Potential prevention of stillbirth caused by placental abruption: a regional population-based study in Japan.

OBJECTIVE: Placental abruption is associated with adverse perinatal outcomes including intrauterine fetal demise, which subsequently results in stillbirth. However, few studies have demonstrated the preventability of stillbirth due to placental abruption. Therefore, we evaluated the possibility of preventing stillbirth caused by placental abruption by reviewing all stillbirths in our region. METHODS: This study reviewed all stillbirths after 22 weeks of gestation in Shiga Prefecture, Japan from 2010 to 2019, excluding lethal disorders. We evaluated 350 stillbirth cases, with and without placental abruption. RESULTS: There were 32 stillbirths with PA and 318 without placental abruption. The probability of preventing stillbirth was significantly higher in patients with placental abruption than in those without (30% vs. 8%, p < 0.001). We also determined the recommendations for preventing stillbirths with placental abruption. CONCLUSION: Some stillbirths caused by placental abruption can be prevented. We recommend improvements to perinatal maternal-fetal care and perinatal emergency transport systems.

Significant improvement in survival outcomes of trisomy 18 with neonatal intensive care compared to non-intensive care: a single-center study.

Background: Trisomy 18 syndrome, also known as Edwards syndrome, is a chromosomal trisomy. The syndrome has historically been considered lethal owing to its poor prognosis, and palliative care was primarily indicated for trisomy 18 neonates. Although there have been several reports on the improvement of survival outcomes in infants with trisomy 18 syndrome through neonatal intensive care, few studies have compared the impact of neonatal intensive care on survival outcomes with that of non-intensive care. Therefore, we compared the survival-related outcomes of neonates with trisomy 18 between intensive and non-intensive care. Methods: Seventeen infants of trisomy 18 admitted to our center between 2007 and 2019 were retrospectively studied. We divided the patients into a non-intensive group (n = 5) and an intensive group (n = 12) and evaluated their perinatal background and survival-related outcomes of the two groups. Results: The 1- and 3-year survival rates were both 33% in the intensive group, which was significantly higher than that in the non-intensive group (p < 0.001). Half of the infants in the intensive care group were discharged alive, whereas in the non-intensive care group, all died during hospitalization (p = 0.049). Conclusions: Neonatal intensive care for neonates with 18 trisomy significantly improved not only survival rates but also survival-discharge rates. Our findings would be helpful in providing 18 trisomy neonates with standard neonatal intensive care when discussing medical care with their parents.

Insufficient antenatal identification of fetal growth restriction leading to intrauterine fetal death: a regional population-based study in Japan.

OBJECTIVE: Fetal growth restriction (FGR) is associated with perinatal adverse outcomes including intrauterine fetal death. Antenatally unidentified FGR has a higher risk of intrauterine fetal death than that identified antenatally. We, therefore, investigated the antenatal identification of FGR among intrauterine fetal deaths, and assessed the perinatal factors associated with the identification of FGR. METHODS: This retrospective and population-based study reviewed all stillbirths in Shiga Prefecture, Japan, from 2007 to 2016 with exclusion criteria of multiple births, births at unidentified gestational weeks or < 22 gestational weeks, and lethal disorders. We analyzed cases of FGR, using the Japanese clinical definition: Z-score of estimated fetal weight for gestational age <-1.5 standard deviations (SD). RESULTS: We identified 94 stillbirths with FGR among 429 stillbirths. Thirty-seven cases were antenatally identified during pregnancy management (39%). Dividing cases by a Z-score of -2.5 SD, 51 cases were classified as ≤-2.5 SD. Twenty-eight of the 51 cases (55%) with a Z-score <-2.5 SD were antenatally identified as having FGR, whereas 9 of the 43 cases (21%) with a Z-score ≥-2.5 SD were antenatally identified as having FGR (p = .002). Among cases with a Z-Score <-2.5 SD, 16 of 21 (76%) beyond 28 weeks' gestation and 12 of 30 (40%) before 28weeks' gestation were antenatally identified as having FGR (p = .023). CONCLUSION: Fetal growth restriction leading to intrauterine fetal death in Japan was antenatally identified in less than half of cases. Antenatal identification of FGR was associated with the severity of growth restriction.

Highest concentration of breast-milk-derived exosomes in colostrum.

