Prenatal diagnosis of bone dysplasias.

Bone dysplasias are individually rare but collectively common. The prenatal diagnosis of bone dysplasias, especially perinatally lethal dysplasias, is of major interest to obstetric services. The current nosology of genetic skeletal disorders addresses over 400 disorders. However, in clinical practice, we encounter only a limited number of disorders, such as FGFR3-related dysplasias, osteogenesis imperfecta, and type II collagenopathies. The recent development of non-invasive prenatal genetic testing using cell-free fetal DNA in maternal blood samples has had a major impact on the prenatal diagnosis of genetic diseases. However, imaging examinations remain critical for the final diagnosis of bone dysplasias because molecular testing only shows genetic variants, and not their pathogenicity - most variants are clinically insignificant. Bone dysplasias are typically suspected when limb shortening is identified by screening ultrasound. Further assessment can be followed by more detailed ultrasound, magnetic resonance imaging (MRI), and CT. Based on these data, rational decision-making is feasible, even when the definitive prenatal diagnosis is not feasible. Here, we highlight key images of common bone dysplasias obtained by currently available modalities.

The detailed obstetric course of the first Japanese patient with AEBP1-related Ehlers-Danlos syndrome (classical-like EDS, type 2).

We reported a detailed obstetric course of a Japanese patient with Ehlers-Danlos syndrome (EDS) caused by biallelic pathogenic variants in the AEBP1 gene. She was diagnosed with classical EDS at 3 years of age. At 33 years, whole-exome sequencing revealed a homozygous nonsense variant (c.1894C > T:p.Arg632*) in AEBP1. This is the 10th case of AEBP1-related EDS (classical-like EDS type 2) and the first in Japan. She was managed as an inpatient at our hospital beginning at 20 weeks of gestation because of the possibility of high-risk pregnancy. She experienced painful urinary retention, migraines, and threatened premature labor. She delivered a healthy female via elective caesarean section at 32 weeks of gestation. She was treated in the intensive care unit for severe paralytic ileus, postoperatively. Conservative therapy resulted in favorable outcomes, and she was safely discharged on postdelivery day 22nd.

Prevalence of common aneuploidy in twin pregnancies.

The incidence of chromosomal abnormalities in twin pregnancies is not well-studied. In this retrospective study, we investigated the frequency of chromosomal abnormalities in twin pregnancies and compared the incidence of chromosomal abnormalities in dichorionic diamniotic (DD) and monochorionic diamniotic (MD) twins. We used data from 57 clinical facilities across Japan. Twin pregnancies of more than 12 weeks of gestation managed between January 2016 and December 2018 were included in the study. A total of 2899 and 1908 cases of DD and MD twins, respectively, were reported, and the incidence of chromosomal abnormalities in one or both fetuses was 0.9% (25/2899) and 0.2% (4/1908) in each group (p = 0.004). In this study, the most common chromosomal abnormality was trisomy 21 (51.7% [15/29]), followed by trisomy 18 (13.8% [4/29]) and trisomy 13 (6.9% [2/29]). The incidence of trisomy 21 in MD twins was lower than that in DD twins (0.05% vs. 0.5%, p = 0.007). Trisomy 21 was less common in MD twins, even when compared with the expected incidence in singletons (0.05% vs. 0.3%, RR 0.15 [95% CI 0.04-0.68]). The risk of chromosomal abnormality decreases in twin pregnancies, especially in MD twins.

Evaluation of the clinical performance of noninvasive prenatal testing at a Japanese laboratory.

