The REPAIR study: oral antibiotics to prevent infection and wound dehiscence after obstetric perineal tear-a double-blinded placebo controlled randomized trial.

BACKGROUND: Approximately 85% of women experience an obstetric tear at delivery and up to 25% subsequently experience wound dehiscence and/or infection. Previous publications suggest that intravenous antibiotics administrated during delivery reduces this risk. We do not know if oral antibiotics given after delivery can reduce the risk of wound dehiscence or infection. Our aim is to investigate whether three doses of oral antibiotics (amoxicillin 500 mg/clavulanic acid 125 mg) given after delivery can reduce the risk of wound dehiscence and infection in patients with a second-degree obstetric tear or episiotomy. METHODS: We will perform a randomized, controlled, double-blinded study including 221women in each arm with allocation 1:1 in relation to the randomization. The study is carried out at Department of Obstetrics & Gynecology, Herlev University Hospital, Copenhagen, Denmark. The women will be included after delivery if they have had a second-degree tear or episiotomy. After inclusion, the women will have a clinical follow-up visit after 1 week. The tear and healing will be evaluated regarding signs of infection and/or dehiscence. The women will again be invited for a 1-year clinical examination including ultrasound. Questionnaires exploring symptoms related to the obstetric tear and possible complications will be answered at both visits. Our primary outcome is wound dehiscence and/or wound infection, which will be calculated using χ2 tests to compare groups. Secondary outcomes are variables that relate to wound healing, as pain, use of painkillers and antibiotics, need for further follow-up, as well as outcomes that may be related to the birth or healing process, urinary or anal incontinence, symptoms of prolapse, female body image, and sexual problems. DISCUSSION: Reducing the risk of wound dehiscence and/or infection would decrease the number of control visits, prevent the need for longer antibiotic treatment, and possibly also decrease both short-term and long-term symptoms. This would be of great importance so the mother, her partner, and the baby could establish and optimize their initial family relation. TRIAL REGISTRATION: The conduction of this study is approved the 2/2-2023 with the EU-CT number: 2022-501930-49-00. CLINICALTRIALS: gov Identifier: NCT05830162.

Hunting for the elusive target antigen in gestational alloimmune liver disease (GALD).

The prevailing concept is that gestational alloimmune liver disease (GALD) is caused by maternal antibodies targeting a currently unknown antigen on the liver of the fetus. This leads to deposition of complement on the fetal hepatocytes and death of the fetal hepatocytes and extensive liver injury. In many cases, the newborn dies. In subsequent pregnancies early treatment of the woman with intravenous immunoglobulin can be instituted, and the prognosis for the fetus will be excellent. Without treatment the prognosis can be severe. Crucial improvements of diagnosis require identification of the target antigen. For this identification, this work was based on two hypotheses: 1. The GALD antigen is exclusively expressed in the fetal liver during normal fetal life in all pregnancies; 2. The GALD antigen is an alloantigen expressed in the fetal liver with the woman being homozygous for the minor allele and the father being, most frequently, homozygous for the major allele. We used three different experimental approaches to identify the liver target antigen of maternal antibodies from women who had given birth to a baby with the clinical GALD diagnosis: 1. Immunoprecipitation of antigens from either a human liver cell line or human fetal livers by immunoprecipitation with maternal antibodies followed by mass spectrometry analysis of captured antigens; 2. Construction of a cDNA expression library from human fetal liver mRNA and screening about 1.3 million recombinants in Escherichia coli using antibodies from mothers of babies diagnosed with GALD; 3. Exome/genome sequencing of DNA from 26 presumably unrelated women who had previously given birth to a child with GALD with husband controls and supplementary HLA typing. In conclusion, using the three experimental approaches we did not identify the GALD target antigen and the exome/genome sequencing results did not support the hypothesis that the GALD antigen is an alloantigen, but the results do not yield basis for excluding that the antigen is exclusively expressed during fetal life., which is the hypothesis we favor.

Perineal resuturing versus conservative treatment for dehisced perineal wounds and episiotomies: a systematic review and meta-analysis.