BACKGROUND: Exosomes are nanosized extracellular vesicles, that play important roles in intercellular immune regulation. They have potential therapeutic utility for neonatal diseases including necrotizing enterocolitis. Breast-milk-derived exosomes have recently shown beneficial effects on intestinal damage in vitro and in vivo. However, the chronological change in breast-milk-derived exosome concentrations after delivery are unclear. METHODS: In this prospective study, we enrolled 17 mothers who delivered premature infants admitted to a neonatal intensive care unit in Japan. We measured the consecutive concentrations of breast-milk-derived exosomes in the mothers for 48 weeks after delivery. RESULTS: The median concentration of breast-milk-derived exosomes was 1.62 × 108 particles/ml in colostrum, showing a significant decrease after 2 weeks (P < 0.01). There was no association between the exosome concentration in colostrum and maternal perinatal factors including parity, mode of delivery, maternal age, and gestational age at delivery. CONCLUSIONS: We concluded that breast-milk-derived exosomes were the richest in colostrum. Our basic data regarding breast-milk-derived exosomes are expected to aid in the clinical application of exosomes for treating neonatal diseases.

Increased Difficulties in Maternal Perception of Decreased Fetal Movement in Cases of Severe Fetal Growth Restriction: A Population-Based Study in Japan.

Fetal growth restriction (FGR) is defined as fetuses who have failed to achieve a normal weight for gestational age. FGR is associated with adverse perinatal outcomes, including stillbirth. Pregnant women often perceive decreased fetal movements before intrauterine fetal death. Previous reports on the association between fetal movements and FGR have mainly targeted livebirths, with few focusing on stillbirths. Studying stillbirths, not livebirths, may help improve perinatal adverse outcomes. This study evaluated the association between FGR leading to stillbirth and maternal perception of decreased fetal movement. This was a population-based study reviewing all stillbirths in Shiga Prefecture, Japan for 10 years. We analyzed 219 stillbirth cases, those with versus without FGR. We then compared maternal visits to healthcare providers due to perception of decreased fetal movement between these two groups. There were 82 stillbirths with FGR, and the remaining 137 stillbirth were without FGR. Women with FGR, compared with those without, were significantly less often to visit the outpatient department due to decreased fetal movement (30%; 25/82 vs. 46%; 63/137: P = 0.034). Pregnant women have more difficulty perceiving decreased fetal movements in cases with severe FGR than in those without FGR. Healthcare providers, including midwives, may need to closely monitor FGR pregnancy in addition to instructing pregnant women to be aware of decreased fetal movement.

Chronological changes of serum exosome in preterm infants: A prospective study.

BACKGROUND: Exosomes, which are observed in all human fluid, including serum, are nanosized extracellular vesicles with a mechanism of intercellular communication. Potential clinical applications of exosomes in neonatal diseases have recently been discussed. However, the characteristics of exosomes in serum during early infancy is unclear. METHODS: In this prospective study, we evaluated the chronological changes in the concentration of serum-derived exosomes of 20 infants for 12 months after birth. RESULTS: The average concentration of serum-derived exosomes was 4.6 × 1010 particles/mL at birth and increased significantly until the age of 48 weeks. There was a moderate correlation between the gestational age and the concentration of serum-derived exosomes both at birth (r = 0.54, P = 0.01) and during the 8 weeks after birth (r = 0.48, P < 0.001). A multivariable analysis showed that gestational age at birth was associated with the concentration of serum-derived exosomes at birth (partial regression coefficient, 0.86; 95% confidence interval, 0.37-1.37; P = 0.002). CONCLUSIONS: The concentration of serum-derived exosomes in preterm infants increased both chronologically and by gestational age after birth. These basic data may help to further understand physiology of exosomes in preterm infants.

Fetal movement counting is associated with the reduction of delayed maternal reaction after perceiving decreased fetal movements: a prospective study.

Maternal perception of decreased fetal movement is associated with adverse perinatal outcomes. Although there have been several studies on interventions related to the fetal movements count, most focused on adverse perinatal outcomes, and little is known about the impact of the fetal movement count on maternal behavior after the perception of decreased fetal movement. We investigated the impact of the daily fetal movement count on maternal behavior after the perception of decreased fetal movement and on the stillbirth rate in this prospective population-based study. Pregnant women in Shiga prefecture of Japan were asked to count the time of 10 fetal movements from 34 weeks of gestation. We analyzed 101 stillbirths after the intervention compared to 121 stillbirths before the intervention. In multivariable analysis, maternal delayed visit to a health care provider after the perception of decreased fetal movement significantly reduced after the intervention (aOR 0.31, 95% CI 0.11-0.83). Our regional stillbirth rates in the pre-intervention and post-intervention periods were 3.06 and 2.70 per 1000 births, respectively. Informing pregnant women about the fetal movement count was associated with a reduction in delayed maternal reaction after the perception of decreased fetal movement, which might reduce stillbirths.