AIM: We aimed to evaluate the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of noninvasive prenatal testing (NIPT) in high-risk pregnant women. METHODS: Pregnant women who underwent GeneTech NIPT, the most commonly used NIPT in Japan, between January 2015 and March 2019, at Japan NIPT Consortium medical sites were recruited for this study. The exclusion criteria were as follows: pregnant women with missing survey items, multiple pregnancy/vanishing twins, chromosomal abnormalities in the fetus other than the NIPT target disease, and nonreportable NIPT results. Sensitivity and specificity were calculated from the obtained data, and maternal age-specific PPV and NPV were estimated. RESULTS: Of the 45 504 cases, 44 263 cases fulfilling the study criteria were included. The mean maternal age and gestational weeks at the time of procedure were 38.5 years and 13.1 weeks, respectively. Sensitivities were 99.78% (95% confidence interval [95% CI]: 98.78-99.96), 99.12% (95% CI: 96.83-99.76), and 100% (95% CI: 88.30-100) for trisomies 21, 18, and 13, respectively. Specificities were more than 99.9% for trisomies 21, 18, and 13, respectively. Maternal age-specific PPVs were more than 93%, 77%, and 43% at the age of 35 years for trisomies 21, 18, and 13, respectively. CONCLUSION: The GeneTech NIPT data showed high sensitivity and specificity in the detection of fetal trisomies 21, 18, and 13 in high-risk pregnant women, and maternal age-specific PPVs were obtained. These results could provide more accurate and improved information regarding NIPT for genetic counseling in Japan.

Real prevalence of neural tube defects in Japan: How many of such pregnancies have been terminated?

The vital role of folic acid is to reduce the risk of having a neonate afflicted with neural tube defects. The prevalence of neural tube defects (myelomeningocele and anencephaly) has been reported in an incomplete form over the last 40 years in Japan. We aimed to evaluate the total number of neural tube defects including those delivered or terminated, to clarify the proportion of those terminated, and to internationally compare their prevalence. Through information on >311 000 deliveries obtained from 262 hospitals/clinics for 2 years of 2014 and 2015, we identified that the rate of total neural tube defects (termination of pregnancy, live births and stillbirths) was 8.29 per 10 000 deliveries for the year 2014 and was 8.72 for 2015, which were 1.5 and 1.6 times higher than the respective values (live births and stillbirths) reported. It is also observed that the ratio of the total number of myelomeningocele (termination of pregnancy, live births, and stillbirths) to that of anencephaly was approximately 1:1.2, that a half of pregnancies afflicted with neural tube defects were terminated, and that the proportion of termination of pregnancy due to myelomeningocele and due to anencephaly was 20% and 80%, respectively. Internationally, the real prevalence of neural tube defects in Japan was comparatively high, ranking fifth among the seven developed countries. In conclusion, the real prevalence of total neural tube defects was approximately 1.5 times higher than that currently reported by the Japan Association of Obstetricians and Gynecologists.

Parental serum alkaline phosphatase activity as an auxiliary tool for prenatal diagnosis of hypophosphatasia.

OBJECTIVE: The objective of this study is to clarify the usefulness of parental alkaline phosphatase (ALP) for prenatal diagnosis of hypophosphatasia (HPP). METHODS: Maternal (m) and paternal (p) ALP values were measured in 77 cases from a multicenter cohort (fetal skeletal dysplasia forum in Japan) of cases with short limbs on ultrasonography during pregnancy. After birth, X-rays, cord blood ALP, and gene analysis were evaluated to achieve an exact diagnosis. The screening usefulness of ALP was examined retrospectively. RESULTS: Seventeen cases were eventually diagnosed as HPP and 60 as not HPP; the overall mean m-ALP and p-ALP (standard deviation) values were 133.4 (53) versus 197 (69) IU/L and 149.6 (71.8) versus 231 (61.4) IU/L (p < 0.001). Receiver operating characteristic curve analysis showed that the optimal m-ALP and p-ALP cutoff values were 123 and 165 IU/L, respectively. Presence of at least one of the m-ALP or p-ALP values abnormally low had a sensitivity, specificity, and positive predictive values of 82% (14/17), 93%, and 78%, respectively, for the diagnosis of HPP. CONCLUSION: Parental ALP measurement might be an auxiliary tool to hone in the prenatal diagnosis of fetal HPP. © 2017 John Wiley & Sons, Ltd.

