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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. [ABSTRACT FROM AUTHOR]

Aim In order to investigate the current status of prenatal testing for genetic disorders, we conducted a multicenter retrospective questionnaire survey. Methods The questionnaire was sent to 105 facilities with genetic counseling systems. The questionnaire consisted of two parts: (i) the number of prenatal tests conducted for genetic disorders from January 2010 to December 2012, whether the laboratory was combined with the counseling facility or separate, the sampling procedure method, the testing results, and the outcomes of the affected fetus in addition to treatment; and (ii) a survey of personal comments regarding prenatal testing for genetic disorders. Results We received responses from 69 of the 105 facilities (65.7%), and genetic testing was performed at 26 of these facilities. Nucleic acid sequential testing was performed on 45 disorders and 252 cases during a three-year period. There were 67 cases of affected fetuses. Six cases continued pregnancy and were treated. The comment survey highlighted difficulties in locating a laboratory to assess prenatal samples, as well as inadequate counseling and preparation for genetic disorders. Conclusions Our study revealed that a number of prenatal testing for genetic disorders are conducted in Japan; however, it is difficult for counselors to locate a laboratory capable of testing for specific genetic disorders. Inadequate counseling and healthcare providers' lack of knowledge is a current problem. A well-established system of prenatal testing for genetic disorders and the further education of general physicians is required. [ABSTRACT FROM AUTHOR]

Aim To determine intrapartum factors associated with neonatal encephalopathy leading to cerebral palsy (NE-CP). Methods A total of 70 NE-CP patients who fulfilled study criteria (cephalic singleton pregnancy with attempted vaginal delivery [AVD] at gestational week [GW] ≥36; intrapartum occurrence of non-reassuring fetal status without apparent cause following reassuring fetal status on admission; and development of NE-CP) were compared with 210 AVD controls who had 1- and 5-min Apgar score ≥8 matched for GW, maternal parity, and use of uterotonics. Suboptimal care was defined as delayed reaction due to misinterpretation of fetal heart rate (FHR) tracing, or inappropriate trial of instrumental delivery (TOID). Successful and failed TOID were defined as vaginal and cesarean delivery after TOID, respectively. The 210 controls were assumed not to have had suboptimal care. Results The rates of successful (34% vs 12%) and failed TOID (11% vs 0.0%), cesarean section (34% vs 14%), suboptimal care (57% vs 0.0%), pregnancy-induced hypertension (11% vs 2.4%), birthweight ≥3800 g (8.6% vs 1.9%), subgaleal hemorrhage (16% vs 0.0%) were significantly higher in NE-CP patients than in controls. Selection with the stepwise method and logistic regression analysis identified four independent risk factors for NE-CP: suboptimal intrapartum care (OR, 2.21; 95%CI: 1.99-2.47), cesarean section (OR, 1.19; 95%CI: 1.08-1.31), successful TOID (OR, 1.14; 95%CI: 1.03-1.25), and hypertension (OR, 1.20; 95%CI: 1.01-1.42). Conclusions Training programs for improved interpretation of FHR tracing and appropriate TOID are required to prevent NE-CP among healthy and mature fetuses in Japan. [ABSTRACT FROM AUTHOR]

Objective: This study examined how clients' selection and preference for noninvasive prenatal testing (NIPT) for aneuploidy changed with genetic counseling (GC) performed by certified geneticists at a primary hospital specializing in obstetrics, where other multiple prenatal genetic tests options were available. Methods: A total of 334 couples who underwent GC between 2017 and 2019 were included in the study. The average age of the pregnant women who underwent GC was 35.1 years. Results: Among the 95 couples (28.4%) who wanted NIPT at the start of GC, 10 (10.5%) switched to other tests, and 4 (4.2%) chose not to undergo any test. Among the 106 (31.7%) couples who wanted the combination of ultrasonography and the serum marker test, 12 (11.3%) chose not to undergo the test. Among the 92 (27.5%) couples who were undecided before GC, 21 (22.8%) wanted NIPT, 31 (33.7%) selected combined tests, and 18 (19.6%) did not undergo any test. Conclusion: We have demonstrated the significance of GC before prenatal genetic testing under widespread use of NIPT. Ideally, obstetric facilities should provide GC, or at least, pre‐counseling at their own facilities, and offer multiple prenatal genetic testing options or refer to other facilities for the same. [ABSTRACT FROM AUTHOR]

