Publications by authors named "Niels Uldbjerg"

202 Publications

A force-measuring device combined with ultrasound-based elastography for assessment of the uterine cervix.

Acta Obstet Gynecol Scand 2022 Jan 20. Epub 2022 Jan 20.

Department of Obstetrics and Gynecology, Aarhus University Hospital, Aarhus, Denmark.

Introduction: In this feasibility study, we hypothesize that the evaluation of cervical biomechanical strength can be improved if cervical length measurement is supplemented with quantitative elastography, which is a technique based on conventional ultrasound elastography combined with a force-measuring device. Our aims were to: (a) develop a force-measuring device; (b) introduce a cervical elastography index (CEI) and a cervical strength index (CSI; defined as cervical length × CEI); (c) evaluate how these indexes assess the cervical softening that takes place during normal pregnancy; and (d) how these indexes predict the cervical dilatation time from 4 to 10 cm.

Material And Methods: An electronic force-measuring device was mounted on the handle of the transvaginal probe, allowing for force measurement when conducting elastography. The study group concerned with normal cervical softening included 44 unselected pregnant women. Outcomes were CEI and CSI at different gestational ages. The study group for labor induction included 26 singleton term pregnant women admitted for labor induction. Outcome was defined as cervical dilatation time from 4 to 10 cm. Elastography measured the changes in mean gray value (intensity) during manual compressions. Region of interest was set within the anterior cervical lip.

Results: We found that the mean of all variables regarding cervical softening decreased from early to late pregnancy: ie cervical length from 34 to 29 mm, CEI from 0.17 to 0.11 N, and CSI from 5.9 to 3.1 N mm. Moreover, the cervical dilatation time during labor induction was associated with CEI, although not statistically significantly (area under the ROC curve of 0.67), but not with the Bishop score, the cervical length, or the CSI.

Conclusions: We propose that quantitative elastography based on changes in the intensity of the B-mode ultrasound recording, in combination with a force-measuring device on the handle of the vaginal probe, deserves further investigation as an approach for evaluation of cervical biomechanical strength.
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http://dx.doi.org/10.1111/aogs.14309DOI Listing
January 2022

Obstetric care for women that use antidepressants in pregnancy.

BJOG 2022 01 29;129(1):172. Epub 2021 Sep 29.

Aarhus University Hospital, Aarhus, Denmark.

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http://dx.doi.org/10.1111/1471-0528.16918DOI Listing
January 2022

Ascorbic acid supports ex vivo generation of plasmacytoid dendritic cells from circulating hematopoietic stem cells.

Elife 2021 09 2;10. Epub 2021 Sep 2.

Department of Biomedicine, Aarhus University, Aarhus, Denmark.

Plasmacytoid dendritic cells (pDCs) constitute a rare type of immune cell with multifaceted functions, but their potential use as a cell-based immunotherapy is challenged by the scarce cell numbers that can be extracted from blood. Here, we systematically investigate culture parameters for generating pDCs from hematopoietic stem and progenitor cells (HSPCs). Using optimized conditions combined with implementation of HSPC pre-expansion, we generate an average of 465 million HSPC-derived pDCs (HSPC-pDCs) starting from 100,000 cord blood-derived HSPCs. Furthermore, we demonstrate that such protocol allows HSPC-pDC generation from whole-blood HSPCs, and these cells display a pDC phenotype and function. Using GMP-compliant medium, we observe a remarkable loss of TLR7/9 responses, which is rescued by ascorbic acid supplementation. Ascorbic acid induces transcriptional signatures associated with pDC-specific innate immune pathways, suggesting an undescribed role of ascorbic acid for pDC functionality. This constitutes the first protocol for generating pDCs from whole blood and lays the foundation for investigating HSPC-pDCs for cell-based immunotherapy.
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http://dx.doi.org/10.7554/eLife.65528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8445615PMC
September 2021

Vedolizumab clearance in neonates, susceptibility to infections and developmental milestones: a prospective multicentre population-based cohort study.

Aliment Pharmacol Ther 2021 11 2;54(10):1320-1329. Epub 2021 Sep 2.

Aarhus, Denmark.

Background: Little is known about the consequences of intrauterine exposure to, and the post-natal clearance of, vedolizumab.

Aims: To investigate the levels of vedolizumab in umbilical cord blood of newborns and rates of clearance after birth, as well as how these correlated with maternal drug levels, risk of infection and developmental milestones during the first year of life METHODS: Vedolizumab-treated pregnant women with inflammatory bowel disease were prospectively recruited from 12 hospitals in Denmark and Canada in 2016-2020. Demographics were collected from medical records. Infant developmental milestones were evaluated by the Ages and Stages Questionnaire (ASQ-3). Vedolizumab levels were measured at delivery and, in infants, every third month until clearance. Non-linear regression analysis was applied to estimate clearance.

Results: In 50 vedolizumab-exposed pregnancies, we observed 43 (86%) live births, seven (14%) miscarriages, no congenital malformations and low risk of adverse pregnancy outcomes. Median infant:mother vedolizumab ratio at birth was 0.44 (95% confidence interval [CI], 0.32-0.56). The mean time to vedolizumab clearance in infants was 3.8 months (95% CI, 3.1-4.4). No infant had detectable levels of vedolizumab at 6 months of age. Developmental milestones at 12 months were normal or above average. Neither vedolizumab exposure in the third trimester (RR 0.54, 95% CI, 0.28-1.03) nor combination therapy with thiopurines (RR 1.29, 95% CI, 0.60-2.77) seemed to increase the risk of infections in the offspring.

Conclusions: Neonatal vedolizumab clearance following intrauterine exposure is rapid. Infant vedolizumab levels did not correlate with the risk of infections during the first year of life. Continuation of vedolizumab throughout pregnancy is safe.
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http://dx.doi.org/10.1111/apt.16593DOI Listing
November 2021

Streptococcus agalactiae do not penetrate human chorioamniotic membranes in vitro but alter their biomechanical properties.

Acta Obstet Gynecol Scand 2021 Oct 2;100(10):1814-1821. Epub 2021 Aug 2.

Faculty of Health, Department of Biomedicine, Aarhus University, Aarhus C, Denmark.

Introduction: Vaginal colonization with Streptococcus agalactiae (group B streptococci) is hypothesized to constitute a risk factor for preterm prelabor rupture of membranes. In vitro studies have shown that S. agalactiae strains isolated from infants with neonatal sepsis adhere to chorion cells of the human chorioamniotic membrane. However, it is still unknown whether S. agalactiae strains penetrate the chorioamniotic membranes and whether S. agalactiae colonization affects the biomechanical properties of the membranes and thus contributes to increased risk of preterm prelabor rupture. The aim of this in vitro study was to explore if different strains of S. agalactiae penetrate and affect the biomechanical properties of human chorioamniotic membranes.

