Relationship between maternal mortality and ritodrine hydrochloride as a tocolytic agent in Japan.

AIM: In Japan, unlike Western countries, tocolytic agents are administered in long-term protocols to treat threatened preterm labor. Evaluating the side effects of this practice is crucial. We examined whether ritodrine hydrochloride had been administered in cases of maternal death, aiming to investigate any relationship between ritodrine administration and maternal death. METHODS: This retrospective cohort study used reports of maternal deaths from multiple institutions in Japan between 2010 and 2020. Data on the reported cases were retrospectively analyzed, and data on the route of administration, administered dose, and clinical findings, including causes of maternal death, were extracted. The amount of tocolytic agents was compared between maternal deaths with ritodrine administration and those without. RESULTS: A total of 390 maternal deaths were reported to the Maternal Death Exploratory Committee in Japan during the study period. Ritodrine hydrochloride was administered in 32 of these cases. The frequencies (n) and median doses (range) of oral or intravenous ritodrine hydrochloride were 34.4% (11) and 945 (5-2100) mg and 84.4% (27) and 4032 (50-18 680) mg, respectively. Frequencies of perinatal cardiomyopathy, cerebral hemorrhage, diabetic ketoacidosis, and pulmonary edema as causes of maternal death were significantly higher with ritodrine administration than without it. CONCLUSIONS: Our results suggest a relationship between long-term administration of ritodrine hydrochloride and an increased risk of maternal death due to perinatal cardiomyopathy, cerebral hemorrhage, diabetic ketoacidosis, and pulmonary edema. In cases where ritodrine should be administered to prevent preterm labor, careful management and monitoring of maternal symptoms are required.

Individualized management of vasa previa and neonatal outcomes.

OBJECTIVE: To describe our individualized management protocol for women with an antenatal diagnosis of vasa previa (VP) and to report maternal and neonatal outcomes in patients managed according to our protocol. METHODS: A retrospective study of prospectively collected data of antenatally diagnosed VP managed at our hospital between 2014 and 2021. Obstetric and neonatal outcomes were reviewed and analyzed. RESULTS: Fourteen cases of antenatally diagnosed VP in 5150 total deliveries were analyzed (0.3%) Five cases (36%) of VP were diagnosed during the routine fetal morphological ultrasound screening, and nine cases (64%) were referred to our hospital due to perinatal complications. There were nine cases that required hospitalization (due to fetal growth restriction [FGR] [1], preterm labor [3], patients' request [5]). The other five were asymptomatic. Eight patients were delivered by scheduled cesarean section at around 36 weeks and only three neonates were admitted to NICU with transient tachypnea of newborn. However, six patients required CS before the scheduled dates because of other complications (preterm labor [3], abnormal cardiotocogram patterns [1], FGR [1] and twin pregnancy [1]). Four neonates born by CS before their scheduled dates were admitted to NICU. No cases required prolonged hospitalization and there were no serious neonatal complications. CONCLUSION: Individualized management may lead to favorable outcomes with VP. Outpatient management may be considered in patients without risk factors. However, maternal hospitalization and earlier scheduled CS should be considered in symptomatic patients or those at risk for preterm delivery.

Long-term outcome of cases of fetal pleural effusion: A study at a single perinatal center in Japan.

PURPOSE: To analyze the long-term prognosis of primary and secondary fetal pleural effusion (FPE). METHODS: We investigated all cases of FPE in a single University hospital (2005-2020). Cases were classified as primary (cases with only pleural effusion) and secondary (cases with other abnormalities such as chromosomal abnormalities or fetal cardiac failure). We retrospectively reviewed the medical records from the time of diagnosis, to assess medical procedures performed, chromosomal test results, and clinical outcomes. RESULTS: Among 18 027 deliveries, 17 FPEs were identified (primary FPE: 8, secondary FPE: 9). Most primary FPEs were diagnosed in the second trimester of pregnancy, while all secondary FPEs were diagnosed in the third trimester. Secondary FPE was often associated with chromosomal abnormalities, including trisomy 21. The prognosis of pleural effusion caused by trisomy 21 was relatively good, except for cases with TAM. Cases of secondary FPE without trisomy 21 were of cardiac origin, and the neonatal prognosis was poor. The short-term prognosis was better in the primary FPE group, but long-term follow-up identified conditions such as acute encephalitis with refractory, repetitive partial seizures, developmental delay and attention deficit hyperactivity disorder. CONCLUSION: Fetal pleural effusion without the presence of chromosomal abnormalities or morphologies has a good short-term prognosis, but the long-term prognosis is poor. Thus, long-term follow-up is necessary for all cases of fetal pleural effusion.