INTRODUCTION AND HYPOTHESIS: Perineal wound dehiscence is associated with complications, such as infections, perineal pain, dyspareunia, and altered sexual function, that severely affects women's health. Currently, few studies have examined secondary repair of first- and second-degree perineal wound dehiscence and episiotomies, and there is currently no consensus on the optimal treatment option for dehisced perineal wounds. The objective was to evaluate whether resuturing or conservative treatment of first- and second-degree dehisced perineal wounds and episiotomies is the optimal treatment modality in terms of postoperative healing time and other secondary outcomes. METHODS: A systematic literature search was carried out using PubMed, Embase, and Cochrane databases. All included studies were evaluated using the SIGN methodology checklist, with the purpose of assessing the study quality. RESULTS: Three randomized controlled trials were included. Only two small sample-sized studies presented data regarding healing time for both the resuturing and the conservative treatment groups. However, no significant difference was found between the two groups at 4-6 weeks' healing time (RR 1.16, 95% CI 0.53-2.52). One study found that women being resutured experienced a significantly reduced healing time and higher satisfaction with the appearance of the wound healing at 3 months compared with the conservative treatment group. CONCLUSION: We found no significant differences in the healing time between the resuturing group and the conservative treatment group. However, the sample sizes of the studies were small. A well-designed, large, and prospective randomized controlled trial is needed to evaluate the optimal treatment modality for dehisced perineal wounds.

Does fetal sex influence the risk of venous thrombosis in pregnancy? A cohort study.

BACKGROUND: Venous thromboembolism is a prominent cause of maternal death. OBJECTIVE: As inflammation is a well-known risk factor for venous thromboembolism and several studies have found a higher grade of inflammation in pregnancies bearing a male compared with female fetuses, we investigated the risk of pregnancy-related venous thromboembolism associated with sex of the fetus. METHODS: This cohort study linked data from national registries and compared event rates and hazard ratios of venous thrombosis for pregnancies bearing a male fetus with those bearing a female fetus during pregnancy and in the first 3 months postpartum. National data from 1995 to 2017 were used. All Danish women aged 15 to 49 years with a live or stillbirth were eligible for inclusion; 1 370 583 pregnancies were included. Women with venous thrombosis, ischemic heart disease, cerebrovascular disease, thrombophilia, or cancer before conception were excluded. RESULTS: The event rate for a venous thrombosis was 8.0 per 10.000 pregnancy years with a male fetus compared with 6.8 for a female fetus. The adjusted hazard ratio for venous thrombosis during pregnancies bearing a male was 1.2 (95% CI, 1.1-1.4), whereas in the postpartum period, it was 0.9 (95% CI, 0.7-1.0). The risk was elevated until week 30. CONCLUSION: These findings indicate a slightly greater risk of venous thrombosis during pregnancies bearing a male fetus than during pregnancies bearing a female fetus. There was no increased risk associated with fetal male sex in the postpartum period.

Non-Invasive Fetal K Status Prediction: 7 Years of Experience.

Introduction: In the Kell blood group system, the K and k antigens are the clinically most important ones. Maternal anti-K IgG antibodies can lead to the demise of a K-positive fetus in early pregnancy. Intervention can save the fetus. Prenatal K status prediction of the fetus in early pregnancy is desirable and gives a good basis for pregnancy risk management. We present the results from 7 years of clinical experience in predicting fetal K status as well as some theoretical considerations relevant for design of the assay and evaluation of results. Methods: Blood was collected from 43 women, all immunized against K, at a mean gestational age of 18 weeks (range 10-38). A total of 56 consecutive samples were tested. The KEL *01.01 /KEL *02 single nucleotide variant that determines K status was amplified from maternal plasma DNA by PCR without allele specificity. The PCR product was sequenced by NGS technology, and the number of sequenced KEL *01.01 and KEL *02 reads were counted. Prediction of the fetal K status was based on this count and was compared with the serologically determined K status of the newborns. Results: All fetal K predictions were in accordance with postnatal serology where available (n = 34), using our current data analysis. Conclusion: We have developed an NGS-based method for the non-invasive prediction of fetal K status. This approach requires special considerations in terms of primer design, stringent preanalytical sample handling, and careful analytical procedures. We analyzed samples starting at GA 10 weeks and demonstrated the correct prediction of fetal K status. This assay enables timely clinical intervention in pregnancies at risk of hemolytic disease of the fetus and newborn caused by maternal anti-K IgG antibodies.