Material And Methods: Three different strains of S. agalactiae were obtained, one from an early-onset neonatal infection, one from a case of preterm prelabor rupture of membranes and one from a healthy pregnant carrier. Chorioamniotic membranes from elective cesarean deliveries were either incubated with S. agalactiae or mounted in a two-chamber incubation cell generating a "maternal" and a "fetal" chamber and incubated with S. agalactiae in the maternal chamber. Subsequently the membranes were examined to evaluate S. agalactiae attachment, penetration and the effect on the biomechanical properties.

Results: At 5 h after incubation, S. agalactiae adhered to the chorioamniotic membranes with increased number at 20 h. Streptococcus agalactiae did not penetrate the membranes even after 20 h of incubation. Streptococcus agalactiae increased the ultimate tensile stress needed to rupture the membranes and increased the work needed to rupture the membranes as well as the elastic modulus.

Conclusions: Human chorioamniotic membranes constitute a physical barrier against S. agalactiae infections. Moreover, S. agalactiae infection leads to increased strength of the membranes.
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http://dx.doi.org/10.1111/aogs.14232DOI Listing
October 2021

Polymerase chain reaction for Group B Streptococci (GBS) at labor highly correlates with vaginal GBS load.

J Matern Fetal Neonatal Med 2021 May 9:1-5. Epub 2021 May 9.

Department of Obstetrics and Gynecology, Aarhus University Hospital, Aarhus, Denmark.

Objective: To explore factors associated with a high vaginal GBS load during labor considering (1) the recto-vaginal GBS load at 35-37 weeks' gestation determined by culture and (2) the vaginal GBS colonization determined by a polymerase chain reaction (PCR) assay during labor.

Methods: From an unselected cohort of 902 pregnant women, we obtained (1) recto-vaginal swabs for culture of GBS at 35-37 weeks' gestation (GBS), (2) vaginal swabs for GBS PCR detection at labor (PCR), and (3) vaginal swabs for culture of GBS at labor (GBS). The GBS load was classified semi quantitatively according to a culture protocol without prior broth enrichment of the swab samples: none (0), few (+), some (++), or many (+++) GBS colonies.

Results: Among 902 unselected pregnant women, 859 (95%) had a vaginal swab culture taken at labor, which was classified semi quantitatively. High load GBS (+++) were found in 31 participants. GBS showed a sensitivity of 90% (28/31) and a PPV of 23% (28/121), whereas PCR had a sensitivity of 98% (30/31, non-significant difference) and a PPV of 42% (30/71,  < .01). PCR at labor had a lower sensitivity (78%) for detection of vaginal colonization with GBS at labor (any load) compared to recto/vaginal colonization with GBS at 36 weeks (92%). Vaginal colonization with GBS at 36 weeks seemed to have a lower sensitivity for detecting GBS in vagina at labor for high load (48%) and for any load (39%).

Conclusion: PCR at labor has higher detection rate (non-significant) and PPV in identification of laboring women with a high load of vaginal GBS compared with recto-vaginal culture at 36 weeks' gestation.
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http://dx.doi.org/10.1080/14767058.2021.1922383DOI Listing
May 2021

Continued versus discontinued oxytocin stimulation in the active phase of labour (CONDISOX): double blind randomised controlled trial.

BMJ 2021 04 14;373:n716. Epub 2021 Apr 14.

Department of Obstetrics and Gynaecology, Randers Regional Hospital, Randers, Denmark.

Objective: To determine whether discontinuing oxytocin stimulation in the active phase of induced labour is associated with lower caesarean section rates.

Design: International multicentre, double blind, randomised controlled trial.

Setting: Nine hospitals in Denmark and one in the Netherlands between 8 April 2016 and 30 June 2020.

Participants: 1200 women stimulated with intravenous oxytocin infusion during the latent phase of induced labour.

Intervention: Women were randomly assigned to have their oxytocin stimulation discontinued or continued in the active phase of labour.

Main Outcome Measure: Delivery by caesarean section.

Results: A total of 607 women were assigned to discontinuation and 593 to continuation of the oxytocin infusion. The rates of caesarean section were 16.6% (n=101) in the discontinued group and 14.2% (n=84) in the continued group (relative risk 1.17, 95% confidence interval 0.90 to 1.53). In 94 parous women with no previous caesarean section, the caesarean section rate was 7.5% (11/147) in the discontinued group and 0.6% (1/155)in the continued group (relative risk 11.6, 1.15 to 88.7). Discontinuation was associated with longer duration of labour (median from randomisation to delivery 282 201 min; P<0.001), a reduced risk of hyperstimulation (20/546 (3.7%) 70/541 (12.9%); P<0.001), and a reduced risk of fetal heart rate abnormalities (153/548 (27.9%) 219/537 (40.8%); P<0.001) but rates of other adverse maternal and neonatal outcomes were similar between groups.

Conclusions: In a setting where monitoring of the fetal condition and the uterine contractions can be guaranteed, routine discontinuation of oxytocin stimulation may lead to a small increase in caesarean section rate but a significantly reduced risk of uterine hyperstimulation and abnormal fetal heart rate patterns.

Trial Registration: ClinicalTrials.gov NCT02553226.
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http://dx.doi.org/10.1136/bmj.n716DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044921PMC
April 2021

Mosaicism for copy number variations in the placenta is even more difficult to interpret than mosaicism for whole chromosome aneuploidy.

Prenat Diagn 2021 May 24;41(6):668-680. Epub 2021 Apr 24.

Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark.

Objective: To compare mosaicisms in prenatal chorionic villus samples (CVSs) with corresponding postpartum placental samples.

Method: We collected placentas from 15 consecutive cases of mosaicism detected in CVSs and obtained five standardized samples on each placenta after delivery. All pre- and postnatal placental samples were uncultured and analyzed by high-resolution chromosomal microarray.

Results: Ten cases of mosaicism for whole chromosome aneuploidy (mWC) and five cases with mosaicism for (sub)chromosomal copy number variations (mCNVs) were included. In 5/10 mWC cases and in 4/5 mCNV cases the prenatally detected aberration was confirmed in the postpartum placenta. Three postpartum placentas revealed various complex aberrations differing from the prenatal results: (1) mosaicisms for different deletions/duplications on 9p and 9q in all samples (prenatal: mosaic 5.3 Mb duplication on 9p24), (2) different regions with deletions/duplications/loss of heterozygosity on 1p in all samples (prenatal: mosaic 2.3 Mb 1p36 duplication), and (3) mosaicism for a duplication on 5q and a deletion on 6p in one out of five samples (prenatal: mosaic trisomy 7).