Differences in perinatal outcomes according to forming period of single umbilical cord in singleton pregnancy.

OBJECTIVES: The aim of this study was to establish the frequency and associations of single umbilical artery (SUA) diagnosed until the first vs second or third trimester. METHODS: A retrospective cohort study was conducted on singleton pregnancies at a tertiary perinatal center. All women underwent both the first and second trimester scans in which the number of arteries in the umbilical cord was routinely documented. SUA was classified as aplastic type when the diagnosis was made in the first trimester and as occlusion type when diagnosed in the second or third trimester. Adverse perinatal outcome was calculated as occurrence of fetal death, birthweight centile < 10th , or Apgar score at 5 minutes < 7. RESULTS: A total of 8675 women underwent ultrasound examinations during the study period. Of the 32 SUA cases, 17 (0.2%) were of the aplastic type and 15 (0.2%) of the occlusion type. Congenital anomalies were more in aplastic than in occlusive SUA (58.8% vs 20%, .043). The occlusive SUA had higher postnatal coiling index (0.3 vs 0.2, .034) and diagnosis of hypercoiled cord (46.7% vs 5.9%, .013) than the aplastic type. CONCLUSIONS: The different gestational age at diagnosis and coiling characteristics suggest two types of SUA, namely, aplastic and occlusion types, which are associated with differences in perinatal outcomes.

Causes of intrauterine fetal death are changing in recent years.

OBJECTIVE: To investigate, how causes of intrauterine fetal death (IUFD) have changed in recent years with the advancement of prenatal diagnosis at a single perinatal center in Japan. METHODS: Medical records were retrospectively reviewed for all cases of IUFDs that occurred between 2001 and 2014. The most commonly associated causes of fetal deaths were compared between 2001-2007 and 2008-2014. RESULTS: The number of IUFD after 20 weeks' gestation/all deliveries in our center was 38/6878 cases (0.53%) in 2001-2007 and 35/7326 (0.48%) in 2008-2014. The leading cause of IUFD in 2001-2007 was fetal abnormalities (43.2%), the prevalence of which was only 8.6% in 2008-2014 (P<0.01). Meanwhile, the prevalence of umbilical cord abnormalities was relatively increased from 30.0% in 2001-2007 to 54.5% in 2008-2014 (P=0.06). In 2001-2007, chromosomal abnormalities were frequently observed (56% of IUFDs due to fetal abnormalities). Hyper-coiled cord (HCC) and umbilical ring constrictions were the most frequent cause of IUFD in both periods. The relatively decreased prevalence of IUFD due to velamentous cord insertion and umbilical cord entanglement, HCC and umbilical cord constriction was increased. CONCLUSIONS: The prevalence of IUFD due to fetal abnormalities was reduced, but IUFD associated with umbilical cord abnormalities tended to increase relatively.

A poor long-term neurological prognosis is associated with abnormal cord insertion in severe growth-restricted fetuses.

