Prenatal diagnosis in estimating the prognosis of sacrococcygeal teratoma.

: Sacrococcygeal teratoma is a rare congenital malformation, the prognosis depends on factors affecting foetal development. The diagnosis is based on ultrasound examination, especially the evaluation of the detailed morphology of the foetus in the 20th week of pregnancy. Therefore, it is crucial to keep looking for ultrasound markers that would prenatally determine the most accurate prognosis for the foetus. Now, we rely on a small number of studies with a predominance of case reports. We offer a literature review of the essential information concerning sacrococcygeal teratoma diagnostics, therapy, and complications of sacrococcygeal teratomas in connection with prenatal diagnosis. It turns out that in cases with a favourable prognosis according to prenatal ultrasound examination and adequate surgical treatment after childbirth, the prognosis of this congenital malformation is excellent.

Metabolic Syndrome Prevalence in Women with Gestational Diabetes Mellitus in the Second Trimester of Gravidity.

Background: Women with gestational diabetes (GDM) have an increased risk of metabolic syndrome (MS) after delivery. MS could precede gravidity. The aims of this study were (i) to detect the prevalence of MS in women at the time of GDM diagnosis, (ii) to detect the prevalence of MS in the subgroup of GDM patients with any form of impaired glucose tolerance after delivery (PGI), and (iii) to determine whether GDM women with MS have a higher risk of peripartal adverse outcomes. Methods: A cross-sectional observational study comprised n = 455 women with GDM. International Diabetes Federation (IDF) criteria for MS definition were modified to the pregnancy situation. Results: MS was detected in 22.6% of GDM patients in those with PGI 40%. The presence of MS in GDM patients was associated with two peripartal outcomes: higher incidence of pathologic Apgar score and macrosomia (p = 0.01 resp. p = 0.0004, chi-square). Conclusions: The presence of MS in GDM patients is a statistically significant risk factor (p = 0.04 chi-square) for PGI. A strong clinical implication of our findings might be to include MS diagnostics within GDM screening using modified MS criteria in the second trimester of pregnancy.

Conservative management of complete fetal expulsion into the abdominal cavity after silent uterine rupture - case report.

BACKGROUND: Clinically silent uterine rupture with complete fetal expulsion into the abdominal cavity is an extremely rare complication. Diagnosis can be difficult and the risk to the mother and fetus is high. Conservative management has been described only in a few cases of partial expulsion of the fetus so far. CASE PRESENTATION: We present a case of 43-year-old tercigravida with a history of previous laparotomic myomectomy and subsequent cesarean section. The subsequent pregnancy was complicated by uterine wall loosening and rupture at the site of the previous uterine scar after myomectomy and complete fetal expulsion into the abdominal cavity. The diagnosis was made at 24 + 6 weeks of gestation. Considering the absence of clinical symptomatology and the good condition of the fetus, a conservative approach was chosen with intensive monitoring of the maternal and fetal conditions. The pregnancy ended by elective cesarean section and hysterectomy at 28 + 0 weeks of gestation. The postpartum course was uneventful and the newborn was discharged to home care 63 days after delivery. CONCLUSIONS: Fetal expulsion into the abdominal cavity after silent uterine rupture of the scarred uterus may be accompanied by minimal symptomatology making early diagnosis difficult. This rare complication must be considered in the differential diagnosis in women after major uterine surgery. In selected cases and under conditions of intensive maternal and fetal monitoring, conservative management may be chosen to reduce the risks associated with prematurity.

Laboring Alone: Perinatal Outcomes during Childbirth without a Birth Partner or Other Companion during the COVID-19 Pandemic.