Aim The aim of this study was to provide better counsel to pregnant women with suspected placental mesenchymal dysplasia (PMD) regarding the risks of preterm birth and intrauterine fetal death. Material and Methods We reviewed the outcomes of 109 PMD pregnancies with gestational week (GW) ≥ 24 abstracted from 63 reports in the English-language published reports, including two cases that we encountered recently. The prospective risk of stillbirth at GW N was defined as the number of women with stillbirth at GW ≥ N divided by the number of women giving birth at GW ≥ N. Results A total of 32 (29.4%) women experienced stillbirth at a median GW of 31 (range, 24-38). Preterm birth (GW < 37) occurred in 52 (67.5%) of the 77 live-born infants. Only 25 (22.9%) women had full-term (GW ≥ 37) live-born infants. The prospective risks of stillbirth were 29.4% (32/109), 27.5% (25/91), 20.9% (14/67) and 13.0% (6/46) for women who reached GW 24+0, 28+0, 32+0 and 36+0 respectively. Conclusion As women with PMD are at markedly elevated risk of intrauterine fetal death, early admission to the hospital and intensive monitoring of fetal status should be considered, although whether this policy improves outcome has not been validated. [ABSTRACT FROM AUTHOR]

Aim: The aim of this study was to determine whether antenatal decline in antithrombin (AT) activity occurs frequently and precedes the development of perinatal liver dysfunction in women with triplet pregnancies. Material and Methods: A retrospective observational study was conducted on all women who gave birth to triplets at gestational week ⩾22 at a single centre during a study period from January 2001 to March 2013. The following eight blood parameters were monitored weekly during the last 5 weeks of pregnancy and postpartum: AT activity, platelet count, fibrinogen, D-dimer, aspartate aminotransferase (AST), lactate dehydrogenase (LDH), uric acid and creatinine. Pregnancy-induced AT deficiency (PIATD) and gestational thrombocytopenia were defined as antenatal AT activity <70% of normal level and antenatal platelet count <150 × 109/L, respectively. Liver dysfunction was defined as AST > 40 IU/L. LDH elevation was defined as LDH > 450 IU/L. Results: Sixteen women were eligible for this study. All variables except LDH exhibited significant changes antenatally: AT activity, platelet count and fibrinogen decreased, while D-dimer, AST, urate and creatinine increased. LDH increased significantly postpartum. PIATD, gestational thrombocytopenia, perinatal liver dysfunction, and LDH elevation occurred in eight, seven, six, and eight women, respectively. Liver dysfunction was preceded by PIATD alone in three, by both PIATD and gestational thrombocytopenia in one and by gestational thrombocytopenia alone in none of the subjects. After delivery, laboratory abnormalities similar to HELLP syndrome were seen in three women exclusively in the presence of PIATD. Conclusions: Reduced AT activity was likely to precede perinatal liver dysfunction in women with triplets. [ABSTRACT FROM AUTHOR]

A woman with twin pregnancy had a gradual decline in anti-thrombin (AT) activity from 72% at gestational week (GW) 29-3/7, to 53% at GW31-2/7, and to 41% at GW32-2/7, at which time hypertension (148/90 mmHg) and proteinuria (protein-to-creatinine ratio [P/Cr], 0.79 mg/mg) developed in the presence of normal platelet count (159 × 109/L) and serum aspartate aminotransferase/lactate dehydrogenase (22/164 IU/L). AT product was given three times to maintain AT activity >50% and blood pressure was maintained below 155/95 mmHg with no treatment, but generalized edema with a weekly weight gain of 4.9 kg and increased proteinuria (to P/Cr, 7.6 mg/mg) required cesarean section at GW33-3/7. This case highlights the occurrence of pregnancy-induced AT deficiency alone in the absence of any other abnormality, including hypertension, proteinuria, or thrombocytopenia. Measurement of AT activity was considered helpful for determination of the appropriate time for delivery in this patient. [ABSTRACT FROM AUTHOR]