OBJECTIVE: To clarify and compare if the neurological outcomes of fetal growth restriction (FGR) cases with abnormal cord insertion (CI) are associated with a higher risk of a poor neurological outcome in subjects aged 3 years or less versus those with normal CI. METHODS: A multicenter retrospective cohort study was conducted among patients with a birth weight lower than the 3rd percentile, based on the standard reference values for Japanese subjects after 22 weeks' gestation, who were treated at a consortium of nine perinatal centers in Japan between June 2005 and March 2011. Patients whose birth weights were less than the 3rd percentile and whose neurological outcomes from birth to 3 years of age could be checked from their medical records were analyzed. The relationship between abnormal CI and neurological outcomes was analyzed. Univariate and multivariate models of multivariate logistic regression were employed to estimate the raw and odds ratio (OR) with 95% confidence intervals comparing marginal (MCI) and velamentous cord insertion (VCI) to normal CI. RESULTS: Among 365 neonates, 63 cases of MCI and 14 cases of VCI were observed. After excluding 24 cases with neonatal or infant death from the total FGR population, the assessment of the outcomes of the infants aged 3 years or younger showed the following rates of neurological complications: 7.3% (n=25) for cerebral palsy, 8.8% (n=30) for developmental disorders, 16.7% (n=57) for small-for-gestational-age short stature (SGA), 0.6% (n=2) for impaired hearing, 0.9% (n=3) for epilepsy, 1.2% (n=4). The ORs (95% confidence intervals) based on multivariate analysis were as follows: cerebral palsy=10.1 (2.4-41.5) in the VCI group and 4.3 (1.6-11.9) in the MCI group, developmental disorders=6.7 (1.7-26) in the VCI group and 3.9 (1.1-14.2) in the single umbilical artery (SUA) group, 5.1 (1.4-18.7) for birth weight <1000 g and 2.8 (1.2-6.7) for placental weight <200 g. CONCLUSIONS: The present results indicate that growth-restricted fetuses diagnosed with a birth weight below the 3rd percentile exhibiting abnormal umbilical CI are at a high risk for poor neurological outcomes, including cerebral palsy and/or developmental disorders.

Silent uterine rupture occluded by intestinal adhesions following laparoscopic myomectomy: A case report.

We present a rare asymptomatic case in which intestinal adhesions covered and occluded a site of uterine rupture, which was found during cesarean section. The patient had undergone laparoscopic myomectomy 5 years previously. However, detailed antenatal ultrasound and magnetic resonance imaging examinations revealed no uterine or placental abnormalities. It is thought that uterine rupture was not detected due to intestinal adhesions, which had occurred following the previous surgery. The present case suggests that women who conceive after laparoscopic myomectomy may be at risk of silent uterine rupture. However, detection of the silent uterine rupture during pregnancy may be limited, even with detailed imaging.

Comparison of perinatal outcomes between long-term and short-term use of tocolytic agent: a historical cohort study in a single perinatal hospital.

AIM: The aim of this study was to evaluate the effect of long-term use of tocolytic agents to prevent preterm delivery and improve perinatal outcome. METHODS: A historical cohort study was performed in a single perinatal center. The maternal characteristics, frequency of preterm labor and prescribed dose of tocolytic agents were compared before and after changing the management protocol for threatened premature delivery. RESULTS: A total of 1548 deliveries were carried out before changing the protocol for the use of tocolytic agents for threatened premature delivery and 1444 deliveries afterwards. There was no significant difference in the maternal characteristics before and after the revision except for maternal age. The total number of ritodrine hydrochloride ampules used was reduced from 4654 to 514, and the total vials of magnesium sulfate used were reduced from 1574 to 193, but perinatal outcomes, such as rate of preterm birth, neonatal weight, and rate of NICU hospitalization were not different between the groups. CONCLUSION: There was no significant change in the frequency of preterm delivery before and after changing of the protocol for threatened premature delivery. Because a decrease in the given dose of tocolytic agents did not affect the timing of delivery and neonatal outcomes, long-term tocolysis in patients with threatened premature delivery should be restricted to prevent maternal and fetal adverse side-effects.

Recommendations for saving mothers' lives in Japan: Report from the Maternal Death Exploratory Committee (2010-2014).