During the first wave of the COVID-19 pandemic in the spring of 2020, the government of the Czech Republic issued a nationwide ban on visitors to maternity wards. We studied whether the absence of a close person during labor due to this ban impacted perinatal indicators. This study was performed using an administrative observational questionnaire focused on absolute frequencies of events sent to maternity facilities across the Czech Republic. Completed answers were received from 33 facilities covering 4805 births during the study period in 2019 and 4514 births in 2020. The differences in individual parameters were tested using Pearson's chi-squared homogeneity test. There were no significant differences between the two periods in spontaneous pre-term births (p = 0.522) or in the number of cesarean sections (p = 0.536). No significant changes were seen in either local or systemic analgesia. Data showed a significantly shorter (p = 0.026) first stage of labor in 2020 compared to 2019, while there was no significant difference (p = 0.673) in the second stage of labor. There was no statistically significant difference found for newborn perinatal adaptation. There were also no significant differences in intrapartum maternal injuries. Overall, we found no significant differences in basic perinatal indicators during the first wave of COVID-19 in 2020 compared to 2019. Although the absence of a close person may cause stress for the laboring women, it does not impair objective clinical outcomes.

[Trichomonas vaginalis - the culprit or the accomplice?]

The case reports describes detection of Trichomonas vaginalis in a 34-year-old patient with preterm prelabor rupture of membranes and a subsequent C-section in week 25 of her pregnancy, with the presence of T. vaginalis not being the only risk factor for preterm labor. Although a rare finding in pregnant women, the presence of this microorganism must be considered in such situations.

Morbidity and psychomotor development of offspring of women with gestational diabetes: a 5-year follow-up.

BACKGROUND: Gestational diabetes mellitus (GDM) represents a risk factor for both mother and her offspring in a short-term (perinatal morbidity) and long-term horizon (postpartum diabetes or foetal programming). Several studies focused at peri/postnatal outcomes of GDM mother´s offspring, however relatively few (and none in Czech population) were designed as prospective. The aim of the study was to ascertain eventual anthropometric and developmental abnormalities and/or morbidity in offspring of GDM mothers compare to controls in a 5-year follow-up using a parent-reported parameters related to psychomotor development and common paediatric morbidities including a sub-study of offspring of GDM mothers experiencing adverse perinatal outcomes. METHODS: A 5 year follow up study of offspring of GDM mothers (n = 26) vs those with a normal pregnancy (n = 63). An electronic questionnaire was used to obtain the parameters (such as growth, psychomotor development, vaccination, morbidity history etc.) available to parents from the parent-held infant health record. Data on pregnancy and delivery were available from the previous study. RESULTS: Offspring of GDM mothers had delayed psychomotor development in early childhood, but in 5 years of age they seemed to gradually achieve results of a control group. Children with macrosomia had a higher percentile of weight-for-height and were significantly more frequently ill than those with a normal birth weight. Offspring of obese mothers had worse verbal language skills in early childhood and a higher percentile of weight-for-height. CONCLUSION: Maternal gestational diabetes and obesity can be considered an important determinant of postnatal offspring development and health status, which further advocates for broader implementation of preventive strategies.

European Guidelines on Perinatal Care - Oxytocin for induction and augmentation of labor[Formula: see text].