Iron supplementation during the first trimester of pregnancy after a national change of recommendation: a Danish cross-sectional study.

In 2013, the Danish Health Authorities recommended a change in prophylactic iron supplementation to 40-50 mg/d from gestational week 10. Hence, the aims of the present study were (1) to estimate the prevalence of women who follow the Danish recommendation on iron supplementation during the last 3 weeks of the first trimester of pregnancy and (2) to identify potential sociodemographic, reproductive and health-related pre-pregnancy predictors for iron supplementation during the first trimester. We conducted a cross-sectional study with data from the hospital-based Copenhagen Pregnancy Cohort. Characteristics were analysed by descriptive statistics and multivariable logistic regression analysis was performed to examine the associations between predictors and iron supplementation during the last 3 weeks of the first trimester. The study population consisted of 23 533 pregnant women attending antenatal care at Copenhagen University Hospital - Rigshospitalet from October 2013 to May 2019. The prevalence of iron supplementation according to recommendations was 49⋅1 %. The pre-pregnancy factors of ≥40 years of age, the educational level below a higher degree and a vegetarian or vegan diet were identified as predictors for iron supplementation during the first trimester of pregnancy. Approximately half of the women were supplemented with the recommended dose of iron during the first trimester of pregnancy. We identified pre-pregnancy predictors associated with iron supplementation. Interventions that target women of reproductive age are needed. An enhanced focus on iron supplementation during pregnancy should be incorporated in pre-pregnancy and interpregnancy counselling.

How often will midwives and obstetricians experience obstetric emergencies or high-risk deliveries: a national cross-sectional study.

OBJECTIVE: To estimate how often midwives, specialty trainees and doctors specialised in obstetrics and gynaecology are attending to specific obstetric emergencies or high-risk deliveries (obstetric events). DESIGN: A national cross-sectional study. SETTING: All hospital labour wards in Denmark. PARTICIPANTS: Midwives (n=1303), specialty trainees (n=179) and doctors specialised in obstetrics and gynaecology (n=343) working in hospital labour wards (n=21) in Denmark in 2018. METHODS: Categories of obstetric events comprised of Apgar score <7/5 min, eclampsia, emergency caesarean sections, severe postpartum haemorrhage, shoulder dystocia, umbilical cord prolapse, vaginal breech deliveries, vaginal twin deliveries and vacuum extraction. Data on number of healthcare professionals were obtained through the Danish maternity wards, the Danish Health Authority and the Danish Society of Obstetricians and Gynaecologists. We calculated the time interval between attending each obstetric event by dividing the number of events occurred with the number of healthcare professionals. OUTCOME MEASURES: The time interval between attending a specific obstetric event. RESULTS: The average time between experiencing obstetric events ranged from days to years. Emergency caesarean sections, which occur relatively frequent, were attended on average every other month by midwives, every 9 days for specialty trainees and every 17 days by specialist doctors. On average, rare events like eclampsia were experienced by midwives only every 42 years, every 6 years by specialty trainees and every 11 years by specialist doctors. CONCLUSIONS: Some obstetric events occur extremely rarely, hindering the ability to obtain and maintain the clinical skills to manage them through clinical practice alone. By assessing the frequency of a healthcare professionals attending an obstetric emergency, our study contributes to assessing the need for supplementary educational initiatives and interventions to learn and maintain clinical skills.

Laboratory Monitoring of Mother, Fetus, and Newborn in Hemolytic Disease of Fetus and Newborn.

