Risks and pregnancy outcome after fetal reduction in dichorionic twin pregnancies: a Danish national retrospective cohort study.

BACKGROUND: Twin pregnancies carry a higher risk of congenital and structural malformations, and pregnancy complications including miscarriage, stillbirth, and intrauterine fetal death, compared with singleton pregnancies. Carrying a fetus with severe malformations or abnormal karyotype places the remaining healthy fetus at an even higher risk of adverse outcome and pregnancy complications. Maternal medical conditions or complicated obstetrical history could, in combination with twin pregnancy, cause increased risks for both the woman and the fetuses. To our knowledge, no previous studies have evaluated and compared the outcomes of all dichorionic twin pregnancies and compared the results of reduced twins with those of nonreduced and primary singletons in a national cohort. These data are important for clinicians when counseling couples about fetal reduction and its implications. OBJECTIVE: This study aimed to describe and compare the risks of adverse pregnancy outcomes, including the risk of pregnancy loss, in a national cohort of all dichorionic twins-reduced, nonreduced, and primary singletons. In addition, we examined the implications of gestational age at fetal reduction on gestational age at delivery. STUDY DESIGN: This was a retrospective cohort study of all Danish dichorionic twin pregnancies, including pregnancies undergoing fetal reduction and a large proportion of randomly selected primary singleton pregnancies with due dates between January 2008 and December 2018. The primary outcome measures were adverse pregnancy outcomes (defined as miscarriage before 24 weeks, stillbirth from 24 weeks, or single intrauterine fetal death in nonreduced twin pregnancies), preterm delivery, and obstetrical pregnancy complications. Outcomes after fetal reduction were compared with those of nonreduced dichorionic twins and primary singletons. RESULTS: In total, 9735 dichorionic twin pregnancies were included, of which 172 (1.8%) were reduced. In addition, 16,465 primary singletons were included. Fetal reductions were performed between 11 and 23 weeks by transabdominal needle-guided injection of potassium chloride, and outcome data were complete for all cases. Adverse pregnancy outcome was observed in 4.1% (95% confidence interval, 1.7%-8.2%) of reduced twin pregnancies, and 2.4% (95% confidence interval, 0.7%-6.1%) were delivered before 28 weeks, and 4.2% (95% confidence interval, 1.7%-8.5%) before 32 weeks. However, when fetal reduction was performed before 14 weeks, adverse pregnancy outcomes occurred in only 1.4% (95% confidence interval, 0.0%-7.4%), and delivery before 28 and 32 weeks diminished to 0% (95% confidence interval, 0.0%-5.0%) and 2.8% (95% confidence interval, 0.3%-9.7%), respectively. In contrast, 3.0% (95% confidence interval, 2.7%-3.4%) of nonreduced dichorionic twins had an adverse pregnancy outcome, and 1.9% (95% confidence interval, 1.7%-2.1%) were delivered before 28 weeks, and 7.3% (95% confidence interval, 6.9%-7.7%) before 32 weeks. Adverse pregnancy outcomes occurred in 0.9% (95% confidence interval, 0.7%-1.0%) of primary singletons, and 0.2% (95% confidence interval, 0.1%-0.3%) were delivered before 28 weeks, and 0.7% (95% confidence interval, 0.6%-0.9%) before 32 weeks. For reduced twins, after taking account of maternal factors and medical history, it was demonstrated that the later the fetal reduction was performed, the earlier the delivery occurred (P<.01). The overall risk of pregnancy complications was significantly lower among reduced twin pregnancies than among nonreduced dichorionic twin pregnancies (P=.02). CONCLUSION: In a national 11-year cohort including all dichorionic twin pregnancies, transabdominal fetal reduction by needle guide for fetal or maternal indication was shown to be safe, with good outcomes for the remaining co-twin. Results were best when the procedure was performed before 14 weeks.

Triple trouble: uncovering the risks and benefits of early fetal reduction in trichorionic triplets in a large national Danish cohort study.