A thick placenta: a predictor of adverse pregnancy outcomes.

PURPOSE: The aim of this study is to evaluate the efficacy of an ultrasonographic measurement of placental thickness and the correlation of a thick placenta with adverse perinatal outcome. METHODS: Placental thickness was measured in single gravidas, 16 to 40 weeks of gestation, between 2005 and 2009. Placentas were considered to be thick if their measured thickness were above the 95th percentile for gestational age. RESULTS: The incidence of thick placentas was 4.3% (138/3,183). Perinatal morbidity and neonatal conditions were worse in cases with thick placenta rather than without thick placenta. CONCLUSIONS: Ultrasonographic measurement of placental thickness is a simple method to estimate placental size. Thick placenta may be a useful predictor of adverse pregnancy outcomes.

Congenital high airway obstruction syndrome in the breech presentation managed by ex utero intrapartum treatment procedure after intraoperative external cephalic version.

Congenital high airway obstruction syndrome (CHAOS) caused by laryngeal atresia was diagnosed by prenatal ultrasound in a male fetus at 26 weeks of gestation. Findings included massive ascites, subcutaneous edema, enlarged hyperechogenic lungs with diaphragmatic inversion, dilated trachea, polyhydramnios, and breech presentation. Those findings of CHAOS spontaneously returned to normal by 33 weeks of gestation. However, the placenta was localized to the anterior uterine wall. In addition, the fetal position had been breech until delivery. At 36 weeks of gestation, a planned ex utero intrapartum treatment (EXIT) procedure was performed following intraoperative external cephalic version (ECV) in which the fetus was approached from the posterior wall of the uterus. Laryngoscopy revealed the predicted laryngeal obstruction, and tracheostomy was placed. Intraoperative ECV may be a useful technique in breech presentation before EXIT procedure.

Japanese women's attitudes towards routine ultrasound screening during pregnancy.

Because there are few published studies from Eastern countries concerning women's experiences of prenatal ultrasound scans, this study investigated this topic in 238 Japanese women in three different prenatal settings. A cross-sectional questionnaire of 33 items was administered to 261 women at 14-37 weeks gestation with no known obstetrical risk, after their ultrasounds. The main reasons for the ultrasounds were evaluation of fetal growth (100%, n = 238); obstetrical conditions (n = 228, 96%); and fetal abnormalities (91%, n = 217). With increasing maternal age, participants worried more about obstetric problems or fetal abnormalities. Many were interested in fetal viability in early pregnancy, and obstetric problems or fetal abnormality in late pregnancy. While most (n = 234, 98%) looked forward to having scans, the majority (n = 235, 99%) wanted to know if their baby had an anomaly, and 72% (n = 171) worried about the detection of abnormalities. Only 50% (n = 118) had obtained information from their care provider. To assist with women's decision-making, prenatal care providers should provide quality information and understand the factors that influence women's concerns.

Prenatal diagnosis and management for a large fetal cardiac tumor complicated with hydrops fetalis.

Fetal cardiac tumor is a rare disease, and its prognosis varies in relation to the complications such as arrhythmia and out-flow obstruction. Hydrops fetalis is one of severe complications that result in an unfavorable outcome. A case is presented herein of a large fetal cardiac tumor diagnosed at 28 weeks gestation. At 30 weeks gestation, the fetus complicated with hydrops fetalis because of impaired cardiac function. Increased peak systolic velocity in the ascending aorta and marked reversed flow in the ductus venosus were observed. Oral digoxin therapy was administered to the mother as a cardiotonic agent and the hydropic condition was immediately diminished. After normal delivery, the cardiac tumor gradually decreased in size and the infant developed normally, but required an antiarrhythmic drug. The case indicates that the in utero digoxin therapy could be a choice for hydrops fetalis caused by cardiac tumor.

Ontogeny of gastric emptying patterns in the human fetus.