OF RECOMMENDATIONS1. Oxytocin for induction or augmentation of labor should not be started when there is a previous scar on the body of the uterus (such as previous classical cesarean section, uterine perforation or myomectomy when uterine cavity is reached) or in any other condition where labor or vaginal delivery are contraindicated. (Moderate quality evidence +++-; Strong recommendation).2. Oxytocin should not be started before at least 1 h has elapsed since amniotomy, 6 h since the use of dinoprostone (30 min if vaginal insert) and 4 h since the use of misoprostol (Low quality evidence ++- -; Moderate recommendation).3. Cardiotocography (CTG) should be performed and a normal pattern without tachysystole should be documented for at least 30 min before oxytocin is used. Continuous CTG, with adequate monitoring of both fetal heart rate and uterine contractions, should be maintained for as long as oxytocin is used, and thereafter until delivery (Low ++- - to moderate +++- quality evidence; Strong recommendation).4. For labor induction, at least 1-h should be allowed after amniotomy before oxytocin infusion is started, to evaluate whether adequate uterine contractility has meanwhile ensued. For augmentation of labor, if the membranes are intact and there are conditions for a safe amniotomy, the latter should be considered before oxytocin is started (Very low quality evidence +- --; Weak recommendation).5. Oxytocin should be administered intravenously using the following regimen: 5 IU oxytocin diluted in 500 mL of 0.9% normal saline (NaCl) (each mL contains 10 mIU of oxytocin), in an infusion pump at increasing rates, as shown in Table 1, until a frequency of 3-4 contractions per 10 min is reached, a non-reassuring CTG pattern ensues, or maximum rates are reached (Low quality evidence ++ - -; Strong recommendation). If the frequency of contractions exceeds 5 in 10 min, the infusion rate should be reduced, even if a normal CTG pattern is present. With a non-reassuring CTG pattern, urgent clinical assessment by an obstetrician is indicated, and strong consideration should be given to reducing or stopping the oxytocin infusion. The minimal effective dose of oxytocin should always be used. (Low ++- - to Moderate +++- - quality evidence; Strong recommendation).[Table: see text]6. Use of oxytocin for induction and augmentation of labor should be regularly audited (Low quality evidence ++--; Strong recommendation).

Application of 96-well plate SPE method for analysis of persistent organic pollutants in low volume blood serum samples.

Though many persistent organic pollutants (POPs) are closely regulated the human population is still exposed to these ubiquitous chemicals from the environment and diet. Safe management and human biomonitoring of POPs is necessary to understand the risk of exposure. Within human biomonitoring the mass of sample is often limited, therefore robust methods using smaller sample amounts are necessary. This study developed a 96-well plate solid phase extraction (SPE) method for determination of selected POPs: polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs), polybrominated diphenyl ethers (PBDEs), hexabromocyclododecane (HBCD) and non-persistent novel flame retardants (NFRs) in low volume blood serum. Non-destructive clean-up coupling Oasis HLB extraction plate with Phree phospholipid removal plate was employed. Extraction efficiency was determined at low and high concentrations in certified reference materials NIST SRM 1957 and 1958, respectively. Target compounds deviated from certified values on average by 15% and 21% for SRM 1957 and SRM 1958, respectively. Observed limit of detections (LODs) ranged from 0.36 pg/mL (PCB 180) to 66.07 pg/mL (δ-HCH). The applicability for real samples is demonstrated on 48 samples from pregnant women enrolled in the pilot phase of the CELSPAC: TNG study. In total, 30 target compounds were detected in at least one sample. The method developed here provides a fast and reliable analysis of human blood serum with possibility to introduce automation for the sample preparation procedure.

COVID-19 Vaccine Acceptance of Pregnant and Lactating Women (PLW) in Czechia: An Analytical Cross-Sectional Study.

Pregnant and lactating women (PLW) represent a particular population subset with increased susceptibility for COVID-19 morbidity and mortality, even though the evidence about the safety and efficacy of COVID-19 vaccines was delayed due to their initial exclusion from development trials. This unclear situation could have led to increased COVID-19 vaccine hesitancy levels among PLW; therefore, this study aimed to evaluate the attitudes of Czech PLW towards COVID-19 vaccines and the determinants of their attitudes. An analytical cross-sectional survey-based study was carried out in the University Hospital Brno (South Moravia, Czechia) between August and October 2021. The study utilised a self-administered questionnaire (SAQ) adapted from previous instruments used for the same purpose. The SAQ included closed-ended items covering demographic characteristics, clinical and obstetric characteristics, attitudes towards COVID-19 vaccination, and potential psychosocial predictors of vaccine acceptance. Out of the 362 included participants, 278 were pregnant (PW) and 84 were lactating women (LW). The overall COVID-19 vaccine acceptance (immediate and delayed) level was substantially high (70.2%), with a significant difference between PW (76.6%) and LW (48.8%). Out of the 70.2% who agreed to receive the vaccine, 3.6% indicated immediate acceptance, and 66.6% indicated delayed acceptance. Only 13.3% of the participants indicated their acceptance of their physician's vaccination recommendation during pregnancy or while lactating, and 62.2% were against it. Our results agreed with the recent studies that revealed that PW tended to have a high level of COVID-19 vaccine acceptance, and they were also inclined to resist professional recommendations because they predominantly preferred to delay their vaccination. The pregnancy trimester, education level, employment status, and previous live births were significant determinants for COVID-19 vaccine acceptance. The most commonly preferred vaccine type was mRNA-based vaccines, followed by viral vector-based and inactivated virus vaccines. The first top priority of PLW was vaccine safety for their children, followed by vaccine safety for the PLW and vaccine effectiveness. Regarding psychosocial predictors, media/social media, trust in the government, the pharmaceutical industry, and healthcare professionals, partners, and a positive risk-benefit ratio were significant promoters for COVID-19 vaccine acceptance. Findings from this study suggest that promotional interventions targeting PLW should use web platforms and focus on vaccine safety evidence, the expected benefits of vaccines and potential harms of the infection.