BACKGROUND: Laboratory monitoring of mother, fetus, and newborn in hemolytic disease of fetus and newborn (HDFN) aims to guide clinicians and the immunized women to focus on the most serious problems of alloimmunization and thus minimize the consequences of HDFN in general and of anti-D in particular. Here, we present the current approach of laboratory screening and testing for prevention and monitoring of HDFN at the Copenhagen University Hospital in Denmark. SUMMARY: All pregnant women are typed and screened in the 1st trimester. This serves to identify the RhD-negative pregnant women who at gestational age (GA) of 25 weeks are offered a second screen test and a non-invasive fetal RhD prediction. At GA 29 weeks, and again after delivery, non-immunized RhD-negative women carrying an RhD-positive fetus are offered Rh immunoglobulin. If the 1st trimester screen reveals an alloantibody, antenatal investigation is initiated. This also includes RhD-positive women with alloantibodies. Specificity and titer are determined, the fetal phenotype is predicted by non-invasive genotyping based on cell-free DNA (RhD, K, Rhc, RhC, RhE, ABO), and serial monitoring of titer commences. Based on titers and specificity, monitoring with serial peak systolic velocity measurements in the fetal middle cerebral artery to detect anemia will take place. Intrauterine transfusion is given when fetal anemia is suspected. Monitoring of the newborn by titer and survival of fetal red blood cells by flow cytometry will help predict the length of the recovery of the newborn.

[Pregnant woman with renal cancer treated with simultaneous section and partial nephrectomy].

This is a case report of a 43-year-old pregnant woman, who in 26+0 was referred to a department of urology on suspicion of a kidney tumor. A CT scan of chest and abdomen showed a 7 cm tumor in the right kidney without signs of metastases. Biopsy revealed a clear cell renal cell carcinoma. The patient was treated in week 32+0 by a joint venture between a department of urology and a department of obstetrics with a midline incision caesarean followed by a right-sided open partial nephrectomy. The delivery of the baby was uncomplicated. The patient showed no signs of relapse in her control regiment after 1,5 years of observation.

[Severe foetal anaemia caused by undetected alloimmunisation in a RhD-positive pregnant woman].

The incidence of haemolytic disease of the foetus or newborn (HDFN) has decreased considerably in Denmark since the introduction of routine administration of prophylactic anti-D immunoglobulin to RhD-negative pregnant women carrying a RhD-positive foetus. RhD-positive pregnant women are screened for irregular antibodies only in the first trimester of their pregnancy, as their risk of clinically relevant immunisation during pregnancy has been considered very low. This is a case report of severe undetected alloimmunisation causing fatal HDFN after the first trimester in a RhD-positive woman.

Prenatal prediction of fetal Rh C, c and E status by amplification of maternal cfDNA and deep sequencing.

BACKGROUND: The Rh blood group system has considerable clinical importance. The C, c, and E antigens are targets of alloantibodies. Anti-C, anti-c or anti-E alloreactive antibodies produced in pregnant women can cause anemia of a fetus carrying the corresponding antigens. AIMS: Based on NGS technology, we have developed a noninvasive diagnostic assay to predict the fetal blood group of C, c or E antigens by sequencing cell-free DNA (cfDNA) during pregnancy. MATERIALS AND METHODS: The SNVs underlying either the C, c or E antigens were PCR amplified and sequenced using NGS on a MiSeq instrument. The DNA sequences encoding the C, c or E antigen were counted, as were the number of total sequences. Based on the percentage of fetally derived target SNVs inherited from the father, the fetal blood group could be predicted. RESULTS: The results of 55 consecutive RHCE prenatal analyses with postnatal serological blood group determination of 30 newborns showed no discordant results. A threshold discerning positive from negative samples was set at 0.05% specific reads. DISCUSSION: Noninvasive, prenatal prediction of fetal blood groups by sequencing cfDNA for the detection of low-level RHCE*C, RHCE*c and RHCE*E sequences was established as an accurate and robust assay applicable for use in clinical settings.

Therapeutic concentration of ciprofloxacin and transfer across the human term placenta.

