Aiko Sasaki

Low prevalence of genetic prenatal diagnosis in Japan.

Aiko Sasaki1, Hideaki Sawai2, Hideaki Masuzaki3, Fumiki Hirahara4 and Haruhiko Sago1* 1Department of Maternal-Fetal and Neonatal Medicine, National Center for Child Health and Development, Tokyo, Japan 2Department of Obstetrics and Gynecology, Hyogo College of Medicine, Nishinomiya, Japan 3Department of Obstetrics and Gynecology, Nagasaki University, Nagasaki, Japan 4Department of Obstetrics and Gynecology, Yokohama City University, Yokohama, Japan

A fetus diagnosed with Casamassima-Morton-Nance syndrome with de novo del(8)(p23.1).

Aiko Sasaki1, Satoshi Hayashi1, Rie Oi1, Ai Anami1, Masachi Hanaoka1, Osamu Miyazaki2, Kentaro Matsuoka3 and Haruhiko Sago1* 1Department of Maternal-Fetal and Neonatal Medicine, National Center for Child Health and Development (NCCHD), Tokyo, Japan 2Department of Radiology, National Center for Child Health and Development (NCCHD), Tokyo, Japan 3Department of Pathology, National Center for Child Health and Development (NCCHD), Tokyo, Japan

The outcomes of 31 cases of trisomy 13 diagnosed in utero with various management options

There are few reports on the prognosis of prenatally diagnosed trisomy 13 in relation to postnatal management. The aim of this study was to report on the prenatal and postnatal outcomes and postnatal management of trisomy 13 fetuses that were prenatally diagnosed at our center between 2003 and 2015. The data were retrospectively reviewed from medical records. Of the 31 cases of trisomy 13, 12 patients were diagnosed before 22 weeks of gestation, and 19 were diagnosed at or after 22 weeks of gestation. Nine families opted for termination of the pregnancy, 14 fetuses died, and 8 were born alive. Aggressive treatment was requested in two of the live births, with one patient achieving long‐term survival (7 years). The other died during infancy (Day 61). One out of four who received palliative treatment is alive at two years of age with only nutrition supplementation. These three patients who achieved neonatal survival had few structural anomalies. Fetal death and early neonatal death are common in trisomy 13; however, fetuses that receive medical treatment for cases without major ultrasound abnormalities may achieve neonatal survival. Therefore, it is useful to provide comprehensive information, including precise ultrasound findings and treatment options, to parents with trisomy 13 fetuses during genetic counseling.

Fetal Magnetic Resonance Imaging Detection of Liver Iron Deposition in Neonatal Hemochromatosis During Prenatal Therapy.

T o the Editor: Neonatal hemochromatosis caused by gestational alloimmune liver disease (NH-GALD) is improved by maternal intravenous immunoglobulin infusions (IVIG) (1). We, however, have no clinical markers for in utero monitoring of fetal hepatic injury caused by NH-GALD. A 36-year-old Japanese woman, whose newborn had died 17 hours after birth as a result of clinically and histologically proven NH-GALD 2 years ago, consulted our hospital. During her next pregnancy, she received IVIG from 14 weeks based on a previous protocol (2). At 38 weeks, we used 2 methods of fetal magnetic resonance imaging (MRI) to evaluate the fetal liver condition (3,4). First, we measured the signal intensity (SI) of the liver in opposedphase and in-phase sequences in T1-weighted images. The median in-phase SI was significantly lower than the opposed-phase SI (Wilcoxon-Mann-Whitney test, P1⁄4 0.012; Supplemental Digital Content 1, Fig. 1, http://links.lww.com/MPG/A727), and the inphase/opposed-phase SI ratio (SIR) was 0.78. Second, we calculated the SIR of the fetal liver (fL) to the fetal iliopsoas muscle (fM) in T2-weighted half-Fourier single-shot turbo spin-echo images. The fL/fM ratio was 0.70, significantly lower than those in 10 fetuses without liver injury (Wilcoxon signed-rank test, P1⁄4 0.002; Supplemental Digital Content 2, Table 1, http://links.lww.com/ MPG/A728). The SIRs for 2 extrahepatic organs (fetal pancreas [fP] and fetal spleen [fS]), that is, fP/fM and fS/fM, were 1.36 and 1.74, suggesting that iron deposition was limited to the liver. The baby was born healthy, but with abnormal laboratory data (Supplemental Digital Content 1, Fig. 2, http://links.lww.com/MPG/A727). Those data became normal, without any specific treatment, after 9 days. Low MRI in-phase SI in the liver also gradually improved during 1 year. These noninvasive methods may predict the degree of NH-GALD liver injury in utero. However, a significant limitation of this study is that only a single patient was enrolled, and further studies are needed to validate the usefulness of such fetal MRI imaging.

