed cases of ICH due to FNAIT were included in the study. The majority of bleedings (23/43, 54%) occurred before 28 gestational weeks and often affected the first born child (27/43, 63%). One-third (35%) of the children died within 4 days after delivery. 23 (53%) children survived with severe neurological disabilities and only 5 (12%) were alive and well at time of discharge. Antenatal treatment was not given in most (91%) cases of fetal/neonatal ICH. CONCLUSIONS: ICH caused by FNAIT often occurs during second trimester and the clinical outcome is poor. In order to prevent ICH caused by FNAIT, at-risk pregnancies must be identified and prevention and/or interventions should start early in the second trimester.