Maternal and neonatal outcomes in pregnancies complicated by eclampsia - analysis of cases from 2008-2018.

OBJECTIVE: Evaluation of perinatal results in a set of pregnancies complicated by eclampsia. METHODS: Analysis of 67,304 births performed at the Department of Gynecology and Obstetrics, Masaryk University, Faculty of Medicine and University Hospital, Brno from 2008-2018. During the given period, eclampsia was dia-gnosed in 16 mothers (0.2). The during the time of eclampsia (week of gestation, prepartum, intrapartum, postpartum) fetal and neonatal status (signs of intrauterine distress, pH of the umbilical artery, Apgar score, intrauterine fetal death, death in the early neonatal period) were evaluated. Symptoms and course of the eclamptic attack, maternal comorbidities, associated obstetric complications (placental abruption, surgical complications, blood loss, hysterectomy) and non-obstetric complications (coagulopathy, renal and hepatic impairment, neurological complications) were monitored. RESULTS: Out of a total of 16 cases of eclampsia, 13 cases (81.3%) were confirmed during pregnancy, one case (6.2%) during childbirth, and two cases (12.5%) within 24 hours after childbirth. The mean gestational week of eclampsia was 33 weeks and 3 days. The typical course of an eclamptic attack characterized by headache and visual disturbances followed by a rapid onset of convulsions was noted in five cases (31%). Fetal hypoxia with a pH of the umbilical artery less than 7.10 occurred in four cases (25%). The dependence of the decrease in pH value on the time interval from the dia-gnosis of eclampsia to the termination of pregnancy was demonstrated. The pH of the umbilical artery decreased on average by 0.054 every 30 minutes from the onset of the eclamptic attack until the end of pregnancy. There were 3 perinatal deaths in the group (19%). Intrauterine fetal death occurred in one case due to partial abruption of the placenta during an eclamptic attack; two newborns died in the early neonatal period. The cause of death was sepsis in one case and perforation of the intestine in necrotizing enterocolitis in the other. The death of the mother was not recorded in the file. The incidence of preeclampsia in subsequent pregnancies reached 18.8%. Non-obstetric and neurological complications (amaurosis, subarachnoid hemorrhage, amnesia) occurred in the group in three cases (18.8%), and renal failure occurred in two cases (12.5%). CONCLUSION: The incidence of eclampsia at the Department of Gynecology and Obstetrics, Masaryk University, Faculty of Medicine and University Hospital, Brno reached 0.2 and was stable for a long time. Associated serious maternal complications occurred in 37.5% of cases and neonatal complications in 31.3% of cases. Early dia-gnosis of eclampsia and minimization of the time delay until the end of pregnancy is a prerequisite for reducing the risk of associated complications. An interdisciplinary approach is needed.