Prenatal genetic testing for a microdeletion at chromosome 14q32.2 imprinted region leading to UPD(14)pat-like phenotype†

© 2013 Wiley Periodicals, Inc.

Distribution of PAPP-A and total hCG between 11 and 13 weeks of gestation in Japanese pregnant women

Abstract Objectives: To establish the reference values for PAPP-A and total hCG between 11 and 13 weeks of gestation for the use of risk assessment of fetal aneuploidy in Japanese pregnant women. Methods: A multicenter prospective study was conducted. The subjects included only Japanese pregnant women with viable singleton who requested the first trimester combined (nuchal translucency and maternal serum marker) screening for fetal aneuploidy. Reference values of PAPP-A and total hCG in Japanese population were made and compared with them in Caucasian. Results: Overall 1,751 Japanese pregnant women were analyzed. Median vales of maternal serum concentration in Japanese pregnant women from 11 + 0–13 + 6 weeks’ gestation were ranged from 3.01 to 9.51 mIU/mL for PAPP-A and from 70.2 to 58.3 IU/mL for total-hCG, respectively. Regression curve of median maternal serum PAPP-A and total-hCG concentration against gestational days are significantly higher in Japanese comparing with Caucasian. At most distant values, Japanese serum concentration indicated 1.45 MoM for total-hCG and 1.70 MoM for PAPP-A based on Caucasian regression curves. Conclusion: A modification of the equations by specific reference values is necessary for Japanese pregnant women at the risk assessment of chromosomal abnormalities using the first trimester maternal serum marker.

The Japanese experience and pharmacokinetics of antenatal maternal high-dose immunoglobulin treatment as a prophylaxis for neonatal hemochromatosis in siblings

Abstract Background: Neonatal hemochromatosis (NH) is a rare but serious disease causing fulminant hepatic failure. The recurrence rate of NH in a subsequent infant of a mother with an affected infant is 70–90%. Recently, antenatal maternal high-dose intravenous immunoglobulin (IVIG) treatment has been reported to be effective for preventing NH recurrence. However, data on the IgG concentrations during this treatment are limited. Objective: We report a Japanese experience and present a pharmacokinetic simulation model of IgG during IVIG treatment. Methods: Women with histories of pregnancy diagnosed with NH were treated with IVIG weekly from the second trimester until the end of gestation. Serum IgG levels during treatment were collected frequently and pharmacokinetics were simulated by a two-compartment model. Results: Six women were included during eight pregnancies. None experienced severe adverse events. Three out of eight infants showed temporary liver dysfunction, but none required any treatment. A simulation study showed that the estimated trough and peak levels of IgG concentrations during IVIG were 2000–3000 and 4000–5000 mg/dl, respectively. Conclusion: This treatment prevented the recurrence of NH in siblings in Japanese women. We examined the details of serum IgG concentrations and introduced a new pharmacokinetic simulation model of IgG concentrations during IVIG treatment.

Successful treatment for a recurrent pregnancy loss woman with high Th1/Th2 ratio using medium-dose corticosteroids

Pregnancy is the most common example of immune tolerance. While the foetus and placenta are perceived as ‘allografts’ by the mother’s immune system, the foetus grows in the uterus during pregnancy ...

Impact of the Introduction of Non-Invasive Prenatal Genetic Testing on Invasive Tests - A Single-Center Study in Japan.