BACKGROUND: Triplet pregnancies are high risk for both the mother and the infants. The risks for infants include premature birth, low birthweight, and neonatal complications. Therefore, the management of triplet pregnancies involves close monitoring and may include interventions, such as fetal reduction, to prolong the pregnancy and improve outcomes. However, the evidence of benefits and risks associated with fetal reduction is inconsistent. OBJECTIVE: This study aimed to compare the outcomes of trichorionic triplet pregnancies with and without fetal reduction and with nonreduced dichorionic twin pregnancies and primary singleton pregnancies. STUDY DESIGN: All trichorionic triplet pregnancies in Denmark, including those with fetal reduction, were identified between 2008 and 2018. In Denmark, all couples expecting triplets are informed about and offered fetal reduction. Pregnancies with viable fetuses at the first-trimester ultrasound scan and pregnancies not terminated were included. Adverse pregnancy outcome was defined as a composite of miscarriage before 24 weeks of gestation, stillbirth at 24 weeks of gestation, or intrauterine fetal death of 1 or 2 fetuses. RESULTS: The study cohort was composed of 317 trichorionic triplet pregnancies, of which 70.0% of pregnancies underwent fetal reduction to a twin pregnancy, 2.2% of pregnancies were reduced to singleton pregnancies, and 27.8% of pregnancies were not reduced. Nonreduced triplet pregnancies had high risks of adverse pregnancy outcomes (28.4%), which was significantly lower in triplets reduced to twins (9.0%; difference, 19.4%, 95% confidence interval, 8.5%-30.3%). Severe preterm deliveries were significantly higher in nonreduced triplet pregnancies (27.9%) than triplet pregnancies reduced to twin pregnancies (13.1%; difference, 14.9%, 95% confidence interval, 7.9%-21.9%). However, triplet pregnancies reduced to twin pregnancies had an insignificantly higher risk of miscarriage (6.8%) than nonreduced twin pregnancies (1.1%; difference, 5.6%; 95% confidence interval, 0.9%-10.4%). CONCLUSION: Triplet pregnancies reduced to twin pregnancies had significantly lower risks of adverse pregnancy outcomes, severe preterm deliveries, and low birthweight than nonreduced triplet pregnancies. However, triplet pregnancies reduced to twin pregnancies were potentially associated with a 5.6% increased risk of miscarriage.

How does cell-based non-invasive prenatal test (NIPT) perform against chorionic villus sampling and cell-free NIPT in detecting trisomies and copy number variations? A clinical study from Denmark.

OBJECTIVES: We aimed to compare cell-based NIPT (cbNIPT) to chorionic villus sampling (CVS) and to examine the test characteristics of cbNIPT in the first clinical validation study of cbNIPT compared to cell-free NIPT (cfNIPT). MATERIAL AND METHODS: Study 1: Women (N = 92) who accepted CVS were recruited for cbNIPT (53 normal and 39 abnormal). Samples were analyzed with chromosomal microarray (CMA). Study 2: Women (N = 282) who accepted cfNIPT were recruited for cbNIPT. cfNIPT was analyzed using sequencing and cbNIPT by CMA. RESULTS: Study 1: cbNIPT detected all aberrations (32/32) found in CVS: trisomies 13, 18 and 21 (23/23), pathogenic copy number variations (CNVs) (6/6) and sex chromosome aberrations (3/3). cbNIPT detected 3/8 cases of mosaicism in the placenta. Study 2: cbNIPT detected all trisomies found with cfNIPT (6/6) and had no false positive (0/246). One of the three CNVs called by cbNIPT was confirmed by CVS but was undetected by cfNIPT, two were false positives. cbNIPT detected mosaicism in five samples, of which two were not detected by cfNIPT. cbNIPT failed in 7.8% compared to 2.8% in cfNIPT. CONCLUSION: Circulating trophoblasts in the maternal circulation provide the potential of screening for aneuploidies and pathogenic CNVs covering the entire fetal genome.