Profiling Tryptophan Catabolites of Human Gut Microbiota and Acute-Phase Protein Levels in Neonatal Dried Blood Specimens.

National screening programs use dried blood specimens to detect metabolic disorders or aberrant protein functions that are not clinically evident in the neonatal period. Similarly, gut microbiota metabolites and immunological acute-phase proteins may reveal latent immune aberrations. Microbial metabolites interact with xenobiotic receptors (i.e., aryl hydrocarbon and pregnane-X) to maintain gastrointestinal tissue health, supported by acute-phase proteins, functioning as sensors of microbial immunomodulation and homeostasis. The delivery (vaginal or cesarean section) shapes the microbial colonization, which substantially modulates both the immune system's response and mucosal homeostasis. This study profiled microbial metabolites of the kynurenine and tryptophan pathway and acute-phase proteins in 134 neonatal dried blood specimens. We newly established neonatal blood levels of microbial xenobiotic receptors ligands (i.e., indole-3-aldehyde, indole-3-butyric acid, and indole-3-acetamide) on the second day of life. Furthermore, we observed diverse microbial metabolic profiles in neonates born vaginally and via cesarean section, potentially due to microbial immunomodulatory influence. In summary, these findings suggest the supportive role of human gut microbiota in developing and maintaining immune system homeostasis.

Guillain-Barré syndrome in pregnancy

OBJECTIVE: A case report of a 23-year-old pregnant woman diagnosed with Guillain-Barré syndrome in the 31st week of pregnancy. CASE REPORT: We present a case study of a patient in the 31st week of pregnancy hospitalized at the University Hospital in Brno for expressed bulbar syndrome, neck muscle weakness, paresthesia of the arms and medical history of diarrhea in the previous week. During hospitalization, there was a rapid progression of symptoms and respiratory failure, requiring orotracheal intubation. The diagnosis of Guillain-Barré syndrome was determined and intravenous immunoglobulin therapy was initiated. The pregnancy was terminated in the 32nd week of gestation based on the maternal indication after a completed lung maturation of the fetus. CONCLUSION: Guillain-Barré syndrome is a neurological disease that can rarely occur during pregnancy and puerperium. The syndrome presents a serious pregnancy complication with an uncertain prognosis and risk for both mother and fetus. If the syndrome is diagnosed in time and treated correctly, the prognosis is favorable despite the complicated course.

Development of a New Risk Score for Stratification of Women with Gestational Diabetes Mellitus at High Risk of Persisting Postpartum Glucose Intolerance Using Routinely Assessed Parameters.

The aims of the study were (i) to find predictive factors for early postpartum conversion of gestational diabetes mellitus (GDM) into persisting glucose intolerance (PGI), (ii) to evaluate potential differences in adverse perinatal outcomes in GDM women with and without early postpartum PGI and, finally, (iii) to establish a risk score to predict postpartum PGI. A cross-sectional study comprised 244 GDM patients with known age, parity, positive family history of diabetes, pre-gestational BMI, comorbidities, smoking history, results of mid-trimester oral glucose tolerance test, HbA1c, obstetric complications, neonatal outcomes and mode of delivery. A risk score was calculated using parameters with highest odds ratios in a statistic scoring model. Significant differences between women with and without PGI postpartum were ascertained for mid-trimester fasting plasma glucose (p < 0.001), HbA1c above 42 mmol/mol (p = 0.035), prevalence of obesity (p = 0.007), hypothyroidism, family history of diabetes and smoking. We also observed higher incidence of prolonged and complicated delivery in PGI group (p = 0.04 and 0.007, respectively). In conclusion, this study identified several parameters with predictive potential for early PGI and also adverse peripartal outcomes. We established a simple risk-stratification score for PGI prediction applicable for GDM affected women prior their leaving maternity ward. Yet, given a relatively small sample size as a main limitation of this study, the proposed score should be validated in the larger cohort.

Maternal body mass index and external cephalic version success rate - are they related?