Impact of advanced maternal age on adverse infant outcomes: A Japanese population-based study.

OBJECTIVE: The number of births among women of higher age has been rapidly increasing in many countries for several decades. While recent epidemiological studies on the impact of maternal age on infant outcomes in developed countries have evaluated the outcomes of singleton infants, few population-based studies have investigated all deliveries including multiple births. Thus, we aimed to assess the impact of maternal age on adverse infant outcomes using data from all birth certificates, including multiple births, in Shiga prefecture, Japan. STUDY DESIGN: The data from all birth certificates in Shiga Prefecture from 2013 to 2014 (23,294 births from 23,048 mothers) were obtained. We evaluated the impact of maternal age on adverse infant outcomes, including small for gestational age (SGA), low birth weight (LBW), and preterm birth (PTB). A multivariable logistic regression analysis was performed to determine adjusted odds ratios (aORs) for infant outcomes with various maternal factors, including multiple pregnancies. Statistical analysis for trend was performed using the Jonckheere-Terpstra test. RESULTS: The incidence rates of adverse infant outcomes began to increase at a maternal age of 30 years. A maternal age of ≥35 years was associated with significantly increased risks of adverse infant outcomes, including SGA (adjusted odds ratio [aOR]: 1.15, 95% confidence interval [95% CI]: 1.03-1.29), LBW (aOR: 1.29, 95% CI: 1.16-1.43), and PTB (aOR: 1.17, 95%CI: 1.04-1.33). CONCLUSIONS: The risk of adverse infant outcomes was significantly increased in women older than 35 years of age. These data would be useful for younger women to decide family-planning in advance.

Fetal movement frequency and the effect of associated perinatal factors: Multicenter study.

BACKGROUND: Decreased fetal movements are associated with adverse perinatal outcomes, including stillbirth. Delayed maternal visits to a health care provider after perceiving decreased fetal movements are frequently observed in stillbirths. Informing pregnant women of the normal range of fetal movement frequency is essential in their earlier visits in order to prevent stillbirth. AIM: To investigate the fetal movement frequency in late pregnancy and the effects of associated perinatal factors. METHODS: This prospective multicenter study was conducted in 20 obstetric facilities in our region of Japan. A total of 2337 pregnant women were asked to record the time it took to perceive 10 fetal movements by the modified 'count to 10' method every day from 34weeks of gestation until delivery. FINDINGS: The 90th percentile of the time for the maternal perception of 10 fetal movements was 18-29min, with a gradually increasing trend toward the end of pregnancy. The numbers of both pregnant women giving birth after 39weeks' gestation and infants with a birth weight exceeding 3000g were significantly higher in mothers who took ≥30min to count 10 fetal movements than in those who took <30min. CONCLUSION: The maternal perception time of fetal movements shows a gradually increasing trend within 30min for 10 fetal movements by the modified 'count to 10' method. Informing pregnant women of the normal range of the fetal movement count time will help improve the maternal recognition of decreased fetal movements, which might prevent fetal death in late pregnancy.

Poor Bifidobacterial Colonization Is Associated with Late Provision of Colostrum and Improved with Probiotic Supplementation in Low Birth Weight Infants.

This study aimed to evaluate the association between bifidobacterial colonization in low birth weight infants and perinatal factors, including the timing of initial colostrum and the effect of probiotics on this colonization. In this non-randomized controlled trial, we enrolled 98 low-birth-weight infants from a neonatal intensive care unit (NICU) in Japan. Infants were divided into three groups: group N (no intervention), group H (received non-live bifidobacteria), and group L (received live bifidobacteria). The number of bifidobacteria in the infants' stools at 1 month of age was measured using real-time polymerase chain reaction (PCR). We divided infants into "rich bifidobacteria" (≥104.8 cells/g feces) and "poor bifidobacteria" (<104.8 cells/g feces) subgroups. The ratio of "rich bifidobacteria" infants was 20/31, 34/36, and 30/30 in groups N, H, and L, respectively. In group N, the "rich bifidobacteria" group received first colostrum significantly earlier than the "poor bifidobacteria" group (1 day vs. 4 days, P < 0.05). Compared with the N group, both groups H and L had a significantly high proportion of "rich bifidobacteria" infants (P < 0.05). Bifidobacterial colonization was poor in premature infants at 1 month compared with term infants, and the level of colonization was associated with the timing of initial provision of colostrum. Providing probiotics to premature infants can improve bifidobacterial colonization.

Impact of the recommendation for embryo transfer limitation on multiple pregnancy: A population-based study in Japan.