Conclusion: CNVs constitute a complex subgroup in placental mosaicism. Counseling of these couples after chorionic villus sampling should not focus on the specific CNV involved, but on the nature of mosaicism and the option of amniocentesis and ultrasound.
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http://dx.doi.org/10.1002/pd.5938DOI Listing
May 2021

Cell-based non-invasive prenatal testing for monogenic disorders: confirmation of unaffected fetuses following preimplantation genetic testing.

J Assist Reprod Genet 2021 Aug 7;38(8):1959-1970. Epub 2021 Mar 7.

Department of Molecular Diagnostics, Aalborg University Hospital, Aalborg, Denmark.

Purpose: Proof of concept of the use of cell-based non-invasive prenatal testing (cbNIPT) as an alternative to chorionic villus sampling (CVS) following preimplantation genetic testing for monogenic disorders (PGT-M).

Method: PGT-M was performed by combined testing of short tandem repeat (STR) markers and direct mutation detection, followed by transfer of an unaffected embryo. Patients who opted for follow-up of PGT-M by CVS had blood sampled, from which potential fetal extravillous throphoblast cells were isolated. The cell origin and mutational status were determined by combined testing of STR markers and direct mutation detection using the same setup as during PGT. The cbNIPT results with respect to the mutational status were compared to those of genetic testing of the CVS.

Results: Eight patients had blood collected between gestational weeks 10 and 13, from which 33 potential fetal cell samples were isolated. Twenty-seven out of 33 isolated cell samples were successfully tested (82%), of which 24 were of fetal origin (89%). This corresponds to a median of 2.5 successfully tested fetal cell samples per case (range 1-6). All fetal cell samples had a genetic profile identical to that of the transferred embryo confirming a pregnancy with an unaffected fetus, in accordance with the CVS results.

Conclusion: These findings show that although measures are needed to enhance the test success rate and the number of cells identified, cbNIPT is a promising alternative to CVS.

Trial Registration Number: N-20180001.
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http://dx.doi.org/10.1007/s10815-021-02104-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8417213PMC
August 2021

Endometriosis and Risk of Adverse Pregnancy Outcome: A Systematic Review and Meta-Analysis.

J Clin Med 2021 Feb 9;10(4). Epub 2021 Feb 9.

Department of Obstetrics and Gynecology, Aarhus University Hospital, 8200 Aarhus, Denmark.

Background: This systematic review and meta-analysis summarizes the evidence for the association between endometriosis and adverse pregnancy outcome, including gestational hypertension, pre-eclampsia, low birth weight, and small for gestational age, preterm birth, placenta previa, placental abruption, cesarean section, stillbirth, postpartum hemorrhage, spontaneous hemoperitoneum in pregnancy, and spontaneous bowel perforation in pregnancy.

Methods: We performed the literature review in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA), by searches in PubMed and EMBASE, until 1 November 2020 (PROSPERO ID CRD42020213999). We included peer-reviewed observational cohort studies and case-control studies and scored them according to the Newcastle-Ottawa Scale, to assess the risk of bias and confounding.

Results: 39 studies were included. Women with endometriosis had an increased risk of gestational hypertension, pre-eclampsia, preterm birth, placenta previa, placental abruption, cesarean section, and stillbirth, compared to women without endometriosis. These results remained unchanged in sub-analyses, including studies on spontaneous pregnancies only. Spontaneous hemoperitoneum in pregnancy and bowel perforation seemed to be associated with endometriosis; however, the studies were few and did not meet the inclusion criteria.

Conclusions: The literature shows that endometriosis is associated with an increased risk of gestational hypertension, pre-eclampsia, preterm birth, placenta previa, placental abruption, cesarean section, and stillbirth.
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http://dx.doi.org/10.3390/jcm10040667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916165PMC
February 2021

Vaginal, Cervical and Uterine pH in Women with Normal and Abnormal Vaginal Microbiota.

Pathogens 2021 Jan 20;10(2). Epub 2021 Jan 20.

Department of Obstetrics and Gynecology, Aarhus University Hospital, DK-8200 Aarhus, Denmark.

Introduction: Healthy women of reproductive age have a vaginal pH around 4.5, whereas little is known about pH in the upper genital tract. A shift in the vaginal microbiota may result in an elevated pH in the upper genital tract. This might contribute to decreased fertility and increased risk of preterm birth. Therefore, we aimed to measure pH in different compartments of the female genital tract in both nonpregnant and pregnant women, stratifying into a normal and abnormal vaginal microbiota.

Material And Methods: In this descriptive study, we included 6 nonpregnant, 12 early-pregnant, and 8 term-pregnant women. A pH gradient was recorded with a flexible pH probe. An abnormal vaginal microbiota was diagnosed by a quantitative polymerase chain reaction technique for ; ; ; bacterial vaginosis-associated bacterium 1, 2, 3, and TM7; and spp. among others.

Results: In all participants we found the pH gradient in the lower reproductive canal to be most acidic in the lower vagina and most alkaline in the upper uterine cavity. Women with an abnormal vaginal microbiota had an increased pH in the lower vagina compared to the other groups.

Conclusions: There is a pronounced pH gradient within the female genital tract. This gradient is not disrupted in women with an abnormal vaginal microbiota.
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http://dx.doi.org/10.3390/pathogens10020090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7909242PMC
January 2021

Associations Between ADHD Medication Use in Pregnancy and Severe Malformations Based on Prenatal and Postnatal Diagnoses: A Danish Registry-Based Study.

J Clin Psychiatry 2021 01 5;82(1). Epub 2021 Jan 5.

Department of Obstetrics and Gynecology, Aarhus University Hospital, Aarhus, Denmark.

Objective: Attention-deficit/hyperactivity disorder (ADHD) medications are increasingly used in pregnancy. Studies on the pregnancy safety of these medications that are restricted to live births may underestimate severe teratogenic effects that cause fetal demise or termination of pregnancy. The present study addresses this limitation by including data from both prenatal and postnatal diagnoses of major malformations.

Methods: A nationwide registry-based study was conducted of 364,012 singleton pregnancies in Denmark from November 1, 2007, to February 1, 2014. Exposures to ADHD medication were obtained from redeemed prescriptions from the Danish Health Services Prescription Database. Outcome data included prenatally diagnosed malformations from the Danish Fetal Medicine Database and postnatally diagnosed malformations from the Danish National Patient Registry. The primary outcome was major malformations overall, and secondary outcomes were malformations of the central nervous system and cardiac malformations. The comparison group was pregnancies with no redeemed prescriptions for ADHD medication. We defined severe cardiac malformations (SCM) as concurrent diagnoses of a cardiac malformation with miscarriage, termination, stillbirth, postnatal death, or cardiac surgery within 1 year of birth.