Aim This study was performed to determine the associations between serum placental growth factor (PlGF) and soluble fms-like tyrosine kinase 1 (sFlt-1) levels at mid-gestation with the risk of small-for-gestational-age (SGA) neonates born at gestational week (GW) ≥ 36 in healthy women. Methods PlGF and sFlt-1 concentrations were determined at GW 24-27 in 183 women with births at GW ≥ 36, but without gestational diabetes mellitus and hypertension. Results Thirteen (7.1%) SGA neonates were born. Median (range) GW at blood sampling was similar between women with and without SGA (25 [24-25] and 24 [24-27], respectively, P = 0.671). Pre-pregnancy body mass index (BMI) and PlGF levels were significantly lower in women with than without SGA, while sFlt-1 levels and sFlt-1 : PlGF ratio (sFlt-1/PlGF) did not differ significantly between the two groups. PlGF and sFlt-1/PlGF, but not BMI or sFlt-1, showed significant correlations with birthweight z-score; the correlation was positive for PlGF and negative for sFlt-1/PlGF. Women with PlGF level < 10th percentile and those with sFlt-1/PlGF level > 90th percentile showed significantly increased risk of SGA compared to those with respective counterpart characteristics; relative risk was 3.8 (95% confidence interval, 1.3-11.3; 21% [4/19] vs 5.5% [9/164]) for PlGF and 7.9 (95% confidence interval, 3.0-20.8, 33.3% [6/18] vs 4.2% [7/165]) for sFlt-1/PlGF. Conclusion Maternal PlGF and sFlt-1/PlGF determined during GW 24-27 were associated with the risk of SGA neonates born at GW ≥ 36, even in women with uncomplicated pregnancies. [ABSTRACT FROM AUTHOR]

Aim Urine podocin mRNA expression and urine podocin : nephrin mRNA expression ratio (PNR) increase with increasing proteinuria during pregnancy complicated with pre-eclampsia (PE). This suggests that urine podocytes with reduced nephrin mRNA expression are abundant in pathological podocyturia. The aim of this study was therefore to determine post-partum changes in podocyturia and PNR in relation to proteinuria after pre-eclampsia (PE). Methods A total of 137 peripartum urine specimens, consisting of 72 and 65 from 24 and 30 women with PE and normotensive control pregnancies (NCP), respectively, were studied. Determination of urine protein and creatinine concentration and quantitative analysis of podocyte-specific podocin and nephrin mRNA expression were carried out using reverse transcription-polymerase chain reaction in pelleted urine samples. Podocyturia was monitored via urine podocin mRNA expression. Podocyturia and proteinuria were normalized by urine creatinine concentration. Results Podocyturia and urine PNR decreased with decreasing proteinuria as well as with increasing time after delivery in the urine from PE women. In physiological proteinuria (i.e. protein : creatinine ratio [P/Cr] 0.005-0.1 mg/mg), however, both podocyturia and PNR were significantly greater in the urine from PE women compared with NPC women, although P/Cr was similar between the groups (median, 0.037 mg/mg for PE vs 0.029 mg/mg for NCP). Conclusions Podocyturia decreases with decreasing proteinuria in PE women after childbirth. In PE women, however, pathological podocyturia consisting of podocytes with decreased nephrin mRNA expression persisted even after proteinuria decreased to a level similar to that in NCP women. [ABSTRACT FROM AUTHOR]