OBJECTIVES: External cephalic version (ECV) is a useful method helping to reduce the incidence of planned caesarean deliveries for fetal malpresentation. There is an effort to look for the best predictors for a successful ECV, the effect of maternal weight is still unclear. The aim of our study is to determine maternal body mass index (BMI) in association with the ECV success rate and the risk of complications. MATERIAL AND METHODS: A retrospective observational cohort study in 981 women after the 36th week of gestation with a fetus in a breech presentation who had undergone an ECV attempt. We evaluated the success rate and complications of ECV in association with BMI categories according to the WHO classification of obesity. RESULTS: ECV was successful in 478 cases (48.7%). In the category of overweight patients (BMI > 25; n = 484), ECV was successful in 51% and unsuccessful in 49% (p = 0.28) of cases. In obese patients (BMI > 30; n = 187), ECV was successful in 44.8% and unsuccessful in 55.2% (p = 0.28) of cases. The effect of BMI on the success rate of ECV for the category of overweight and obesity was not proven by statistical analysis. Serious complications occurred in seven cases in similar numbers in all three subgroups according to BMI. CONCLUSIONS: BMI in the categories of overweight and obesity is not a factor influencing the success rate and risk of complications of ECV. These results can be helpful when consulting pregnant women the chance of successful ECV.

Cervical Gardnerella vaginalis in women with preterm prelabor rupture of membranes.

OBJECTIVE: To determine the association between microbial invasion of the amniotic cavity (MIAC) and/or intra-amniotic inflammation (IAI) and the cervical prevalence of Gardnerella vaginalis DNA in pregnancies with preterm prelabor rupture of membrane (PPROM). METHOD: In total, 405 women with singleton pregnancies complicated with PPROM were included. Cervical fluid and amniotic fluid samples were collected at the time of admission. Bacterial and G. vaginalis DNA were assessed in the cervical fluid samples using quantitative PCR technique. Concentrations of interleukin-6 and MIAC were evaluated in the amniotic fluid samples. Loads of G. vaginalis DNA ≥ 1% of the total cervical bacterial DNA were used to define the cervical prevalence of G. vaginalis as abundant. Based on the MIAC and IAI, women were categorized into four groups: with intra-amniotic infection (both MIAC and IAI), with sterile IAI (IAI without MIAC), with MIAC without IAI, and without either MIAC or IAI. RESULTS: The presence of the abundant cervical G. vaginalis was related to MIAC (with: 65% vs. without: 44%; p = 0.0004) but not IAI (with: 52% vs. without: 48%; p = 0.70). Women with MIAC without IAI had the highest load of the cervical G. vaginalis DNA (median 2.0 × 104 copies DNA/mL) and the highest presence of abundant cervical G. vaginalis (73%). CONCLUSIONS: In women with PPROM, the presence of cervical G. vaginalis was associated with MIAC, mainly without the concurrent presence of IAI.

The effect of transient fetal bradycardia and other heart rate changes during and after external cephalic version on perinatal outcomes.

OBJECTIVES: To evaluate the effect of transient fetal bradycardia and other heart rate changes during and after external cephalic version (ECV) on perinatal outcomes. To determine factors associated with a higher risk of occurrence of transient fetal bradycardia during and after ECV. STUDY DESIGN: Prospective study in 286 women after the 36th week of gestation with a fetus in breech presentation who have undergone an ECV attempt. The study analyses the incidence of transient fetal bradycardia during and immediately after ECV, the time interval to complete adjustment of fetal bradycardia, the factors associated with the occurrence of transient fetal bradycardia, cardiotocography (CTG) changes after ECV and perinatal outcomes. All the data were statistically analyzed. RESULTS: The ECV was successful in 51 % (146/286). Transient fetal bradycardia occurred during and after ECV in 81 cases (28.3 %). A successful version was a factor significantly associated with fetal bradycardia (54; 37.0 % versus 27; 19.3 %; p < 0.01). Clinically significant hypotension of the mother was accompanied by transient fetal bradycardia in 12 cases (4.2 %). After the successful ECV there was no significant difference in the percentage of vaginal deliveries between subgroups with and without transient fetal bradycardia (85.2 % versus 83.7 %; p = 1.00). Nor in occurrence of acute fetal distress during labor (18.5 % versus 15.6 %; p = 0.65). In cases of a successful ECV transient CTG changes after ECV had no effect on the incidence of acute fetal distress during labor (23.5 % versus 15.7 %; p = 0.49). CONCLUSIONS: Transient fetal bradycardia and other heart rate changes during and immediately after ECV was not associated with a higher incidence of acute fetal distress during labor and did not affect perinatal outcomes. Higher occurrence of transient bradycardia after ECV was associated only with successful ECV. Transient hypotension of the mother as one of the causes of transient fetal bradycardia during ECV should be considered.