A decade of change - lessons learned from prenatal diagnostics in Central Denmark region in 2008-2018.

INTRODUCTION: In 2011, it was decided to implement chromosomal microarray in prenatal testing in the Central Denmark Region, mainly due to the expected higher diagnostic yield. Chromosomal microarray was introduced gradually for an increasing number of pregnancies and without a transition period where both karyotyping and chromosomal microarray were performed: first malformations (2011), then large nuchal translucency (2013), then high risk at combined first trimester risk screening (2016) and finally for all indications (2018). This retrospective study summarizes 11 years of using chromosomal microarray in invasive prenatal testing and presents the effect on diagnostic yield and turnaround time. Furthermore, the concerns when introducing chromosomal microarray are presented and discussed. MATERIAL AND METHODS: Registry data from the Danish Fetal Medicine Database, the regional fetal medicine database, the Danish Cytogenetic Central Register and the local laboratory database at Department of Clinical Genetics were all combined, and a cohort of 147 158 singleton pregnancies with at least one ultrasound examination was established RESULTS: Of the 147 158 pregnancies, invasive sampling was performed (chorionic villi or amniocytes) in 8456, corresponding to an overall invasive rate of 5.8%. Between 2016 and 2018, 3.4% (95% confidence interval [CI] 2.8-4.2%; n = 86) of the invasive samples (n = 2533) had a disease causing copy number variant and 5.3% (95% CI 4.4-6.2%; n = 133) had trisomies and other aneuploidies. The turnaround time more than halved from 14 days to an average of 5.5 days for chorionic villus sampling. CONCLUSIONS: Chromosomal microarray identified 5.3% trisomies and 3.4% copy number variants, thereby increased the diagnostic yield by more than 64% compared with karyotype only and it also more than halved the turnaround time. Some preliminary concerns proved real, eg prenatal counseling complexity, but these have been resolved over time in a clinical path with expert consultations.

Burst Spinal Cord Stimulation in Pregnancy: First Clinical Experiences.

OBJECTIVES: Spinal cord stimulation (SCS) is a treatment for chronic neuropathic pain. It is based on the delivery of electric impulses to the spinal cord, traditionally in a regular square-wave pattern ("tonic" stimulation) and, more recently, in a rhythmic train-of-five "BurstDR" pattern. The safety of active SCS therapy in pregnancy is not established, and recommendations are based on limited casuistic evidence. We present in this study clinical data on a case series of six women treated with burst SCS during pregnancy. In addition, we present the ultrasonographic flow measurements of fetal and uteroplacental blood flow in a pregnant patient. MATERIALS AND METHODS: Patients were included if they had been implanted with a full SCS system at Aarhus University Hospital, Denmark, between 2006 and 2020 and received active burst SCS stimulation during a pregnancy. Telephone interviews were conducted, including details on SCS therapy, medication, pregnancy course and outcome, and health status of the offspring. In one patient, the uteroplacental and fetal blood flow was assessed in gestational week 29 by Doppler flow measurements performed during both ON and OFF phases of the SCS system. RESULTS: Six patients were included with a total of 11 pregnancies. Three pregnancies ended in miscarriages, all in the same patient who had preexisting significant risk factors for miscarriage. Eight resulted in a live-born child with normal birth weight for gestational age; seven were born at term, and one was born late preterm, in gestational week 36. Ultrasonographic Doppler flow, measured in one patient, was normal and did not reveal any immediate changes between burst SCS ON and OFF. Seven children were reported healthy with normal neurodevelopment and one physically healthy but with developmental delays. CONCLUSIONS: The data presented in this study add to the accumulating evidence of the safety of SCS in pregnancy.

The importance of information and support following a suspected second-trimester anomaly that is later discarded: A qualitative study of women's experiences.