Aim Dipstick results for proteinuria are affected by urine concentration, and thus urine creatinine concentration ([Cr]). This study was performed to determine whether spot urine [Cr] changes significantly during pregnancy, leading to a significantly different false-negative rate (FNR) on dipstick test between trimester. Methods The [Cr] and protein concentrations ([P]) were analyzed in 631 spot urine samples with negative/equivocal dipstick from 425 pregnant women. False-negative dipstick was defined as [P] : [Cr] ratio (P/Cr) > 0.27 mg/mg. Results Median [Cr] was 117 mg/dL (range, 6.5-326 mg/dL), 72 mg/dL (range, 4.3-477 mg/dL), and 73 mg/dL (range, 8.4-396 mg/dL) in the first ( n = 96), second ( n = 344), and third ( n = 191) trimester urine samples, respectively ( P = 0.000, Kruskal-Wallis). Both [P] and P/Cr increased significantly with advancing gestation. FNR 9.4% (18/191) in the third trimester was significantly higher than that of 0.0% (0/96) in the second trimester and that of 0.5% (2/344) in the third trimester. In the 20 urine samples with false-negative dipstick, median [Cr] was 47.0 mg/dL (range, 11.0-358 mg/dL) and the proportion of samples with dilute urine, that is, [Cr] <47 mg/dL, was significantly higher than in the remaining 611 urine samples (50%, 10/20 vs 28%, 174/611, respectively, P = 0.046). Conclusions Urine samples in the second and third trimesters were more likely to be diluted compared with the first trimester. This was associated with high FNR in third trimester urine samples. [ABSTRACT FROM AUTHOR]

Aim Hyperfiltration is a cause of podocyturia and occurs physiologically in the kidney of pregnant women. Podocyturia is increased in preeclamptic pregnancies, but it is unclear whether there is also any increase in uncomplicated pregnancies. This study was performed to examine whether podocyturia and urine aquaporin 2 mRNA expression are increased in healthy pregnant women (PW) compared to healthy non-pregnant women (NPW). Methods Eleven urines obtained from 11 NPW and longitudinal 76 urines from 40 PW with uncomplicated pregnancies (median number [range] of urine samples/person, 2 [1 - 3]) were studied. Determination of protein and creatinine concentrations and number of cells in urine other than blood cells, and quantitative analyses of the mRNA expression of aquaporin 2 (AQP2-mRNA), podocin (Pod-mRNA), and nephrin (Nep-mRNA) were performed using RT-PCR in pelleted urine samples. Podocyturia was monitored with urine Pod- and Nep-mRNA expression levels normalized relative to creatinine. Results Urine cell density and urine AQP2-, Pod-, and Nep-mRNA expression normalized relative to creatinine were significantly higher in PW than NPW. The number of cells per milligram of creatinine was significantly positively correlated with expression of all three mRNAs with correlation coefficients (R-value) of 0.442, 0.481, and 0.561 for Pod-, Nep-, and AQP2-mRNA, respectively. AQP2-mRNA expression was strongly (R > 0.8) positively correlated with both Pod- and Nep-mRNA expression. Conclusion Podocyturia monitored by Pod- and Nep-mRNA expression and urine cells expressing AQP2-mRNA were increased in uncomplicated pregnancies compared to healthy non-pregnant women. Urine cells expressing AQP2-mRNA increased with increasing podocyturia in healthy women. [ABSTRACT FROM AUTHOR]

Aim This study was performed to determine risk factors for central serous chorioretinopathy (CSC) in pregnant women. Methods This retrospective observational study was performed in a cohort of all 1881 women giving birth at a single center. The hospital database was searched to abstract all women diagnosed with pre-eclampsia (PE) as well as those visiting the eye clinic during the current pregnancy. Medical chart review was performed in all women diagnosed with CSC and PE. Results PE developed in 73 (3.9%) women, six (8.2%) of whom visited the eye clinic for problems occurring in the current pregnancy; 47 of 1808 (2.6%) women without PE visited the eye clinic ( P = 0.015). Four women were identified as having developed CSC after onset of PE, and none of those without PE developed CSC (5.5% [4/73] vs 0.0% [0/1808], respectively, P < 0.0001). Stepwise regression analysis selected four risk factors for CSC: hematocrit value > 38.0% (odds ratio [OR], 22.9; 95% confidence interval [CI], 2.12-247), serum creatinine > 0.7 mg/dL (OR, 21.7; 95%CI, 1.12-422), time interval from diagnosis of PE until delivery > 14 days (OR, 20.0; 95%CI, 1.87-214), and urine protein : creatinine ratio (mg/mg) > 4.5 (OR, 15.7; 95%CI, 0.81-304). Hematocrit value > 38.0% was finally identified as the only independent risk factor (OR, 22.9; 95%CI, 2.12-1716) for CSC in PE women. Conclusion CSC was likely to occur in PE women, especially in those with hemoconcentration as a result of plasma leakage from the circulating blood due to increased vascular permeability. [ABSTRACT FROM AUTHOR]