To make recommendations for saving mothers' lives, issues related to maternal deaths including diseases, causes, treatments, and hospital and regional systems are analyzed by the Maternal Death Exploratory Committee in Japan. In this report, we present ten clinical important recommendations based on the analysis of maternal deaths between 2010 and 2014 in Japan.

Repeated Measurement of Crown-Rump Length at 9 and 11-13 Weeks' Gestation: Association with Adverse Pregnancy Outcome.

AIMS: To clarify whether ultrasonographic measurements of crown-rump length (CRL) at 11-13 weeks - based on the number of gestational days determined using the CRL at 9 weeks - can predict fetal prognosis. METHODS: A prospective cohort study was conducted to evaluate the association between fetal growth in the first trimester and fetal prognosis. Fetal growth in the first trimester was evaluated measuring CRLs at 11-13 weeks determined using the CRL at 9 weeks. The subjects were divided into short CRL (s-CRL) and normal CRL (n-CRL). The prognoses were compared between the two groups. RESULTS: A total of 126 patients in the s-CRL group and 1,130 patients in the n-CRL group were enrolled. Abortion occurred in 7.1% of s-CRL and 0.9% of n-CRL subjects (p < 0.001). Among the patients with chromosomal abnormalities, the incidence of trisomy 18 was significantly greater in s-CRL (4.8 vs. 0.1%, p < 0.001). Without abortion, placental weight, frequency of small for gestational age (SGA) and birth weight in s-CRL were significantly higher than those in the n-CRL group (12.8 vs. 3.6%, p < 0.001). CONCLUSIONS: Measuring CRL at 9 weeks is useful for determining gestational days prior to measuring CRL at 11-13 weeks. After reconfirming the gestational age at 9 weeks, measuring CRL at 11-13 weeks is useful for predicting the incidence of trisomy 18 as well as SGA later in pregnancy.

Administration of oral and vaginal prebiotic lactoferrin for a woman with a refractory vaginitis recurring preterm delivery: appearance of lactobacillus in vaginal flora followed by term delivery.

Lactoferrin (LF) is one of the prebiotics present in the human body. A 38-year-old multiparous woman with poor obstetrical histories, three consecutive preterm premature rupture of membrane at the 19th, 23rd and 25th week of pregnancy, was referred to our hospital. She was diagnosed as having refractory vaginitis. Although estriol vaginal tablets were used for 4 months, the vaginitis was not cured. We administrated vaginal tablets and oral agents of prebiotic LF, resulting in a Lactobacillus predominant vaginal flora. When she was pregnant, she continued to use the LF, and the Lactobacillus in the vaginal flora was continuously observed during pregnancy. An elective cesarean section was performed at the 38th week of pregnancy. When the administration of LF was discontinued after the delivery, Lactobacillus in the vaginal flora was disappeared.

Sonohysterography is a useful diagnostic approach for uterine arteriovenous malformation.

Uterine arteriovenous malformation (AVM) is a rare cause of abnormal uterine bleeding; nevertheless, it is a potentially life-threatening condition when the diagnosis is not made. We report a case of uterine AVM with a secondary uterine hematoma diagnosed 2 weeks after curettage due to spontaneous abortion. Ultrasound examination revealed a mixed echogenic mass of approximately 4 cm × 1.5 cm with no blood flow and an additional contiguous heterogeneous mass with turbulent blood flow depicted by color Doppler. Transvaginal sonohysterography enabled us to exclude residual chorionic tissues and to make precise diagnosis of uterine AVM with a secondary hematoma.

Is maternal anemia associated with small placental volume in the first trimester?