Results: The prevalence of first-trimester exposure to ADHD medication increased during the study period from 0.05% in 2008 to 0.27% in 2013, with the majority (473/569) of the exposures being to methylphenidate. There were 5.1% malformations overall and 2.1% cardiac malformations among the exposed compared to 4.6% and 1.0%, respectively, among the unexposed. For methylphenidate, the adjusted prevalence ratios (PRs) were 1.04 (95% confidence interval [CI], 0.70-1.55) for malformations overall and 1.65 (95% CI, 0.89-3.05) for any cardiac malformations (number needed to harm [NNH] = 92), with septum defects in 10 out of 12 cases. The PR for ventricular septal defect was 2.74 (95% CI, 1.03-7.28) and for SCM, 2.59 (95% CI, 0.98-6.90).

Conclusions: Exposure to methylphenidate was not associated with an increased risk of malformations overall in data that included information from both prenatal and postnatal diagnoses of major malformations. There was an increased risk of cardiac malformations with NNH of 92 based on 12 cases among the exposed. More data are needed on other types of ADHD medication.
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http://dx.doi.org/10.4088/JCP.20m13458DOI Listing
January 2021

Cell-based noninvasive prenatal testing (cbNIPT) detects pathogenic copy number variations.

Clin Case Rep 2020 Dec 9;8(12):2561-2567. Epub 2020 Aug 9.

Center for Fetal Diagnostics Department of Clinical Genetics Aarhus University Hospital Aarhus Denmark.

In two cases, cell-based noninvasive prenatal testing (cbNIPT) detected pathogenic copy number variations (CNVs) in the fetal genome. cbNIPT may potentially be an improved noninvasive alternative for the detection of smaller CNVs.
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http://dx.doi.org/10.1002/ccr3.3211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752386PMC
December 2020

Hydatidiform mole diagnostics using circulating gestational trophoblasts isolated from maternal blood.

Mol Genet Genomic Med 2021 01 11;9(1):e1565. Epub 2020 Dec 11.

ARCEDI Biotech ApS, Vejle, Denmark.

Background: In gestational trophoblastic disease, the prognosis is related to the genetic constitution. In some cases, taking a biopsy is contraindicated.

Methods: In a pregnant woman, ultrasound scanning suggested hydatidiform mole. To explore if the genetic constitution can be established without taking a biopsy (or terminating the pregnancy), cell-free DNA and circulating gestational trophoblasts were isolated from maternal blood before evacuation of the uterus. The evacuated tissue showed the morphology of a complete hydatidiform mole. Without prior whole-genome amplification, short tandem repeat analysis of 24 DNA markers was performed on the samples, and on DNA isolated from evacuated tissue, and from the blood of the patient and her partner.

Results: Identical genetic results were obtained in each of three circulating gestational trophoblasts and the evacuated tissue, showing that this conceptus had a diploid androgenetic nuclear genome. In contrast, analysis of cell-free DNA was less informative and less specific due to the inherent presence of cell-free DNA from the patient.

Conclusion: Our results show that it is possible to isolate and analyze circulating gestational trophoblasts originating in a pregnancy without maternal nuclear genome. For diagnosing gestational trophoblastic diseases, genotyping circulating gestational trophoblasts appears to be superior to analysis of cell-free DNA.
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http://dx.doi.org/10.1002/mgg3.1565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7963416PMC
January 2021

Effect of early discharge after planned cesarean section on recovery and parental sense of security. A randomized clinical trial.

Acta Obstet Gynecol Scand 2021 05 25;100(5):955-963. Epub 2020 Dec 25.

Department of Obstetrics and Gynecology, Regional Hospital West Jutland, Herning, Denmark.

Introduction: In some European countries, discharge the day after planned cesarean section has become an accepted procedure. However, little is known about the patients' perception of early discharge. The aim of this study was to compare early discharge with standard care in relation to parental sense of security. Further, we evaluated postoperative pain, mobilization, and readmission.

Material And Methods: We performed a randomized clinical trial including parous, singleton pregnant women with a planned cesarean section at term. The women were allocated to either discharge within 28 hours (intervention group) or after 48 hours (standard care group) following the cesarean section. Women discharged within 28 hours after cesarean section were offered a home visit by a midwife the following day. The primary outcome was the postnatal sense of security, which was reported by the woman and her partner in the "Parents' Postnatal Sense of Security" questionnaire 1 week postpartum. Secondary outcomes were pain score, use of analgesics, mobilization, readmission, and contacts with the healthcare system in the postoperative period.

Results: We included 143 women, of whom 72 were allocated to the intervention group and 71 were allocated to the standard care group. There were no differences in baseline characteristics. The two groups did not differ concerning the postnatal sense of security for the women (P = .98) or the postnatal sense of security for the partners (P = .38). We found no difference in pain scores, step count, use of analgesics, or number of contacts with the health-care system between the groups.

Conclusions: Parental postnatal sense of security is not compromised by discharge within 28 hours followed by a home visit compared with discharge after 48 hours after planned cesarean section among parous women.
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http://dx.doi.org/10.1111/aogs.14041DOI Listing
May 2021

Cell-based non-invasive prenatal diagnosis in a pregnancy at risk of cystic fibrosis.

Prenat Diagn 2021 01 14;41(2):234-240. Epub 2020 Nov 14.

Department of Clinical Genetics, Lillebaelt Hospital, University Hospital of Southern Denmark, Vejle, Denmark.

Objective: We aimed to develop cell-based NIPT for cystic fibrosis (CF) and test a pregnancy at risk of two common pathogenic variants.

Method: A pregnant woman carrying monozygotic twins opted for prenatal testing as she and her partner were heterozygote carriers of F508del (c.1521:1523del). The partner was also positive for the CFTR-related variant R117H (c.350G>A). Fetal trophoblasts from maternal blood were enriched and isolated using antibodies and a capillary-based cell-picking instrument. Multiplex PCR-based fragment length analysis was performed on the extracted fetal DNA for STR-genotyping, fetal gender and F508del variant status. The R117H variant status was tested using SNaPshot analysis.

Results: The fetal origin of the isolated cells was verified by detection of two paternally inherited STR alleles and an Y chromosome marker, while no maternal DNA contamination was detected. The direct variant analysis detected F508del heterozygosity and the SNaPshot analysis for R117H detected only the normal allele. Thus, the results showed that the fetuses were healthy carriers of F508del, concordant with the findings of conventional prenatal testing.

Conclusion: Cell-based NIPT could accurately state the fetal variant status and distinguish fetal trophoblasts from maternal cells. In the future, cell-based NIPT may provide an accurate less invasive alternative to chorionic villous sampling.
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http://dx.doi.org/10.1002/pd.5861DOI Listing
January 2021

Fetal Heart Rate Variability Is Affected by Fetal Movements: A Systematic Review.

Front Physiol 2020 30;11:578898. Epub 2020 Sep 30.

Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark.