Lactobacilli-dominated cervical microbiota in women with preterm prelabor rupture of membranes.

BACKGROUND: To determine the association between microbial invasion of the amniotic cavity (MIAC) and the presence of Lactobacillus crispatus- or Lactobacillus iners-dominated cervical microbiota in pregnancies with preterm prelabor rupture of membrane. Next, to assess the relationship between the presence of L. crispatus- or L. iners-dominated cervical microbiota and short-term neonatal morbidity. METHOD: A total of 311 women were included. Cervical samples were obtained using a Dacron polyester swab and amniotic fluid samples were obtained by transabdominal amniocentesis. Bacterial DNA, L. crispatus, and L. iners in the cervical samples were assessed by PCR. Cervical microbiota was assigned as L. crispatus- or L. iners-dominated when the relative abundance of L. crispatus or L. iners was ≥50% of the whole cervical microbiota, respectively. RESULTS: Women with MIAC showed a lower rate of L. crispatus-dominated cervical microbiota (21% vs. 39%; p = 0.003) than those without MIAC. Lactobacillus crispatus-dominated cervical microbiota was associated with a lower rate of early-onset sepsis (0% vs. 5%; p = 0.02). CONCLUSIONS: The presence of L. crispatus-dominated cervical microbiota in women with preterm prelabor rupture of membrane was associated with a lower risk of intra-amniotic complications and subsequent development of early-onset sepsis of newborns.

Association of rare non-coding SNVs in the lung-specific FOXF1 enhancer with a mitigation of the lethal ACDMPV phenotype.

Haploinsufficiency of FOXF1 causes alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV), a lethal neonatal lung developmental disorder. We describe two similar heterozygous CNV deletions involving the FOXF1 enhancer and re-analyze FOXF1 missense mutation, all associated with an unexpectedly mitigated disease phenotype. In one case, the deletion of the maternal allele of the FOXF1 enhancer caused pulmonary hypertension and histopathologically diagnosed MPV without the typical ACD features. In the second case, the deletion of the paternal enhancer resulted in ACDMPV rather than the expected neonatal lethality. In both cases, FOXF1 expression in lung tissue was higher than usually seen or expected in patients with similar deletions, suggesting an increased activity of the remaining allele of the enhancer. Sequencing of these alleles revealed two rare SNVs, rs150502618-A and rs79301423-T, mapping to the partially overlapping binding sites for TFAP2s and CTCF in the core region of the enhancer. Moreover, in a family with three histopathologically-diagnosed ACDMPV siblings whose missense FOXF1 mutation was inherited from the healthy non-mosaic carrier mother, we have identified a rare SNV rs28571077-A within 2-kb of the above-mentioned non-coding SNVs in the FOXF1 enhancer in the mother, that was absent in the affected newborns and 13 unrelated ACDMPV patients with CNV deletions of this genomic region. Based on the low population frequencies of these three variants, their absence in ACDMPV patients, the results of reporter assay, RNAi and EMSA experiments, and in silico predictions, we propose that the described SNVs might have acted on FOXF1 enhancer as hypermorphs.