AIM: To clarify whether maternal anemia could reduce placental volume in the early gestation. METHODS: A prospective cross-sectional study was conducted. Consecutive women who visited at 11-13 + 6 weeks' gestation were enrolled. Subjects were divided into two groups by maternal hemoglobin concentration. Cases with maternal anemia were defined as a hemoglobin level less than 11 g/dl on a blood test (cases), and the others were defined as controls. An ultrasound examination was performed to measure the placental volume and the uterine arterial blood flow. The three-dimensional volume of the placenta using virtual organ computer-aided analysis (VOCAL) technique was acquired by transabdominal ultrasonography. Placental volumes were compared in women with and without anemia. RESULTS: 31 cases and 486 controls were analyzed. Maternal characteristics were not different between two groups except anemia. Placental volumes were 63.6 ± 22.2 and 60.9 ± 22.8 cm(3) (ns), uterine arterial RIs were 0.7 ± 0.1 and 0.8 ± 0.1 (ns), and PIs were 1.7 ± 0.5 and 1.8 ± 0.6 (ns) in cases and controls, respectively. CONCLUSIONS: Maternal anemia was not associated with reduced placental volume and uterine arterial Doppler wave form at 11-13 weeks' gestation.

The volume of the chorion villosum is associated with the location of the umbilical cord in the first trimester.

AIMS: To clarify whether villous placental volumes in cases with low cord insertion (CI) are smaller than those with normal cord insertion. METHODS: A prospective cohort study was conducted to evaluate the association between location of umbilical CI and placental volume at 11 to 13 weeks' gestation. An ultrasound examination was performed to measure the crown-rump length, the distance between the histological internal cervical os and the CI site, the placental volume, and the uterine arterial blood flow. To standardize the distribution of the ultrasonographic measurements, we transformed data by crown-rump length-weighted linear regression. RESULTS: Six hundred fifty-nine subjects were analyzed. Scatter plots showed a slightly positive correlation between the z-scores of the distance from the CI site to the internal cervical os and villous placental volume (r = 0.102, p = 0.009) and a negative correlation between the z-scores of the villous placental volume and the uterine arterial pulsatility index (r = -0.165, p < 0.001) as well as the uterine arterial resistance index (r = -0.187, p < 0.001). CONCLUSION: The placental volume was likely to be smaller in cases with CI located in the lower uterine segment.

Relationship between the umbilical cord coiling index and the umbilical blood flow at 11-13 weeks of gestation.

OBJECTIVES: The aim of this study was to clarify the effects of umbilical cord coiling on the umbilical blood flow at 11-13 weeks of gestation. METHODS: A cross-sectional study was conducted among consecutive pregnant females at 11-13 weeks of gestation. Transabdominal ultrasound examinations were performed to obtain the umbilical coiling index (CI), the maximum umbilical arterial peak velocity at the free loop, the venous velocities at the free loop and the umbilical ring, and the umbilical arterial and venous flow volumes. After every measurement was standardized according to the crown-rump length (CRL), correlations between the CI and these measurements were analyzed. RESULTS: A total of 364 subjects were enrolled. The CI significantly decreased in association with advancing gestation. There were significant correlations between the CRLs and the umbilical arterial peak velocities, the venous velocities at the free loop and the umbilical ring, and the umbilical arterial and venous flow volumes. The z-scores of the umbilical arterial and venous velocimetries exhibited no significant correlations with the CI. The umbilical arterial and venous flow volumes were also not found to correlate with the CI. CONCLUSIONS: The CI does not affect either the umbilical arterial or venous blood flow at 11-13 weeks of gestation.

Distribution of nuchal translucency thickness in Japanese fetuses.

AIM: To establish reference values for the nuchal translucency (NT) thickness in Japanese fetuses. MATERIAL AND METHODS: Ultrasonographic measurements of the crown-rump length (CRL) and NT were performed from 11 to 13 + 6 weeks of gestation in consecutive Japanese fetuses examined during prenatal visits between February 2011 and January 2012. The median, 5th and 95th percentiles of the NT thickness with 5 mm intervals of the CRL were confirmed. RESULTS: A total of 970 cases were enrolled in the study. The median NT thickness for a CRL between 45 and 80 mm ranged from 1.2 mm to 1.9 mm, and the 95th percentile of these values ranged from 2.1 mm to 3.2 mm, respectively. CONCLUSION: The reference values for the NT thickness in Japanese fetuses were determined. These values should be useful for fetal biometry, morphological assessment and first trimester screening for chromosomal abnormalities in Japan.