OBJECTIVE: Limitations on the number of embryos transferred have been recommended worldwide to reduce the number of medically assisted multiple births. Our aim was to evaluate the impact of this recommendation for embryo transfer limitation on perinatal outcomes of multiple births. STUDY DESIGN: A retrospective and population-based study compared all multiple births in Shiga prefecture of Japan in 2014-2015 (2015 group) with those in 2007-2008 (2008 group). The perinatal background and neonatal outcomes of multiple births were compared. RESULTS: The number of multiple pregnancies in the 2015 group (n = 251) was almost the same as in the 2008 group (n = 245). The proportion of multiple pregnancies conceived through assisted reproductive technology significantly decreased to 23% in the 2015 group compared to 31% in the 2008 group. In contrast, the rate of ovulation induction significantly increased to 24% in the 2015 group from 15% in the 2008 group. There was no significant difference in the outcome of multiple-birth infants between the two groups. CONCLUSION: The method of conception in multiple pregnancies markedly shifted from in vitro fertilization to non-in vitro fertilization after the issuance of a recommendation for limits on embryo transfer. It should be necessary for the assessment of the impact of this recommendation to monitor closely multiple pregnancies via non-in vitro fertilization as well as via in vitro fertilization.

Excessively delayed maternal reaction after their perception of decreased fetal movements in stillbirths: Population-based study in Japan.

BACKGROUND: Fetal movement is the most common method to evaluate fetal well-being. Furthermore, maternal perception of decreased fetal movements is associated with perinatal demise. Previously, we showed that perception of decreased fetal movements was the most common reason for mothers visiting the outpatient department among those who had stillbirths in our region. Further investigation of stillbirths with decreased fetal movements is essential to find a possible way of preventing stillbirth. AIM: To investigate maternal reaction time after their perceiving decreased fetal movements among stillbirths in our region of Japan. METHODS: This is a population-based study of stillbirths in Shiga Prefecture, Japan conducted from 2007 to 2011. We sent a questionnaire to each obstetrician who had submitted the stillbirth certificate. We reviewed and evaluated the questionnaires returned from the obstetricians. FINDINGS: There were 66 cases (35%) with decreased fetal movements among 188 stillbirths in Shiga during the study period. The number of maternal visits to outpatient department after perception of decreased fetal movements within 24h was only seven (11%) among 64 stillbirths diagnosed at outpatient department. CONCLUSION: We conclude that delayed maternal visit after perceiving decreased fetal movements is frequently observed in stillbirths. Promoting more thorough maternal education on fetal movements, including emphasizing earlier visitation after perceiving decreased fetal movements, may prevent stillbirths.

Bifidobacterium bifidum OLB6378 Simultaneously Enhances Systemic and Mucosal Humoral Immunity in Low Birth Weight Infants: A Non-Randomized Study.

Probiotic supplementation has been part of the discussion on methods to enhance humoral immunity. Administration of Bifidobacterium bifidum OLB6378 (OLB6378) reduced the incidence of late-onset sepsis in infants. In this non-randomized study, we aimed to determine the effect of administration of live OLB6378 on infants' humoral immunity. Secondly, we tried to elucidate whether similar effects would be observed with administration of non-live OLB6378. Low birth weight (LBW) infants weighing 1500-2500 g were divided into three groups: Group N (no intervention), Group L (administered live OLB6378 concentrate), and Group H (administered non-live OLB6378 concentrate). The interventions were started within 48 h after birth and continued until six months of age. Serum immunoglobulin G (IgG) levels (IgG at one month/IgG at birth) were significantly higher in Group L than in Group N (p < 0.01). Group H exhibited significantly higher serum IgG levels (p < 0.01) at one month of age and significantly higher intestinal secretory immunoglobulin A (SIgA) levels (p < 0.05) at one and two months of age than Group N. No difference was observed in the mortality or morbidity between groups. Thus, OLB6378 administration in LBW infants enhanced humoral immunity, and non-live OLB6378, which is more useful as a food ingredient, showed a more marked effect than the viable bacteria.

Perinatal Backgrounds and NICU Bed Occupancy of Multiple-Birth Infants in Japan.