INTRODUCTION: A second-trimester anatomy scan may identify a suspected minor fetal anomaly and/or "soft marker," such as choroid plexus cysts or femoral shortening. Such findings can raise a medical concern, as they could indicate severe fetal disease; however, they are also often transient or a "false alarm." The aim of this study was to explore the experiences of pregnant women, where a medical concern was raised at the second-trimester ultrasound scan and later discarded after follow-up examinations and diagnostic testing. MATERIAL AND METHODS: This study consists of qualitative, in-depth interviews with nine women, where a minor anomaly/soft marker was identified at the second-trimester scan and a severe anomaly was later ruled out. Data were analyzed using thematic analysis. RESULTS: The main source of worry was uncertainty about the possible implications for the pregnancy and the baby, particularly concerns about potential termination of pregnancy for a severe fetal condition. The women described four strategies to manage worry and uncertainty during the diagnostic process: (a) seeking additional information to feel more in control, and (b) using social networks to share their concerns. Some women tried to (c) mentally distance themselves from the pregnancy during the diagnostic period, while (d) extra scans could relieve worry and support attachment. The women appreciated when the fetal medicine specialist pointed to normal features in the pregnancy and the baby, as this provided some counterbalance to the sense of uncertainty. In general, the women expressed satisfaction with the information received during the diagnostic process. However, all of them were worried during the diagnostic process, and where this process was prolonged, such worry lingered even after the minor anomaly/soft marker had been discarded. CONCLUSIONS: Diagnostic uncertainty cannot be avoided in obstetric ultrasound and the women concerned appreciated being informed about the suspected findings even if it caused increased worry. Expedient diagnostic processes may alleviate worry, but are not always possible. Women in a prolonged diagnostic process may benefit from psychological and social support in parallel with, and even beyond, the obstetric investigation. However, further research is warranted.

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

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.

Implementation of exome sequencing in fetal diagnostics-Data and experiences from a tertiary center in Denmark.

INTRODUCTION: Applying whole-exome sequencing (WES) for the diagnosis of diseases in children has shown significant diagnostic strength compared with chromosomal microarray. WES may also have the potential of adding clinically relevant prenatal information in cases where a fetus is found to have structural anomalies. We present results from the first fetal exomes performed in a tertiary center in Denmark. MATERIAL AND METHODS: Couples/expectant parents were included in Central Denmark Region from July 2016 to March 2019. Inclusion was not systematic, but where one or more fetal malformations or severe fetal hydrops were detected, and a specific diagnosis had not been obtained by chromosomal microarray. WES was performed in ongoing pregnancies (N = 11), after intrauterine demise (N = 5), or after termination of pregnancy based on ultrasound findings (N = 19). In most cases, a trio format was applied comprising fetal and parental DNA. RESULTS: WES was performed in 35 highly selected fetal cases. Pathogenic variants, or variants likely to explain the phenotype, were detected in 9/35 (26%). Variants of uncertain significance were detected in 7/35 (20%) and there was one secondary finding (3%). Out of the 11 ongoing pregnancies, four reached a genetic diagnosis (36%). Detection rate was highest in cases of multisystem anomalies (7/13, 54%). WES was completed in all three trimesters and both autosomal dominant, autosomal recessive and X-linked inheritance were revealed. CONCLUSIONS: We present data from 35 cases of exome sequencing applied in a setting of fetal malformations. Importantly, though, we wish to share our personal experiences with implementing WES into a prenatal setting. As a medical society, we must continue to share what we do not understand, what went wrong, what is difficult, and what we do not agree upon. A common understanding and language are warranted. We also advocate that more research is needed concerning the clinical value, as well as costs and patient perspectives, of using WES in pregnancy. We believe that WES will lead to improved prenatal and perinatal care.

Second-trimester fetal head circumference in more than 350 000 pregnancies: Outcome and suggestion for sex-dependent cutoffs for small heads.