A case report of umbilical ring constriction with application of amnioinfusion.

This is a case report of a pregnant 38-year-old primigravida woman. Due to severe fetal growth restriction and oligohydramnios, she was referred to our tertiary perinatal center at 24 weeks' gestation. To rule out chromosomal abnormalities and facilitate ultrasound evaluation of fetal morphology, we performed amniocentesis and subsequent amnioinfusion. Thereafter, a precise ultrasound examination revealed no obvious fetal morphological abnormalities except for a hyper-coiled cord and marginal placenta previa. During expectant management, the amount of amniotic fluid was maintained at 20-26 mm for a few days; however, the pregnancy resulted in intrauterine fetal death after 26 weeks + 5 days of gestation. The stillborn infant weighed 530 g (-3.3 SD) and had no obvious external abnormalities apart from umbilical ring constriction. Although a postmortem autopsy was not performed, it is suspected that the fetal growth restriction and the intrauterine fetal death were associated with the hyper-coiled cord and the umbilical ring constriction. It is thought that umbilical ring constriction might therefore be an irreversible fatal condition in cases with a hyper-coiled cord.

Declaration of emergency state due to COVID-19 spread in Japan reduced maternal transports without reduction in preterm delivery.

INTRODUCTION: To clarify whether the declaration of an emergency state due to the spread of COVID-19 in Japan affected the number of maternal transports and premature births. METHODS: A questionnaire-based descriptive study was conducted in perinatal centers throughout Japan in 2020. The incidence of maternal transport and preterm delivery rates every month after the COVID-19 spread in 2020 were compared with those in 2019. RESULTS: Participants were recruited from 52 perinatal centres. The maternal transport rate (maternal transports per number of deliveries) was 10.6% in April and 11.0% in June 2020, compared with 12.5% in 2019 (P < 0.05). The maternal transport rate due to preterm labor was 4.8% in April 2020 and 5.8% in 2019 (P < 0.05). The maternal transport rate during the declaration of emergency state decreased by 21% in April 2020 in non-emergency-declared prefectures, and decreased by 17% in May 2020 in emergency-declared prefectures. However, there was no significant difference in the preterm delivery rate between 2020 and 2019, regardless of the prefecture and gestational period. CONCLUSION: Declaration of the emergency status due to COVID-19 spread in Japan reduced maternal transport due to preterm labor, but did not reduce preterm delivery itself.

High maternal mortality rate associated with advanced maternal age in Japan.

This study aimed to clarify the relationship between maternal mortality and advanced maternal age in Japan and to provide useful information for future perinatal management. Maternal death rates by age group were investigated for all maternal deaths in Japan for an 11-year period, from 2010 to 2021. Maternal deaths among those aged ≥ 40 years were examined in detail to determine the cause, and the number of deaths by cause was calculated. The causes of onset of the most common causes of death were also investigated. The maternal mortality rates were 0.8 (95% confidence interval [CI] 0.3-4.7) for < 20 years, 2.6 (95% CI 1.7-3.8) for 20-24 years, 2.9 (95% CI 2.3-3.6) for 25-29 years, 3.9 (95% CI 3.3-4.5) for 30-34 years, 6.8 (95% CI 5.9-7.9) for 35-39 years, and 11.2 (95% CI 8.8-14.3) for ≥ 40 years of age. Patients who were ≥ 40 years of age had a significantly higher mortality rate compared to that in other age groups. Hemorrhagic stroke was the most common cause of death in patients aged ≥ 40 years (15/65 [23%]), and preeclampsia (8/15 [54%]) was the most common cause of hemorrhagic stroke. Maternal mortality is significantly higher in older than in younger pregnant women in Japan, with hemorrhagic stroke being the most common cause of maternal death among women > 40 years of age. More than half of hemorrhagic strokes are associated with hypertension disorder of pregnancy. These facts should be considered by women who become pregnant at an advanced age and by healthcare providers involved in their perinatal care.