BACKGROUND: Pregnant women have an increased risk of infections, and early and decisive treatment is preferred to prevent complications. Although ciprofloxacin is very commonly used, safety aspects of maternal treatment during pregnancy are limited, and avoidance of its use during late pregnancy is recommended. OBJECTIVE: The aim is to estimate maternal-to-fetal transfer clearance of ciprofloxacin at a therapeutic concentration and to determine fetal exposure to maternally administered ciprofloxacin. STUDY DESIGN: Transplacental pharmacokinetics were determined with an ex vivo placental model, which is a reliable experimental model for estimating fetal drug exposure. Human placentas from uncomplicated term pregnancies were collected after delivery and a suitable cotyledon was cannulated. Ciprofloxacin was added at a therapeutic concentration (1.6 µg/mL) to the maternal compartment, and antipyrine was included as a reference drug (10.0 µg/mL). Samples were collected from the maternal and fetal compartment at 12 time points (-2 to 180 minutes), and the integrity and metabolic parameters were measured consecutively. Drug concentrations were determined using ultra-performance liquid chromatography-tandem mass spectrometry. RESULTS: A total of 5 human placentas from healthy term pregnancies were collected after delivery and cannulated with success. Ciprofloxacin crossed the placenta; its mean concentration in the fetal compartment was 0.3 µg/mL, accounting for 22% (0.29/1.30; range, 15%-31%) of the maternal concentration after 3 hours. The fetal/maternal ciprofloxacin concentration ratio increased gradually over time and reached 0.53. The transfer clearance for ciprofloxacin was 0.28 mL/min (range, 0.21-0.41 mL/min) during the first hour and 0.21 mL/min (range, 0.14-0.26 mL/min) during the following 2 hours. After end perfusion, the mean tissue concentration and proportion of ciprofloxacin were 0.7 µg/g and 11% (14/130; range, 7%-14%), respectively. CONCLUSION: Ciprofloxacin crossed the placenta at a slow, constant rate, indicating moderate fetal exposure. This study verifies an accumulation of ciprofloxacin in the placenta that may lengthen the duration of fetal exposure. These results are an essential element of fetal risk assessment, but further studies are needed to estimate fetal safety.

Prediction of ABO hemolytic disease of the newborn using pre- and perinatal quantification of maternal anti-A/anti-B IgG titer.

BACKGROUND: Hemolysis in fetus/newborns is often caused by maternal antibodies. There are currently no established screening procedures for maternal ABO antibodies harmful to fetus/newborn. We investigated the clinical significance, and predictive value of maternal anti-A/B titer for hyperbilirubinemia in ABO-incompatible newborns. METHODS: We conducted a case-control study of blood group O mothers and their ABO-compatible (O) vs. -incompatible (A/B) newborns receiving phototherapy, and of ABO-incompatible newborns receiving phototherapy vs. no phototherapy. Newborn data and treatment modalities were recorded, and total serum bilirubin and hemoglobin were measured. Maternal anti-A/B immunoglobulin-γ (IgG) titers were measured prenatally and perinatally, and negative and positive predictive values (NPV, PPV) were calculated to assess the risk of developing hyperbilirubinemia requiring phototherapy. RESULTS: We found a significantly higher maternal IgG antibody titer in the case group (p < 0.001). Maternal anti-A/B titers at first trimester had modest predictive values: NPV = 0.82 and PPV = 0.65 for neonatal hyperbilirubinemia; titers at birth improved the predictive values: NPV = 0.93 and PPV = 0.73. Newborn hemoglobin was significantly lower in incompatibles compared to compatibles (p = 0.034). Furthermore, increased anti-A/B IgG production during pregnancy was associated with hyperbilirubinemia and hemolysis in incompatible newborns. CONCLUSIONS: There was a significant association between maternal anti-A/B IgG titer and hyperbilirubinemia requiring treatment. IMPACT: Maternal anti-A/B IgG titer in the first trimester and at birth is predictive of hemolytic disease of the ABO-incompatible newborn. Increased IgG anti-A/B production throughout pregnancy in mothers to ABO-incompatible newborns developing hyperbilirubinemia contrasts a constant or reduced production in mothers to newborns not developing hyperbilirubinemia. Screening tools available in most immunohematology laboratories can identify clinically important IgG anti-A/B. Use of maternal samples taken at birth yielded NPV = 0.93 and PPV = 0.73.