OBJECTIVE: To explore the relationship between small fetal second-trimester head circumference (HC) and pregnancy outcome and identify a cutoff point for offering genetic testing. METHOD: Data from second-trimester scans in Denmark were linked to national registers. Fetuses with anomalies diagnosed before this scan were excluded. Fetuses were grouped according to HC z-score. RESULTS: We included 352 515 singleton fetuses. The mean HC was significantly larger among males than among females with z-scores averaging 0.52 more in males. Small HC was associated with chromosomal anomaly, malformations of the CNS and heart, miscarriage/perinatal death, termination, preterm delivery, and intrauterine growth restriction (test for trend: P < .001 for all outcomes). Fetuses in the group with z-score less than -3 had the highest incidence of adverse outcome, irrespective of fetal sex. In the groups with z-scores between -3 and -2.5, and between -2.5 and -2, risk of adverse outcome was lower for females than males for all outcome categories. CONCLUSION: Small HC in second trimester is a prognostic marker for adverse outcome. The smaller the HC, the higher the risk of adverse outcome. We suggest an HC cutoff point of -2 SD for males and -2.5 SD for females for offering genetic testing.

Cervical collagen is reduced in non-pregnant women with a history of cervical insufficiency and a short cervix.

INTRODUCTION: Preterm cervical shortening and cervical insufficiency may be caused by a constitutional weakness of the cervix. The aim of this study was to assess the cervical collagen concentration in non-pregnant women with a history of cervical insufficiency or of a short cervix in the second trimester of pregnancy. MATERIAL AND METHODS: In this case-control study we included non-pregnant women one year or more after pregnancy: 55 controls with a history of normal delivery; 27 women with a history of cervical insufficiency; and 10 women with a history of a short cervix (<5th percentile) and 10 women with a history of a long cervix (>95th percentile) at gestational weeks 18-20. We obtained biopsies (3 × 3-4 mm) from the ectocervix and determined the collagen concentration by measuring the hydroxyproline concentration. RESULTS: Women with cervical insufficiency had lower collagen concentrations (63.5 ± 5.1%; mean ± SD) compared with controls (68.2 ± 5.4%; p = 0.0004); area under the ROC curve 0.73 (95% CI 0.62-0.84). A cut-off value at 67.6% collagen resulted in a positive likelihood ratio of 3.2, a sensitivity of 60%, and a specificity of 81%. Also, women with a short cervix in the second trimester had lower collagen concentrations in a non-pregnant state (62.1% ± 4.9%) compared with women with a long cervix (67.8% ± 5.0%; p = 0.02). CONCLUSIONS: Both cervical insufficiency and a short cervix in the second trimester of pregnancy are associated with low cervical collagen concentrations in a non-pregnant state more than one year after pregnancy.

Quantitative sonoelastography of the uterine cervix prior to induction of labor as a predictor of cervical dilation time.

OBJECTIVE: To evaluate how the approximate Young's modulus of the uterine cervix assessed by quantitative sonoelastography in patients undergoing induction of labor is associated with the cervical dilation time and to evaluate the approximate Young's modulus as a predictor of prolonged cervical dilation time. DESIGN: Cross-sectional study. SETTING: Aarhus University Hospital, Aarhus, Denmark. POPULATION: Term-pregnant women. METHODS: A total of 49 term-pregnant women were included before induction of labor. The approximate Young's modulus of the anterior cervical lip was determined by the use of a reference cap applied on the end of the transvaginal transducer during sonoelastography. MAIN OUTCOME MEASURES: Cervical dilation time during active labor. RESULTS: The approximate Young's modulus was associated with the cervical dilation time during active labor (R(2) log  = 0.24, p < 0.01) and predicted prolonged duration of cervical dilation time (>330 min) with the area under the receiver operating characteristic (ROC) curve of 0.71, sensitivity 74%, and specificity 69%. Equivalent figures for the Bishop's score were R(2) log  = 0.02 (p = 0.37), the area under the ROC curve 0.53, sensitivity 53%, and specificity 46%. For the cervical length measurements the corresponding results were: R(2) log  = 0.02, p = 0.35, area under the ROC curve 0.57, sensitivity 66% and specificity 54%. The intra-observer and inter-observer intraclass correlations were 88% and 58%, respectively, with quantitative elastography. CONCLUSIONS: The approximate Young's modulus is superior to the Bishop score and the cervical length measurements concerning the prediction of cervical dilation time and the risk of prolonged dilation time after induction of labor.