Fetal heart rate variability (FHRV) evaluates the fetal neurological state, which is poorly assessed by conventional prenatal surveillance including cardiotocography (CTG). Accurate FHRV on a beat-to-beat basis, assessed by time domain and spectral domain analyses, has shown promising results in the scope of fetal surveillance. However, accepted standards for these techniques are lacking, and the influence of fetal breathing movements and gross movements may be especially challenging. Thus, current standards for equivalent assessments in adults prescribe rest and controlled respiration. The aim of this review is to clarify the importance of fetal movements on FHRV. A systematic review in accordance with the PRISMA guidelines based on publications in the EMBASE, the MEDLINE, and the Cochrane Library databases was performed. Studies describing the impact of fetal movements on time domain, spectral domain and entropy analyses in healthy human fetuses were reviewed. Only studies based on fetal electrocardiography or fetal magnetocardiography were included. PROSPERO registration number: CRD42018068806. In total, 14 observational studies were included. Fetal movement detection, signal processing, length, and selection of appropriate time series varied across studies. Despite these divergences, all studies showed an increase in overall FHRV in the moving fetus compared to the resting fetus. Especially short-term, vagal mediated indexes showed an increase during fetal breathing movements including an increase in Root Mean Square of the Successive Differences (RMSSD) and High Frequency power (HF) and a decrease in Low Frequency power/High Frequency power (LF/HF). These findings were present even in analyses restricted to one specific fetal behavioral state defined by Nijhuis. On the other hand, fetal body movements seemed to increase parameters supposed to represent the sympathetic response [LF and Standard Deviation of RR-intervals from normal sinus beats (SDNN)] proportionally more than parameters representing the parasympathetic response (RMSSD, HF). Results regarding entropy analyses were inconclusive. Time domain analyses as well as spectral domain analyses are affected by fetal movements. Fetal movements and especially breathing movements should be considered in these analyses of FHRV.
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http://dx.doi.org/10.3389/fphys.2020.578898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554531PMC
September 2020

Vitamin D and the risk of dystocia: A case-control study.

PLoS One 2020 14;15(10):e0240406. Epub 2020 Oct 14.

Department of Obstetrics and Gynecology, Aarhus University Hospital, Aarhus, Denmark.

Background: Dystocia is one of the most common causes of cesarean section in nulliparous women. Studies have described the presence of vitamin D receptors in the myometrium, but it is still unclear whether vitamin D affects the contractility of the smooth muscles. We therefore aimed to determine the association between the vitamin D serum level at labor and the risk of dystocia.

Method: We conducted a case-control study between January 2012 and June 2017. Cases were primiparous women, with spontaneous onset of labor, who gave birth by cesarean section due to dystocia. Controls were primiparous women with a spontaneous vaginal delivery. We included 60 women (30 cases and 30 controls) in the analysis. The differences between cases and controls were assessed using chi-squared test for categorical variables and two-sample t-test or unequal t-test for continuous variables, as appropriate, after evaluation of whether they followed the normal distributions.

Results: The mean serum 25-hydroxyvitamin D concentrations were 53.1nmol/l (95%CI; 45.2 to 60.9) among cases and 69.9nmol/l (95%CI; 57.5 to 82.4) among controls (P = 0.02). The mean plasma parathyroid hormone levels were 2.25 pmol/l and 2.38, respectively (P = 0.57). Even though 78% of all women reported taking a minimum of 10μg/day of vitamin D throughout pregnancy, 43% had vitamin D insufficiency, defined as serum 25-hydroxyvitamin D levels below 50nmol/l.

Conclusions: In a Danish group of women having a cesarean section due to dystocia, we found decreased vitamin D levels.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240406PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556460PMC
December 2020

Effect of clindamycin and a live biotherapeutic on the reproductive outcomes of IVF patients with abnormal vaginal microbiota: protocol for a double-blind, placebo-controlled multicentre trial.

BMJ Open 2020 10 13;10(10):e035866. Epub 2020 Oct 13.

Department of Clinical Medicine, Aarhus Universitet, Aarhus, Denmark.

Introduction: Recent studies in in vitro fertilisation (IVF) patients have associated abnormal vaginal microbiota (AVM) with poor clinical pregnancy rates of 6%-9% per embryo transfer. The biological plausibility for this finding is hypothesised to be ascending infection to the endometrium which in turn hampers embryo implantation. New molecular based diagnosis may offer advantages compared to microscopical diagnosis of AVM which has huge inter-study variability ranging from 4 to 38%; however, the important question is whether screening and treatment of AVM would improve reproductive outcomes in IVF patients. Herein, we describe a protocol for an ongoing double-blind, placebo-controlled multicentre trial of IVF patients diagnosed with AVM and randomised in three parallel groups 1:1:1.

Methods And Analysis: This is a drug intervention study where IVF patients will be screened for AVM, using a qPCR assay targeting and . If positive, patients will be randomised to one of the three study arms. The first arm consists of clindamycin 300 mg ×2 daily for 7 days followed by vaginal CTV-05 until clinical pregnancy scan week 7-9. The second arm consists of clindamycin and placebo CTV-05, whereas patients in the third arm will be treated with placebo/placebo. We used a superiority design to estimate that active treatment in both arms will increase the primary outcome, clinical pregnancy rate per embryo transfer, from 20% to 40%. A potential difference between the two active arms was considered exploratory. With a power of 80% and an alpha at 5%, the sample size is estimated to be 333 patients randomised. A pre-planned interim analysis is scheduled at 167 patients randomised.

Ethics And Dissemination: All patients have to give informed consent. Dissemination of results is ensured in clinical trial agreements whether they be positive or not. Ethics committee, Central Denmark Region approved this protocol.

Trial Registration Number: ICH-GCP monitored trial, EudraCT 2016-002385-31; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2019-035866DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554508PMC
October 2020

Vitamin D insufficiency among Danish pregnant women-Prevalence and association with adverse obstetric outcomes and placental vitamin D metabolism.

Acta Obstet Gynecol Scand 2021 03 12;100(3):480-488. Epub 2021 Jan 12.

Department of Obstetrics and Gynecology, Randers Regional Hospital, Randers, Denmark.

Introduction: In pregnancy, vitamin D deficiency is associated with increased risk of fetal growth restriction and preeclampsia. The underlying mechanisms are not known, but placental dysfunction is believed to play a role. In a Danish population, where health authorities recommend a 10 µg/day vitamin D supplement during pregnancy, we explored current use of vitamin D supplements and vitamin D status. In term placentas, alterations in vitamin D metabolism and placental growth, evaluated by the key placental growth factor pregnancy-associated plasma protein-A (PAPP-A), and their relation to vitamin D insufficiency were investigated.