Non-invasive prenatal genetic testing (NIPT) using massively parallel sequencing of cell-free DNA is a technique to screen for fetal aneuploidies by evaluating the amount of cell-free DNA of target chromosomes in maternal blood (Chiu et al. 2008). NIPT demonstrates a sensitivity and specificity of higher than 99% for fetal trisomy 21 (Palomaki et al. 2011). NIPT was first introduced in 2011 in the United States, and since then there have been a report on the decrease in invasive prenatal procedures (Larion et al. 2014). NIPT was introduced in Japan in April 2013 as a nationwide clinical research (Sago and Sekizawa 2015). A decrease in the proportion of invasive testing among pregnant women who underwent prenatal genetic testing was reported, although the total number of invasive testing did not decrease at a single center after one year (Akaishi et al. 2015). Notably, the impact of NIPT on invasive testing in Japan has not been elucidated. Table 1 shows the numbers and clinical indications of amniocentesis (AC) and chorionic villus sampling (CVS), and the numbers of quadruple test (QT) and NIPT between April 2011 and March 2015. The number of AC increased before the introduction of NIPT, then decreased remarkably after the introduction of NIPT, whereas the change in the number of CVS was relatively small. The number of QT showed similar changes to that of AC, that is, increased before the introduction of NIPT then decreased remarkably after the introduction of NIPT. The number of NIPT was high compared with that of other prenatal tests. AC owing to advanced maternal age (AMA), abnormal ultrasonography (USG) findings and positive QT at the second trimester decreased after the introduction of NIPT. When comparing the numbers of AC and CVS in the first year after the introduction of NIPTwith those in the year before the introduction of NIPT, AC and CVS decreased 38% (from 347 to 216) and 11% (from 82 to 73), respectively. In the second year after the introduction of NIPT, AC and CVS decreased 58% (from 347 to 147) and 28% (from 82 to 59), respectively. The change in the number of AC after the introduction of NIPT in our hospital was similar to that in the United States (52.5% reduction) (Larion et al. 2014), while the change in the number of CVS was smaller than that in the United States (77.2% reduction) (Larion et al. 2014). In a population in which first and second trimester prenatal screening tests are widely prevalent, both AC and CVS may decrease because NIPT can reduce the rate of “screen-positive” which can be confirmed by AC or CVS; this would be the main reason for the decrease in invasive tests in the United States. In Japan, prenatal screening tests are not widely accepted due to ethical issues. Obstetricians are reluctant to offer prenatal screening tests for fetal aneuploidies to pregnant women without their request. Thus, the rate of prenatal genetic testing in Japan remained low at about 3%, with AC being the main invasive diagnostic procedure (Sasaki et al. 2011). The most frequent indication for AC was AMA in the pre-NIPT period (Nishiyama et al. 2015). Many pregnant women who wanted to have prenatal genetic testing for AMA have chosen NIPT instead of AC. This would be the main reason for the decrease in AC in our hospital. The decrease of AC owing to positive QT or USG abnormality was suspected to be a reflection of the decrease in the number of QT or NT measurement performed in the post-NIPT period. A possible reason for the relatively small change in the number of CVS is that the indication criteria for CVS has been limited for women at higher risk for genetic disorders or USG abnormality, which implies chromosomal abnormality in the first trimester. Therefore, CVS could not be replaced by NIPT for trisomy 21, 18 and 13. In conclusion, the number of AC decreased remarkably after the introduction of NIPT, whereas the change in the number of CVS was relatively small. The impact of NIPT on prenatal testing may vary among populations with different prenatal screening situations in which screening tests are widely accepted or not.

Efficacy of advice from healthcare professionals to pregnant women on avoiding constrictive clothing around the trunk: a study protocol for a randomised controlled trial.

Introduction As a component of midwife care, eliminating clothing that constricts the trunk has been shown to markedly elevate the uterine fundus, soften the uterus and abdomen, and reduce the abdominal wall tension in women admitted to hospital due to the risk of miscarriage or premature delivery. However, no prospective study has conclusively verified the efficacy of avoiding constrictive clothes around the trunk in pregnant women. We aim to verify the efficacy of instructing pregnant women to wear loose clothing that does not constrict the trunk to reduce the risk of premature birth and improve quality of life (QoL) during pregnancy. Methods and analysis We will conduct a randomised controlled trial of pregnant women scheduled to deliver at the National Center for Child Health and Development in Tokyo, Japan. A total of 616 pregnant women, from whom written informed consent will be obtained, will be allocated randomly to an intervention group or a control group. Women in the control group will be provided with anaemia prevention leaflets at 20 weeks’ gestation and skin-care leaflets at 30 weeks’ gestation. Women in the intervention group will be provided with the same leaflets and will also receive health advice from health professionals to avoid constrictive clothing around the trunk. The primary outcome will be a difference between these groups in the frequency of any one of the following category variables: (1) cervical length <30 mm up to 28 weeks’ gestation, (2) hospital admission for threatened premature delivery, or (3) premature delivery. Secondary outcomes will include QoL during pregnancy, maternal state of health, and status of fetal development. Ethics and dissemination The Institutional Review Board and Ethics Committee at the National Center for Child Health and Development, Japan, has approved this study. Our findings will be widely disseminated through conference presentations and peer-reviewed publications. Trial registration number UMIN000016853.