Copeptin is not a useful biomarker for small-for-gestational-age: a case control study.

OBJECTIVE: To investigate copeptin as a biomarker for small-for-gestational-age. METHODS: We conducted a nested case-control study on maternal copeptin levels measured in gestational week 12 and 19 and risk of small-for-gestational age. Cases were defined as pregnant women who delivered a small-for-gestational-age infant. Small-for-gestational age was defined as a birth weight - 22% or less than expected according to gestational age (n = 39). Controls were pregnant women who delivered a normal-weight infant (n = 119). The copeptin ultrasensitive Kryptor kit (BRAHMS) was used to determine copeptin in maternal serum. We established reference ranges for copeptin by 95% prediction intervals with 90% confidence intervals. Paired and unpaired t-tests were performed to test the null-hypothesis of no difference in copeptin levels within and between the groups. RESULTS: The reference intervals for copeptin in normal pregnancies were 1.24-5.51 pmol/L (90% confidence intervals on upper and lower limit were 1.13-1.37 and 5.00-6.08 pmol/L) at gestational week 12, and 1.30-5.09 pmol/L (90% confidence intervals were 1.19-1.42 and 4.65-5.57 pmol/L) at gestational week 19. Copeptin levels decreased from week 12-19 in cases (p = 0.02), whereas no change was observed in controls (p = 0.61). We found no difference in copeptin levels in cases compared to controls in gestational week 12 (p = 0.10) and week 19 (p = 0.81). CONCLUSION: The present study could not demonstrate copeptin as a novel biomarker for small-for-gestational-age.

Quantitative sonoelastography of the uterine cervix by interposition of a synthetic reference material.

OBJECTIVE: To develop a reference material that allows quantitative elastography of the uterine cervix using the calculation of the approximate tissue stiffness expressed as Young's modulus (N/mm(2) ). Further, to test the elastography equipment on phantoms from a clinical perspective regarding the distance dependence and the influence of a heterogeneous material. DESIGN: Methodological study. SETTING: Aarhus University Hospital, Denmark. POPULATION: Six mid- and five full-term pregnant women. METHODS: Reference caps and phantoms with Young's moduli between 0.07 and 0.40 N/mm(2) were made of silicone and oil. By using reference caps, the approximate Young's moduli of the cervixes were calculated from strain ratios obtained by elastography. MAIN OUTCOME MEASURES: Approximate Young's modulus of the cervix. RESULTS: The recordings of the phantoms revealed that the calculation of the approximate Young's moduli became unreliable at distances above 10-15 mm from the transducer. This was further increased for a phantom which included a soft layer imitating the cervical canal. The approximate Young's modulus obtained from the anterior cervical lip was 0.08 N/mm(2) in mid-term and 0.03 N/mm(2) in full-term pregnant women (Wilcoxon rank-sum test, p = 0.01). CONCLUSION: The reference cap constitutes a promising tool for quantitative elastography of the anterior cervical lip. Figures obtained from the posterior cervical lip are less plausible due to the distance from the transducer and the heterogeneity introduced by the cervical canal. The method has the potential to be used to supplement cervical length assessment when evaluating women at risk of preterm delivery and when planning induction of labor.

Quantitative strain elastography of the uterine cervix assessed by the GE Voluson E10 system in combination with a force-measuring device.