Material And Methods: We included 225 randomly selected pregnant women attending a nuchal translucency scan at gestational weeks 11-14. Information on use of vitamin D supplements and body mass index (BMI) at inclusion was obtained using self-reported questionnaires. Plasma 25-hydroxyvitamin D was measured at inclusion and correlated with pregnancy outcomes and placental biology, as judged by expression of PAPP-A and enzymes involved in vitamin D metabolism (CYP24A1, CYP27B1) in term placentas.

Results: Vitamin D supplements were used by 92% of the women, but 42% were vitamin D insufficient (plasma 25-hydroxyvitamin D <75 nmol/L). Eleven women with singleton pregnancies developed fetal growth restriction or preeclampsia. In this small subset, first-trimester mean plasma 25-hydroxyvitamin D was lower in women who developed fetal growth restriction (43 ± 33nmol/L; n = 3; P = .006) and there was a tendency towards lower plasma 25-hydroxyvitamin D among women who developed preeclampsia (65 ± 19 nmol/L; n = 8; P = .08) in third trimester compared with uncomplicated pregnancies (79 ± 22 nmol/L; n = 187). In term placentas, PAPP-A expression was lower among participants with first-trimester vitamin D insufficiency (P = .009; n = 30) but no correlation was found between plasma 25-hydroxyvitamin D and mRNA expression of CYP24A1 (P = .67) and CYP27B1 (P = .34). BMI was negatively correlated with plasma 25-hydroxyvitamin D (P = .03) and positively correlated with placental mRNA expression of CYP24A1 (P = .003; n = 30).

Conclusions: Despite high compliance with official guidelines regarding vitamin D supplements, vitamin D insufficiency was frequent and the findings indicate that vitamin D insufficiency may affect placental growth. High BMI was associated with vitamin D insufficiency and increased placental vitamin D turnover, but further investigations are needed.
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http://dx.doi.org/10.1111/aogs.14019DOI Listing
March 2021

Length of hospital stay after cesarean section in Denmark from 2004 to 2016: A national register-based study.

Acta Obstet Gynecol Scand 2021 02 16;100(2):244-251. Epub 2020 Oct 16.

Department of Obstetrics and Gynecology, Aalborg University Hospital, Aalborg, Denmark.

Introduction: Length of hospital stay after birth has decreased during the last decades, but nationwide data on length of hospital stay after cesarean section are lacking. Elements of Enhanced Recovery Programs were reported to reduce the length of hospital stay. The aim of this nationwide study was to describe the length of hospital stay after cesarean section in Denmark from 2004 to 2016 taking into account birth- and health-related factors as well as demographic changes and, further, to assess potential differences between the five Danish regions.

Material And Methods: Length of hospital stay was assessed in 164 209 deliveries by cesarean section in Denmark from 2004 to 2016. Data were obtained from the Danish National Patient Register. All deliveries by cesarean section at gestational age <22 weeks were excluded. Median length of hospital stay was reported based on crude and adjusted analyses.

Results: The median length of hospital stay was significantly reduced by 39 hours (95% confidence interval [CI] 37.9-40.1), from 97 hours (4.0 days) in 2004 to 58 hours (2.4 days) in 2016. Reductions were observed among both planned and emergency cesarean sections. When birth- and health-related factors as well as demographic changes were accounted for, median length of hospital stay was reduced by 30 hours (95% CI 29.3-30.8) in the period. The decrease in length of hospital stay from 2004 to 2016 varied between the five Danish regions, with adjusted reductions between 19 and 46 hours.

Conclusions: A nationwide decrease in length of hospital stay after cesarean section was observed from 2004 to 2016 across all five regions but with significant regional variations. Further studies on the optimal length of hospital stay are needed, especially with regard to implementation of enhanced recovery programs.
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http://dx.doi.org/10.1111/aogs.14000DOI Listing
February 2021

The Number of Circulating Fetal Extravillous Trophoblasts Varies from Gestational Week 6 to 20.

Reprod Sci 2020 12 29;27(12):2170-2174. Epub 2020 Jun 29.

Aagaard Fertility Clinic, Aarhus, Denmark.

Cell-based non-invasive prenatal testing (cbNIPT) based on circulating fetal extravillous trophoblasts (fEVTs) has shown to be possible in gestational week (GW) 10-13. Prenatal testing is relevant for a wider time period than GW 10-13, but it is unclear if fEVTs are present in sufficient numbers for cbNIPT at other time points during pregnancy. We present the first longitudinal study where the number of circulating fEVTs was determined from the mid first trimester to the mid second, specifically GW 6-8, 12-13, and 19-20. Blood samples from 13 women opting for assisted reproduction were collected at GW 6-8, 12-13, and 19-20. fEVTs were enriched using a magnetic-activated cell sorting system, stained with anti-cytokeratin antibodies, and fEVTs were identified with the use of a MetaSystem fluorescence microscope scanner. Blood samples drawn at GW 6-8 yielded an average of 5.5 fEVTs per 30 mL of blood. This increased significantly to an average of 11.8 in GW 12-13 (P value: 0.0070, Mann-Whitney test), and decreased significantly to an average of 5.3 in GW 19-20 (P value: 0.0063, Mann-Whitney test). In 9 out of 13 cases, the number of fEVTs peaked in GW 12-13 compared to GW 6-8 and GW 19-20. For the majority of cases, fEVTs can be identified at GW 6-8 and GW 19-20, but the highest number of fEVTs is observed at GW 12-13 indicating this is the optimal time point for cbNIPT.
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http://dx.doi.org/10.1007/s43032-020-00243-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7593292PMC
December 2020

Improvement of selection of pregnant women for intrapartum polymerase chain reaction screening for vaginal Group B Streptococci (GBS) colonization by adding GBS urine screening at 35-37 weeks of pregnancy.

Int J Gynaecol Obstet 2020 Oct 9;151(1):124-127. Epub 2020 Jul 9.

Department of Clinical Microbiology, University Hospital of Southern Denmark, Vejle Hospital, Vejle, Denmark.

Objective: To evaluate whether systematic antepartum screening for Group B Streptococci (GBS) by urine culture improves the risk factor-based selection of pregnant women for intrapartum GBS screening with a rapid polymerase chain reaction (PCR) assay.

Methods: A prospective observational study was conducted between April 2013 and June 2014. GBS colonization judged by urine culture at 35-37 weeks of gestation was compared with the result of a vaginal GBS PCR test at labor as outcome. The results of urine culture were used as exposure variable. The PCR test was performed on intrapartum vaginal samples.

Results: Screening for urine GBS in 902 unselected pregnant Danish women at 35-37 weeks of gestation predicted intrapartum PCR GBS status with a sensitivity of 33.6%. A positive predictive value of 41.2% was seen among women with low GBS counts (<104 CFU/mL) and 83.3% among women with high GBS counts (≥104 CFU/mL). Systematic GBS screening of urine at 35-37 weeks of gestation added 30.9% extra women for intrapartum GBS PCR screening in the study group.