Adherence to guidelines on red blood cell transfusions in women having post-partum haemorrhage.

INTRODUCTION: Transfusion of blood products occurs frequently as part of the treatment of post-partum haemorrhage, but since it is both expensive and has potentially severe complications, prescription of blood products should be restricted. The aim of this study was to examine if restrictive red blood cell transfusion (RBC-T) practice for obstetric patients was in line with national Danish guidelines. METHODS: A retrospective quality assurance study was conducted at Rigshospitalet, Denmark. The study counted the participation of the Department of Anaesthesiology and Surgery, the Juliane Marie Centre, the Danish Blood Bank and the Department of Obstetrics. Patients were identified via the patient database of the Danish Blood Bank in 2015-2017, and patient files were read. RESULTS: Out of 16,698 delivering women, 196 (1.2%) received one or more RBC-T from 2015 to 2017. A total of 133 women (67.9%) received more than one RBC-T and the median was two. The most common reason for RBC-T was a "low haemoglobin level (Hb) + anaemic symptoms" (37.0%). A total of 20.3% of all RBC-Ts were prescribed based simply on a low Hb. The most common symptom of anaemia was dizziness. CONCLUSIONS: The majority of RBC-Ts for obstetric patients were conducted in line with the guidelines. However, 6.0% of RBC-Ts were registered to be in discrepancy with the guidelines and 20.3% of RBC-Ts were prescribed on the "low Hb" criterium solely. It is possible, though, that the 20.3% is overestimated due to insufficient descriptions of indications for RBC-T in patient files. FUNDING: none. TRIAL REGISTRATION: The study was approved by the management at Rigshospitalet.

Is cesarean section a cause of affective disorders?-A national cohort study using sibling designs.

BACKGROUND: The gut microbiota of children delivered by cesarean section differs from that of children delivered vaginally. In light of the gut-brain axis hypothesis, cesarean section may influence risk of affective disorders. METHODS: Population based prospective cohort study included Danish children born 1982 through 2001, with follow-up until 2015. The effect of delivery mode on the risk of affective disorders was assessed using a standard Cox model and two types of Cox sibling models. Diagnostic codes or prescriptions for antidepressants and lithium were used to define cases of affective disorders. RESULTS: 1,009,444 children were followed for 8,880,794 person-years from the age of 13 years, with relevant covariates available from birth. There are strong calendar time trends in the occurrence of affective disorders with an increasingly younger age at first diagnosis and with a hotspot between the years 2007-2012. Fully adjusted standard Cox models showed an increased risk of affective disorders for both pre-labor (hazard ratio [HR], 1.11; 95% confidence interval [CI], 1.08-1.15) and intrapartum (HR, 1.07; 95% CI, 1.05-1.10) cesarean section, compared to vaginal delivery. This effect disappeared in the between-within sibling model for pre-labor (HR, 1.00; 95% CI, 0.94-1.07) but not intrapartum (HR, 1.05; 95% CI, 1.00-1.12) cesarean section. LIMITATIONS: Interpretation of results from sibling models may not be relevant to children without siblings. CONCLUSIONS: These results do not support the hypothesis that a delivery-mode dependent change in gut microbiota is a cause of subsequent affective disorders, despite an apparent association with delivery mode.

Next Generation Sequencing-Based Fetal ABO Blood Group Prediction by Analysis of Cell-Free DNA from Maternal Plasma.