OBJECTIVE: During pregnancy, the stiffness of the cervical tissue decreases long before the cervical length decreases. Therefore, several approaches have been proposed in order to ensure a more objective assessment of cervical stiffness than that achieved by digital evaluation. Strain elastography has shown promising results. This technique is based on an ultrasound assessment of the tissue deformation that occurs when the examiner applies pressure on the tissue with the ultrasound probe. However, the results are only semi-quantitative as they depend on the unmeasured force used by the examiner. We, therefore, hypothesized that a force-measuring device applied to the handle of the ultrasound probe may render the technique quantitative. With this approach, the stiffness is the force (measured by the device) divided by the compression (measured by the elastography platform). One perspective is the early identification of women at risk of preterm birth in whom cervical stiffness may decrease long before cervical shortening. Another perspective is cervical evaluation when planning labor induction. In this feasibility study, we aimed to evaluate how quantitative strain elastography performs when a commercially available strain elastography platform (by which the algorithm is unavailable) is combined with a custom-made, force-measuring device. We studied how the assessments were associated with the gestational age in women with uncomplicated pregnancies and how they were associated with cervical dilatation time from 4 to 10 cm in women undergoing labor induction. METHODS: In the analysis, we included quantitative strain elastography assessments from 47 women with uncomplicated singleton pregnancies, with gestational age between 12+0 and 40+0, and from 27 singleton term-pregnant women undergoing labor induction. The force-measuring device was mounted on the handle of a transvaginal probe. The strain values (i.e. the compression of the cervical tissue) were obtained by the elastography software of the ultrasound scanner (GE Voluson E10). The region of interest was placed within the central part of the anterior cervical lip. Based on the force data and strain values, we calculated the outcomes cervical elastography indexGE (CEIGE) and the cervical strength indexGE (CEIGE x cervical length: CSIGE). RESULTS: The average CEIGE was 0.24 N at week 12 and 0.15 N at week 30-34. For CSIGE these figures were 8.2 and 4.7 N mm, respectively (p = 0.002). Among women undergoing labor induction, the CEIGE was associated with a cervical dilatation time (4-10 cm) beyond 7 h. For nulliparous women, this area under the ROC curve was 0.94. CONCLUSION: Quantitative strain elastography may constitute a tool for the evaluation of a uterine cervix with normal length in women at risk of preterm birth and in women undergoing labor induction. The performance of this tool deserves evaluation in larger clinical trials.

Maternal smoking and impaired endothelium-dependent nitric oxide-mediated relaxation of uterine small arteries in vitro.

OBJECTIVE: This study aimed to investigate the endothelium-dependent relaxation of uterine small arteries from pregnant nonsmokers, smokers, and ex-smokers who stopped smoking early in pregnancy. STUDY DESIGN: Uterine arteries were dissected from myometrial biopsies obtained during elective cesarean sections of 34 uncomplicated, singleton pregnancies, and the vascular function was assessed in a wire myograph for isometric recordings. Serum cotinine verified self-reported smoking; 15 were nonsmokers, 10 were smokers, and 9 were ex-smokers. RESULTS: Arteries from smokers and ex-smokers had reduced bradykinin-induced relaxation compared to arteries from nonsmokers (P < .05). The relaxation response to the nitric oxide donor sodium nitroprusside was similar in arteries from nonsmokers and smokers but was better in arteries from ex-smokers (P < .05). CONCLUSION: The findings suggest that maternal smoking reduces endothelium-dependent nitric oxide-mediated relaxation in uterine small arteries and that smoking cessation early in pregnancy does not fully abolish this deleterious effect, despite improvement in relaxation to nitroprusside.

Low serum interleukin-17 is associated with preterm delivery.