Conclusion: Systematic antepartum GBS screening of urine should be implemented in order to improve risk stratification for early onset GBS by offering laboring women an intrapartum GBS PCR test.
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http://dx.doi.org/10.1002/ijgo.13267DOI Listing
October 2020

The Childbirth Experience Questionnaire (CEQ)-Validation of its use in a Danish-speaking population of new mothers stimulated with oxytocin during labour.

PLoS One 2020 14;15(5):e0233122. Epub 2020 May 14.

Department of Obstetrics and Gynaecology, Regional Hospital of Randers, Randers NØ, Denmark.

Background: When determining optimal treatment regimens, patient reported outcomes including satisfaction are increasingly appreciated. It is well established that the birth experience may affect the postnatal attachment to the newborn and the management of subsequent pregnancies and deliveries. As we have no robust validated Danish tool to evaluate the childbirth experience exists, we aimed to perform a transcultural adaptation of the Childbirth Experience Questionnaire (CEQ) to a Danish context.

Methods: In accordance with the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN), we translated the Swedish-CEQ to Danish. The Danish-CEQ was tested for content validity among 10 new mothers. In a population of women who have had their labour induced, we then assessed the electronic questionnaire for validity and reliability using factor analytical design, hypothesis testing, and internal consistency. Based on these data, we determined criterion and construct responsiveness in addition to floor and ceiling effects.

Results: The content validation resulted in minor adjustments in two items. This improved the comprehensibility. The electronic questionnaire was completed by 377 of 495 women (76.2%). The original Swedish-CEQ was four-dimensional, however an exploratory factor analysis revealed a three-dimensional structure in our Danish population (Own capacity, Participation, and Professional support). Parous women, women who delivered vaginally, and women with a labour duration <12 hours had a higher score in each domain. The internal consistency (Cronbach's alpha) ranged between 0.75 and 0.89 and the ICC between 0.68-0.93. We found ceiling effects of 57.6% in the domain Professional support and of 25.5% in the domain Participation.

Conclusion: This study offers transcultural adaptation of the Swedish-CEQ to a Danish context. The 3-dimensional Danish-CEQ demonstrates construct validity and reliability. Our results revealed significant ceiling effect especially in the domain Professional support, which needs to be acknowledged when considering implementing the Danish-CEQ into trials and clinical practice.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0233122PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7224492PMC
August 2020

"I guess baby was just too comfy in there…": A qualitative study of women's experiences of elective late-term induction of labour.

Women Birth 2021 May 11;34(3):242-249. Epub 2020 May 11.

Department of Obstetrics and Gynecology, Aarhus University Hospital, Aarhus, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.

Background: The frequency of induction of labour (IOL) in late-term pregnancy has increased significantly, but little is known about how women with uncomplicated pregnancies experience IOL for late-term indication alone.

Aim: To explore how women with uncomplicated pregnancies experienced late-term IOL.

Methods: Qualitative interviews were conducted with 23 women who all had labour induced on late-term indication only. Participants were recruited from two Danish hospitals who offered an outpatient induction regime. The women were interviewed 4-8 weeks after birth. Data were analysed using thematic analysis.

Results: All women had hoped for a spontaneous birth. Prolonged pregnancy was understood as the body/baby "not being ready", but generally, the women were not worried at that point. Most women felt adequately informed about the reasons for IOL, but some requested more information and time to consider their options. The majority considered IOL to be both an offer and a recommendation. One-third of the participants were initially hesitant but chose/accepted IOL because of weariness from pregnancy and the impatience to deliver a healthy child. The opportunity of outpatient induction was generally appreciated as it allowed the women to continue everyday activities while waiting for labour to begin. Nineteen women reported having a good birthing experience. Two women felt that negative birthing experiences were partly related to IOL.

Conclusions: Most women considered the late-term IOL to be a positive experience. Some women requested more information and time to consider alternatives. These women should be provided with supported opportunities to consider the options.
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http://dx.doi.org/10.1016/j.wombi.2020.03.012DOI Listing
May 2021

Effects of antenatal hypnosis on maternal salivary cortisol during childbirth and six weeks postpartum-A randomized controlled trial.

PLoS One 2020 1;15(5):e0230704. Epub 2020 May 1.

Department of Public Health, University of Copenhagen, Copenhagen, Denmark.

Background: Cortisol has been used to capture psychophysiological stress during childbirth and postpartum wellbeing. We explored the effect of a brief antenatal training course in self-hypnosis on salivary cortisol during childbirth and 6 weeks postpartum.

Methods: In a randomized, controlled trial conducted at Aarhus University Hospital Skejby Denmark during the period January 2010 until October 2010, a total of 349 healthy nulliparous women were included. They were randomly allocated to a hypnosis group (n = 136) receiving three one-hour lessons in self-hypnosis with additional audio-recordings, a relaxation group (n = 134) receiving three one-hour lessons in various relaxation methods with audio-recordings for additional training, and a usual care group (n = 79) receiving ordinary antenatal care only. Salivary cortisol samples were collected during childbirth (at the beginning of the pushing state, 30 minutes, and 2 hours after childbirth), and 6 weeks postpartum (at wake up, 30 minutes after wake up, and evening). Cortisol concentrations were compared using a linear mixed-effects model. Correlations between cortisol concentrations and length of birth, experienced pain and calmness during birth were examined by a Spearman rank correlation test.

Findings: During childbirth, week correlations were found between cortisol concentrations 30 minutes after childbirth and length of birth. In the beginning of the pushing state and 2 hours after childbirth, we found a tendency towards higher cortisol concentrations in the hypnosis group compared to the other two groups (hypnosis versus relaxation p = 0.02 and 0.03, hypnosis versus usual care p = 0.08 and 0.05). No differences were observed in cortisol concentrations between the groups 30 minutes after childbirth (hypnosis versus relaxation p = 0.08, hypnosis versus usual care 0.10) or 6 weeks postpartum (hypnosis versus relaxation: p = 0.85, 0.51, and 0.68, hypnosis versus usual care: p = 0.85, 0.93, and 0.96).

Conclusion: Antenatal hypnosis training may increase the release of cortisol during childbirth with no long-term consequences. Further research is needed to help interpret these findings.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0230704PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7194394PMC
July 2020

Do fetal extravillous trophoblasts circulate in maternal blood postpartum?

Acta Obstet Gynecol Scand 2020 06 17;99(6):751-756. Epub 2020 May 17.

Department of Women's Disease and Birth, Aarhus University Hospital, Aarhus, Denmark.

Introduction: Circulating fetal extravillous trophoblasts may offer a superior alternative to cell-free fetal DNA for noninvasive prenatal testing. Cells of fetal origin are a pure source of fetal genome; hence, unlike the cell-free noninvasive prenatal test, the fetal cell-based noninvasive prenatal test is not expected to be affected by maternal DNA. However, circulating fetal cells from previous pregnancies may lead to confounding results.