Aim This retrospective study was performed to determine the frequency of malformed infants born at a tertiary center in Hokkaido, Japan. The accuracy of prenatal diagnosis rates was also investigated. Methods An observational study was performed using data of 1509 and 1743 newborn infants at a single center during two study periods, 2005-2009 (first) and 2010-2014 (second), respectively. Cases including minor anomalies (accessory auricle, nevus and fistula auris congenita) were not included. Results In total, 274 and 569 malformations were identified in 191 and 337 newborn infants in the first and second study periods, respectively. The number of malformed infants increased significantly over time (13% [191/1509] vs 19% [337/1743], respectively; P < 0.001), mainly as a result of an increase in cases of congenital heart disease (CHD), from 59 to 141 (31% [59/191] vs 42% [141/337] of all malformed infants in the first and second periods, respectively). The overall accurate prenatal diagnosis rate improved over time from 47% (128/274) to 58% (329/569) because of significant improvements in accurate prenatal diagnosis of CHD subtypes (23% [16/70] vs 65% [151/232] in the first and second periods, respectively, P < 0.0001). Conclusions The frequency of malformed newborns was higher in the tertiary center than in the general population. The increased number of cases with prenatal suspicion and diagnosis of CHD contributed to the increased frequency of malformed infants during the study period. [ABSTRACT FROM AUTHOR]

Aim Podocyte depletion in the kidney is associated with end-stage kidney disease (ESKD). Pre-eclampsia (PE) increases the risk of ESKD in later life. This study was performed to determine whether nephrinuria (soluble nephrin in the urine) is correlated with proteinuria and/or podocyturia (podocytes in the urine) in PE women. Methods Eighty-three urine samples, consisting of 45 and 38 samples from 27 normotensive and nine PE women, respectively, underwent simultaneous determination of nephrin, protein, and creatinine concentrations in the urine supernatant and quantitative analysis of podocyte-specific protein mRNA expression. This included podocin (Pod-mRNA) and nephrin (Nep-mRNA), using real-time polymerase chain reaction in the pelleted urine. Nephrinuria and proteinuria were corrected by creatinine concentration. Pod- and Nep-mRNA expression levels were corrected by GAPDH. Results Nephrinuria, proteinuria, Pod-mRNA expression, and Nep-mRNA expression all increased with advancing gestation in PE women, while not in normotensive women. The nephrinuria was strongly correlated with proteinuria ( R = 0.901, P < 0.001), Pod-mRNA expression level ( R = 0.824, P < 0.001), and Nep-mRNA expression level ( R = 0.724, P < 0.001) in urine samples from PE women, while the nephrinuria was significantly correlated with proteinuria alone ( R = 0.419, P < 0.005) in urine samples from normotensive women. Conclusion Nephrinuria reflected well the degrees of proteinuria and podocyturia in PE women. This suggested that increased nephrinuria/proteinuria was associated with podocyte loss in the kidneys of PE women. [ABSTRACT FROM AUTHOR]

There have been few reports on the effects of everolimus on the fetus, but none of six infants with documented everolimus exposure in utero had congenital malformations. A 32-year-old nulliparous woman on everolimus (5.0 mg/day) for renal angiomyolipoma (AML) due to tuberous sclerosis complex (TSC) was found to be pregnant at gestational week (GW) 7-5/7, at which time everolimus was withheld. To control AML in this patient, transarterial embolization was performed in the right and left kidneys at GW 21 and 24, respectively, and everolimus was reinitiated at GW 25. The patient gave birth at GW 37 to a normally formed infant weighing 3057 g, but who had cardiac tumors thought to be rhabdomyomas due to inherited TSC. Thus, although data are still limited, everolimus may be promising with respect to teratogenicity. Everolimus concentration in the maternal and umbilical cord blood at birth was 1.1 ng/mL and 1.0 ng/mL, respectively. [ABSTRACT FROM AUTHOR]