OBJECTIVE: To study maternal serum interleukin-17 (IL-17) during normal pregnancy and evaluate the association with preterm delivery. DESIGN: Prospective study. SETTING: Aarhus University Hospital, Denmark. POPULATION: Three cohorts: (a) low-risk cohort of 1,069 women who had serum drawn in weeks 12 and 19, (b) subgroup of the low-risk cohort, consisting of 40 women, who had serum drawn at 12, 19, 26, 33 and 39 weeks of gestation and (c) a symptomatic cohort of 93 women admitted with symptoms of preterm delivery at a gestational age of 24(+ 0) weeks to 33(+ 6) weeks. METHODS: Serum IL-17 determined by an in-house developed multiplex sandwich immunoassay. MAIN OUTCOME MEASURES: Preterm delivery <37(+0) weeks gestation. RESULTS: Serum IL-17 did not change during normal pregnancy. At admission to hospital, women with preterm contractions had significantly decreased serum IL-17 as compared with normal pregnancies (median <4 [interquartile ranges, IQR, <4-10 pg/ml] vs. 174 pg/ml [IQR, 92 - 485 pg/ml]); this difference was enhanced and highly significant for women delivering preterm versus term (median <4 [IQR, <4-7.9 pg/ml] vs. median 6.0 [IQR, <4-221 pg/ml]; p-value 0.03). Serum IL-17 was also lower in women with preterm prelabor rupture of membranes. A slightly, but not statistically significant decrease was found in weeks 12 and 19 in low-risk women who subsequently delivered preterm. CONCLUSION: Maternal serum IL-17 may be involved in preterm delivery.

Sertraline use during pregnancy and effect on fetal cardiac function.

OBJECTIVES: The objective of this study was to evaluate the fetal cardiac function in human pregnancies exposed to sertraline (a selective serotonin reuptake inhibitor) compared to unexposed pregnancies. METHOD: We included 44 women in gestational week 25 + 0 days to week 26 + 6 days. Fifteen women used sertraline (50-150 mg per day), and 29 women used no daily medication. We assessed fetal cardiac function by Myocardial Performance Index (MPI), E/A ratios and by tricuspid and mitral annular plane systolic excursion (TAPSE and MAPSE) measured by 2D M-mode and by 4D eSTIC M-mode. RESULTS: There were no differences between the sertraline exposed and the unexposed. The mean difference of MPI was 0.03 (95% CI -0.08-0.03), of tricuspid and mitral E/A ratios 0.00 (95% CI -0.03-0.05) and 0.03 (95% CI -0.07-0.01), respectively. The mean difference of TAPSE, by 2D and eSTIC, was 0.07 mm (95% CI -0.56-0.41) and 0.10 mm (95% CI -0.55-0.34). Mean difference of MAPSE, by 2D and eSTIC was 0.16 mm (95% CI -0.22-0.53) and 0.24 mm (95% CI -0.16-0.65), respectively. Serum levels of sertraline in exposed participants ranged from 33-266, median 92 nmol/L. CONCLUSIONS: We found no significant differences in fetal cardiac function, assessed by TAPSE, MAPSE, MPI and E/A ratios, in pregnancies exposed to sertraline compared to the unexposed.

A novel homozygous variant in C1QBP causes severe IUGR, edema, and cardiomyopathy in two fetuses.

The C1QBP protein (complement component 1 Q subcomponent-binding protein), encoded by the C1QBP gene, is a multifunctional protein predominantly localized in the mitochondrial matrix. Biallelic variants have previously been shown to give rise to combined respiratory-chain deficiencies with variable phenotypic presentation, severity, and age at onset, from intrauterine with a mostly lethal course, to a late-onset mild myopathy. We present two fetuses, one male and one female, of first-cousin parents, with severe intrauterine growth retardation, oligo/anhydramnios, edema, and cardiomyopathy as the most prominent prenatal symptoms. Both fetuses showed no copy number variants by chromosome microarray analysis. Analysis of a fibroblast culture from one of the fetuses showed deficiency of respiratory chain complex IV, and using exome sequencing, we identified homozygosity for a novel variant in C1QBP in both fetuses. To our knowledge, only six patients with pathogenic variants in C1QBP have been reported previously and with this report, we add a novel pathogenic variant in C1QBP found in two related fetuses.

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

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.