Material And Methods: To study whether fetal trophoblast cells persist in maternal circulation postpartum, blood samples were collected from 11 women who had given birth to a boy, with blood sampling at 1-3 days (W0), 4-5 weeks (W4-5), around 8 weeks (W8) and around 12 weeks (W12) postpartum. The existence of fetal extravillous trophoblasts was verified either by X and Y chromosome fluorescence in situ hybridization analysis or by short tandem repeat analysis. To exclude technological bias in isolating fetal cells, blood samples were also collected from 10 pregnant women between a gestational age of 10 and 14 weeks, the optimal time frame for cell-based noninvasive prenatal test sampling. All the samples were processed according to protocols established by ARCEDI Biotech for fetal extravillous trophoblast enrichment and isolation.

Results: Fetal extravillous trophoblasts were found in all the 10 samples from pregnant women between a gestational age of 10 and 14 weeks. However, only 4 of 11 blood samples taken from women at 1-3 days postpartum rendered fetal extravillous trophoblasts, and only 2 of 11 samples rendered fetal extravillous trophoblasts at 4 weeks postpartum.

Conclusions: In this preliminary dataset on few pregnancies, none of the samples rendered any fetal cells at or after 8 weeks postpartum, showing that cell-based noninvasive prenatal testing based on fetal extravillous trophoblasts is unlikely to be influenced by circulating cells from previous pregnancies.
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http://dx.doi.org/10.1111/aogs.13880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7384123PMC
June 2020

Drug exposure during pregnancy and fetal cardiac function - a systematic review.

J Perinat Med 2020 Mar;48(3):199-208

Department of Obstetrics and Gynecology, Aarhus University Hospital, Aarhus, Denmark.

Background The aim of this systematic review was to describe the effects of drug exposure during pregnancy on fetal cardiac function. Methods We searched MEDLINE, Embase, Cochrane and SCOPUS for studies assessing fetal cardiac function in drug-exposed human pregnancies. Risk of bias was assessed by the Risk Of Bias In Non-randomized Studies of Interventions (ROBIN-I) tool. Results We included 32 studies on eight different drug groups. They included 51 outcome variables, which were all based on ultrasound techniques primarily assessing systolic function: pulsed wave Doppler, tissue Doppler imaging (TDI), and B- and M-mode. Overall, the risk of bias was moderate. β2 agonists increased the systolic velocity in the ductus arteriosus and the fetal heart rate. β-blockers caused unchanged or decreased systolic velocity of the pulmonary trunk. Corticosteroids increased the velocity in the ductus arteriosus. Furthermore, in growth-restricted fetuses with an increased myocardial performance index (MPI') on the right side, corticosteroids normalized this variable. Nonsteroidal anti-inflammatory drugs (NSAIDs), but not acetylsalicylic acid, increased the flow velocities in the ductus arteriosus, decreased the shortening fraction and increased the end-diastolic ventricular diameters. Metformin and insulin normalized the diastolic strain and global longitudinal strain in diabetic pregnancies. Highly active antiretroviral therapy (HAART) exposure increased the E/A ratio on the right side, prolonged the isovolumic relaxation time (IRT) and ejection time, shortened the isovolumic contraction time (ICT), and decreased left myocardial systolic peak velocities. Chemotherapy did not cause detectable changes. Conclusion Six of the eight drug groups caused detectable changes in fetal cardiac function. However, the evidence was hampered by only a few studies for some drugs.
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http://dx.doi.org/10.1515/jpm-2019-0402DOI Listing
March 2020

Humanized NOG Mice for Intravaginal HIV Exposure and Treatment of HIV Infection.

J Vis Exp 2020 01 31(155). Epub 2020 Jan 31.

Department of Clinical Medicine, Aarhus University; Department of Infectious Diseases, Aarhus University Hospital.

Humanized mice provide a sophisticated platform to study human immunodeficiency virus (HIV) virology and to test antiviral drugs. This protocol describes the establishment of a human immune system in adult NOG mice. Here, we explain all the practical steps from isolation of umbilical cord blood derived human CD34+ cells and their subsequent intravenous transplantation into the mice, to the manipulation of the model through HIV infection, combination antiretroviral therapy (cART), and blood sampling. Approximately 75,000 hCD34+ cells are injected intravenously into the mice and the level of human chimerism, also known as humanization, in the peripheral blood is estimated longitudinally for months by flow cytometry. A total of 75,000 hCD34+ cells yields 20%-50% human CD45+ cells in the peripheral blood. The mice are susceptible to intravaginal infection with HIV and blood can be sampled once weekly for analysis, and twice monthly for extended periods. This protocol describes an assay for quantification of plasma viral load using droplet digital PCR (ddPCR). We show how the mice can be effectively treated with a standard-of-care cART regimen in the diet. The delivery of cART in the form of regular mouse chow is a significant refinement of the experimental model. This model can be used for preclinical analysis of both systemic and topical pre-exposure prophylaxis compounds as well as for testing of novel treatments and HIV cure strategies.
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http://dx.doi.org/10.3791/60723DOI Listing
January 2020

Use of stimulants, over-the-counter and prescription drugs among Danish pregnant women.

Basic Clin Pharmacol Toxicol 2020 Sep 10;127(3):205-210. Epub 2020 Mar 10.

Department of Obstetrics and Gynaecology, Randers Regional Hospital, Randers, Denmark.

Using self-reports and blood samples from 225 unselected Danish first trimester pregnant women, the purpose of this study was to assess their use of stimulants, for example caffeine and nicotine as well as over-the-counter (OTC) and prescription drugs. According to self-reported information, 24% had used prescription drugs and 48% had used OTC drugs mainly acetaminophen (42%), 9.3% were habitual smokers, 44% stated a daily use of caffeinated beverages, and 1.3% used illegal drugs. Ultra-performance liquid chromatography with high-resolution time-of-flight mass spectrometry (UPLC-HR-TOFMS) analysis was performed on corresponding blood samples applying golden standards for use of UPLC-HR-TOFMS in forensic medicine. Traces of prescription drugs were detected in 5.3% of the samples and 8.9% contained OTC drugs (acetaminophen 7.1%). Traces of smoking were identified in 8.0%, caffeine in 83% and illegal drugs in 0.9%. These results indicate a substantial use of OTC drugs and caffeine among Danish pregnant women. Blood analysis indicated that many women could be unaware of their caffeine intake. As common substances may be associated with adverse pregnancy outcomes, healthcare professionals should inquire about such habits during pregnancy. The results also underline the need for more research into the molecular effects of such drugs on placental function and foetal development.
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http://dx.doi.org/10.1111/bcpt.13396DOI Listing
September 2020
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