INTRODUCTION: ABO blood group incompatibility between a pregnant woman and her fetus as a cause of morbidity or mortality of the fetus or newborn remains an important, albeit rare, risk. When a pregnant woman has a high level of anti-A or anti-B IgG antibodies, the child may be at risk for hemolytic disease of the fetus and newborn (HDFN). Performing a direct prenatal determination of the fetal ABO blood group can provide valuable clinical information. OBJECTIVE: Here, we report a next generation sequencing (NGS)-based assay for predicting the prenatal ABO blood group. MATERIALS AND METHODS: A total of 26 plasma samples from 26 pregnant women were tested from gestational weeks 12 to 35. Of these samples, 20 were clinical samples and 6 were test samples. Extracted cell-free DNA was PCR-amplified using 2 primer sets followed by NGS. NGS data were analyzed by 2 different methods, FASTQ analysis and a grep search, to ensure robust results. The fetal ABO prediction was compared with the known serological infant ABO type, which was available for 19 samples. RESULTS: There was concordance for 19 of 19 predictable samples where the phenotype information was available and when the analysis was done by the 2 methods. For immunized pregnant women (n = 20), the risk of HDFN was predicted for 12 fetuses, and no risk was predicted for 7 fetuses; one result of the clinical samples was indeterminable. Cloning and sequencing revealed a novel variant harboring the same single nucleotide variations as ABO*O.01.24 with an additional c.220C>T substitution. An additional indeterminable result was found among the 6 test samples and was caused by maternal heterozygosity. The 2 indeterminable samples demonstrated limitations to the assay due to hybrid ABO genes or maternal heterozygosity. CONCLUSIONS: We pioneered an NGS-based fetal ABO prediction assay based on a cell-free DNA analysis from maternal plasma and demonstrated its application in a small number of samples. Based on the calculations of variant frequencies and ABO*O.01/ABO*O.02 heterozygote frequency, we estimate that we can assign a reliable fetal ABO type in approximately 95% of the forthcoming clinical samples of type O pregnant women. Despite the vast genetic variations underlying the ABO blood groups, many variants are rare, and prenatal ABO prediction is possible and adds valuable early information for the prevention of ABO HDFN.

Incidences of obstetric outcomes and sample size calculations: A Danish national registry study based on all deliveries from 2008 to 2015.

INTRODUCTION: In high-income countries the majority of pregnancies have a good outcome, and many adverse obstetric outcomes rarely occur. This makes demonstrating clinically relevant and statistically significant effects of new interventions a challenge. The objective of the study was to report incidences of important obstetric outcomes and to calculate sample sizes for tentative studies. MATERIAL AND METHODS: The study was a registry-based study. Data were retrieved from the Danish Medical Birth Registry and included all deliveries in Denmark from 2008 to 2015. The total population included 465 919 deliveries. The study population comprised intended vaginal deliveries with a single fetus in cephalic presentation at term (n = 381 567). Incidences were reported for 20 outcomes considering the relevance for the patients and the severity of the outcomes. We calculated the sample sizes required in tentative obstetric studies to detect risk reductions of 25 and 50%, for tests at the 5% level, using a power of 80 and 90%. For the randomized controlled trials we calculated the sample size required for comparing two proportions with equal-sized groups. For the cohort study we calculated the sample size also required for two proportions but with unequal sized groups. Outcome measures for sample size calculation were neonatal mortality, Apgar score <7 at 5 minutes and emergency cesarean section. RESULTS: The incidence of neonatal mortality, Apgar score <7 at 5 minutes and emergency cesarean section was 0.05, 0.58 and 10.5%, respectively. Using neonatal mortality as the outcome in a tentative randomized controlled trial with an expected risk reduction of 50% and power of 80%, our calculation showed a sample size of 195 036 deliveries. Using Apgar score <7 at 5 minutes or emergency cesarean section as the outcome, 16 254 and 818 deliveries, respectively, were required. In tentative cohort studies, the required sample sizes were larger due to the unequal proportion of exposed/non-exposed women. CONCLUSIONS: Most adverse obstetric outcomes occur rarely; thus, very large sample sizes are required to achieve adequate statistical power in randomized controlled trials. Multicenter studies, international collaborations or alternative study designs to randomized controlled trials could be considered.

Maternal age and risk of cesarean section in women with induced labor at term-A Nordic register-based study.