OBJECTIVE: Fetal swallowing and gastric emptying contribute importantly to amniotic fluid (AF) homeostasis and fetal gastrointestinal development. We speculated that fetal gastric emptying must be functional early in gestation to prevent rapid increases in AF. We sought to determine the human fetal ontogenic pattern of gastric emptying. STUDY DESIGN: Gastric emptying of eighty normal fetuses at 12-39 weeks was studied. Real-time ultrasound of the fetal stomach was continuously recorded for 1 hour. The gastric area ratio (GAR) was defined as the gastric area divided by the abdominal transverse area. The delta GAR was defined as the change between the maximum and the minimum gastric area ratiox100 (expressed as percent). A change of the fetal gastric area more than the 10th percentile of the delta GAR at 36-39 weeks was used to define gastric emptying. RESULTS: The 10th, 50th and 90th percentile of delta GAR at 36-39 weeks' was 5.2, 6.5 and 8.7%, respectively. Fetal gastric emptying was detected as early as 12 5/7 weeks of gestation. The proportion of fetuses demonstrating gastric emptying (>10th percentile delta GAR) increased with gestational age: 4/33 (12.1%) 12-23 weeks, 3/9 (33.3%) at 24-27 weeks, 8/11 (72.7%) at 28-31 weeks, 12/14 (85.7%) at 32-35 weeks, and 11/13 (84.6%) at 36-39 weeks. CONCLUSIONS: Fetal gastric emptying occurs by the beginning of the second trimester, contributing to AF regulation. The increased frequency of gastric emptying in late gestation is likely secondary to increased swallowing, altered fetal behavioral state or endogenous production of gastrointestinal motility factors.

Gastric emptying cycles in the human fetus.

OBJECTIVE: Fetal swallowing contributes greatly to amniotic fluid homeostasis and fetal somatic development. Despite the absorption and recirculation of significant volumes of amniotic fluid, little is known about the rates of fetal gastric emptying or gastrointestinal absorption. We sought to determine the patterns of human fetal gastric emptying cycles across gestation. STUDY DESIGN: The gastric emptying cycle of 80 normal human fetuses at 12 to 39 weeks of gestation was studied. Real-time ultrasound examination of the fetal stomach (defined as the largest gastric area inclusive of the pylorus) was recorded continuously for a minimum of 1 hour (60-112 minutes). Images were replayed with measurements of gastric size every minute. The gastric area ratio was defined as the ratio of the fetal gastric area divided by the area of the fetal abdominal transverse section. The changes in gastric area ratio of all subjects were analyzed with the discrete Fourier transform method. The calculable maximum cycle was 60 or 112 minutes, and the minimum cycle was 2 minutes. The highest and second highest peaks of all power spectrum were recorded, and each cycle was converted from frequency of each peak. RESULTS: The gastric emptying cycles of the highest peak before 24 weeks of gestation were scattered between 30 and 100 minutes with low power. At 32 to 35 weeks of gestation, cycles were focused at approximately 40 minutes with increased power. At term, the cycles increased to >80 minutes. The gastric emptying cycles of the second highest peak were constant at 20 minutes, with stronger power after 24 weeks of gestation. CONCLUSION: Fetal gastric emptying cycles normalize during the early third trimester. The near-term evidence of delayed emptying may contribute to newborn infant feeding satiation.

Maternal steroid enhancement of fetal rabbit gastrointestinal motility.

AIM: The purpose of the present study was to determine the potential maturational effects of maternal dexamethasone administration on fetal upper gastrointestinal motility. METHODS: Nineteen pregnant rabbits were randomized into two groups (DEX and CONT) and studied on either day 24, 27 or 30 of pregnancy (term 31 days). The DEX group received intramuscular dexamethasone (DEX) 2 days before study and the controls received saline. Under ultrasound guidance, a needle was percutaneously inserted into each fetal stomach and fluorescein, labeled with color-coded microspheres, was injected. Two hours later, the length of fluorescein travel throughout the small intestine was measured. The percent motility was calculated by dividing the length of fluorescein travel by the total fetal small intestinal length x 100%. RESULTS: All maternal and fetal rabbits survived. On day 24 the length of fluorescein travel and the percent motility of the DEX group were significantly longer than controls. There were no differences on either day 27 or 30. Fetal growth was significantly suppressed by a single course of DEX at all gestational ages. CONCLUSIONS: Fetal rabbit gastrointestinal motility is significantly increased after prenatal steroids are given early in the last trimester (day 24 of a 31-day gestation). Although beneficial in end-organ maturation, the timing of prenatal steroid administration is crucial to minimize its potential detrimental effects on fetal somatic growth.