INTRODUCTION: Over the last decades, induction of labor has increased in many countries along with increasing maternal age. We assessed the effects of maternal age and labor induction on cesarean section at term among nulliparous and multiparous women without previous cesarean section. MATERIAL AND METHODS: We performed a retrospective national registry-based study from Denmark, Finland, Iceland, Norway, and Sweden including 3 398 586 deliveries between 2000 and 2011. We investigated the impact of age on cesarean section among 196 220 nulliparous and 188 158 multiparous women whose labor was induced, had single cephalic presentation at term, and no previous cesarean section. Confounders comprised country, time-period, and gestational age. RESULTS: In nulliparous women with induced labor the rate of cesarean section increased from 14.0% in women less than 20 years of age to 39.9% in women 40 years and older. Compared with women aged 25-29 years, the corresponding relative risks were 0.60 (95% confidence interval [95% CI] 0.57 to 0.64) and 1.72 (95% CI 1.66 to 1.79). In multiparous induced women the risk of cesarean section was 3.9% in women less than 20 years rising to 9.1% in women 40 years and older. Compared with women aged 25-29 years, the relative risks were 0.86 (95% CI 0.54 to 1.37) and 1.98 (95% CI 1.84 to 2.12), respectively. There were minimal confounding effects of country, time-period, and gestational age on risk for cesarean section. CONCLUSIONS: Advanced maternal age is associated with increased risk of cesarean section in women undergoing labor induction with a single cephalic presentation at term without a previous cesarean section. The absolute risk of cesarean section is 3-5 times higher across 5-year age groups in nulliparous relative to multiparous women having induced labor.

The impact of a national cardiotocography education program on neonatal and maternal outcomes: A historical cohort study.

INTRODUCTION: Studies indicate an association between errors in cardiotocography (CTG) management and hypoxic brain injuries among newborns. Continuing professional education is recommended. We aimed to examine whether the implementation of a national interprofessional CTG education program in Denmark was associated with a decrease in risk of fetal hypoxia measured by umbilical cord pH < 7.00, 5-minute Apgar score <7 or neonatal therapeutic hypothermia. As a secondary aim, we assessed whether the educational intervention was associated with an increase in operative deliveries. MATERIAL AND METHODS: We conducted a historical cohort study from 2009 to 2015 including all intended vaginal deliveries with liveborn singletons in cephalic presentation and gestational age ≥37 weeks. Data were retrieved from the Medical Birth Register and the National Patient Register. The study period was divided in three: pre-implementation (2009-2012), implementation (2013) and post-implementation (2014-2015). Using logistic regression we estimated odds ratios (OR) of fetal hypoxia outcomes using the pre-implementation period as reference. Analyses were adjusted for potential maternal, neonatal and delivery-associated confounders. Missing data were accounted for by multiple imputation. RESULTS: In all, 331 282 deliveries were included. Overall risks of pH < 7.00, Apgar score <7 and therapeutic hypothermia were respectively 0.45%, 0.58% and 0.06%. Adjusted OR in the post-implementation period were 1.12 (95% confidence interval [CI] 1.00-1.26), 0.99 (95% CI 0.90-1.10) and 1.34 (95% CI 0.99-1.82) for the three outcomes, respectively. The pH missingness equaled 12.4%. Odds of emergency cesarean section was unaltered, whereas the odds of assisted vaginal delivery decreased by 14% (0.86, 95% CI 0.84-0.89). CONCLUSIONS: Healthcare professionals are considered the weakest link of CTG technology. We did not find that increasing healthcare professionals' CTG interpretation skills affected the risk of fetal hypoxia. Missing data for pH values were substantial and represent a limitation of the study. We cannot with certainty rule out that missingness masked a true effect of the intervention. Our study indicates that assisted vaginal deliveries can be decreased without an increased risk of fetal hypoxia. Dilution of effect in a complex clinical setting, rare outcomes, insufficient intervention and a possible overestimation of the impact of errors in CTG management might explain the lack of effect.