Ultrasonographic findings of facial dysmorphism in Wolf-Hirschhorn syndrome.

Wolf-Hirschhorn syndrome has characteristic craniofacial dysmorphism with severe fetal growth restriction. We present a case that revealed facial dysmorphism characteristic of Wolf-Hirschhorn syndrome with two- and three-dimensional ultrasonography. The facial dysmorphic features in the present case were dolichocephaly; high forehead; large rectangular nose continuing to the eyebrows; hypertelorism; short philtrum; carp-shaped mouth; microretrognathia; and large, simply modeled, low-set ears. Chromosome analysis of amniotic fluid cells was 46,XX,del(4)(p15.2), confirming the ultrasonographic result. Examination with two- and three-dimensional ultrasonography is useful to observe the face of fetuses with severe intrauterine growth restriction to diagnose multiple congenital anomaly syndromes.

Prenatal sonographic chest and lung measurements for predicting severe pulmonary hypoplasia in left-sided congenital diaphragmatic hernia.

To assess the prenatal evaluation of lung hypoplasia in congenital diaphragmatic hernia (CDH), we attempted to measure the right lung area/thorax area ratio (rLT ratio) in normal fetuses and in seven cases of left-sided CDH. In addition, we analyzed early neonatal blood gas data, which were compared with the prenatal evaluation. The rLT ratio was significantly (p<0.05) higher in normal fetuses (0.27+/-0.02) than in CDH (0.14+/-0.18). The values of PaO(2), arterial-alveolar oxygen difference (A-aDO(2)) and oxygenation index (OI) showed no significant relationship with the rLT ratio in CDH at the early neonatal period. Three infants with CDH survived and showed significant higher values of rLT ratio compared with those in nonsurvived infants (p<0.05). All of the rLT ratios in nonsurvived infants were <0.11. PaO(2) at the early neonatal period was significantly (p<0.05) higher, and both A-aDO(2) and OI were significantly (p<0.05) lower in survived infants than in nonsurvived infants. These results indicated that prenatal evaluation of rLT ratio is useful to predict the severity of lung hypoplasia in infants with left-sided CDH, and blood gas analysis at early neonatal period is also useful to predict the neonatal outcome.

Successful treatment of supraventricular tachycardia exhibiting hydrops fetalis with flecainide acetate. A case report.

BACKGROUND: The efficacy of flecainide acetate for the treatment of fetal supraventricular tachycardia with hydrops fetalis and changes in venous blood flow patterns in the fetus during treatment are reported. CASE: Oral flecainide administration was started at 30 weeks of gestation. Cardioversion was achieved 6 days after treatment. Sustained abnormal venous Doppler indices were shown and complete normalization of venous returns was observed 6 days after cardioversion. A vigorous male baby was born, and he is now 1 year of age and in good condition with no medication. CONCLUSION: Reversible cardiac dysfunction was observed even after cardioversion in the fetus with supraventricular tachycardia, which could be assessed precisely by venous Doppler analysis.

Successful treatment of primary fetal hydrothorax with a double basket catheter.

Fetal pleural effusions can sometimes be detected before birth with ultrasonography. Intervention may be warranted when there is a condition that results in hydroplastic lung and/or fetal hydrops. A 22-week-old fetus with a severe pleural effusion and hydrops was successfully treated by long-term pleural drainage with a double basket catheter from 22 to 39 weeks of gestation.