Multiple pregnancies (twin, triplet, and higher-order pregnancy) are associated with an increased risk of resultant preterm and low birth weight infants. The increase of multiple pregnancies for several decades in Japan has been an important consideration in bed allocation planning for neonatal intensive care unit (NICU). The guideline of the Japan Society of Obstetrics and Gynecology (JSOG) in 2008 recommended that embryo transfer be limited to one. The epidemiological data of Japanese regional multiple pregnancies before the JSOG recommendation are valuable in assessing the perinatal effects after this recommendation. The aim of this study was to investigate regional backgrounds of multiple pregnancies and neonatal outcomes of multiple births including NICU admission before the JSOG recommendation. This is a retrospective population-based study for 20 months (January, 2007 through August, 2008) in Shiga Prefecture, Japan. Sending questionnaires to institutions treating multiple births in Shiga, we extracted relevant data from the responses of respective obstetricians and neonatologists. There were 245 multiple births including 241 twins and 4 triplets. We found more twin deliveries with higher risks such as monochorionic diamniotic twins or preterm twins less than 34 weeks in hospitals including perinatal centers than in primary obstetrics clinics. More than half of multiple-birth infants (57%) required NICU admission, and nearly 20% of NICU beds in Shiga are occupied with multiple-birth infants. Furthermore, half of multiple-birth infants were conceived with medical assistance. We conclude that multiple pregnancies resulting from medically assisted conception could have a significant impact upon the NICU bed occupancy in Japan.

Possible Prevention of Neonatal Death: A Regional Population-Based Study in Japan.

PURPOSE: The neonatal mortality rate in Japan has currently been at the lowest level in the world. However, it is unclear whether there are still some potentially preventable neonatal deaths. We, therefore, aimed to examine the backgrounds of neonatal death and the possibilities of prevention in a region of Japan. MATERIALS AND METHODS: This is a population-based study of neonatal death in Shiga Prefecture of Japan. RESULTS: The 103 neonatal deaths in our prefecture between 2007 and 2011 were included. After reviewing by a peer-review team, we classified the backgrounds of these neonatal deaths and analyzed end-of-life care approaches associated with prenatal diagnosis. Furthermore, we evaluated the possibilities of preventable neonatal death, suggesting specific recommendations for its prevention. We analyzed 102 (99%) of the neonatal deaths. Congenital malformations and extreme prematurity were the first and the second most common causes of death, respectively. More than half of the congenital abnormalities (59%) including malformations and chromosome abnormality had been diagnosed before births. We had 22 neonates with non-intensive care including eighteen cases with congenital abnormality and four with extreme prematurity. Twenty three cases were judged to have had some possibility of prevention with one having had a strong possibility of prevention. Among specific recommendations of preventable neonatal death, more than half of them were for obstetricians. CONCLUSION: There is room to reduce neonatal deaths in Japan. Prevention of neonatal death requires grater prenatal care by obstetricians before birth rather than improved neonatal care by neonatologists after birth.

Neonatal Meckel diverticulum: Obstruction due to a short mesodiverticular band.

This is the first report of symptomatic Meckel diverticulum in a newborn, in which direct compression by a short mesodiverticular band (MDB) caused intestinal obstruction. A short MDB can cause intestinal obstruction due to direct compression. There are two mechanisms by which Meckel diverticulum with MDB can cause intestinal obstruction: internal hernia and direct compression. Onset of intestinal obstruction due to direct compression by a short MDB might be earlier than that for internal hernia with long MDB.

Recommendations for preventing stillbirth: a regional population-based study in Japan during 2007-2011.

The perinatal mortality rate in Japan has recently been at the lowest level in the world. However, the perinatal mortality rate of Shiga prefecture has been continuously higher than the Japanese average. The reason for this has not yet been explained. The perinatal mortality rate comprises both stillbirths and neonatal deaths. As stillbirths were almost double neonatal deaths, we focused on the stillbirths to determine how they might be prevented. All of the stillbirth certificates in Shiga Prefecture during 2007-2011 were inspected. On the basis of that information, we designed the original questionnaire and sent it to each obstetrician submitting a death certificate to obtain further information associated with the stillbirth. Reviewing retrospectively returned questionnaires by a peer-review team, we evaluated the possibility of preventing stillbirth along with recommendations for prevention. There were 252 stillbirths among 66,682 deliveries in Shiga during this period. We were able to analyze 188 stillbirths (75%). The audit conference judged that 47 cases of them (25%) were determined to have had some possibility of prevention with seven cases (4%) having strong possibility. We identified major causes of preventable stillbirths, including substandard obstetrical management, delayed referral of high-risk women from primary obstetrical clinics to higher perinatal centers, and delayed visits of pregnant women with decreased fetal movements to clinics or hospitals. Based on the results of this study, we conclude that education for pregnant women is required as well as the necessity of improving obstetric care to prevent stillbirths.

Suspected fetal onset of neonatal transient eosinophilic colitis and development of respiratory distress.

Neonatal transient eosinophilic colitis (NTEC) is a new disease concept within eosinophilic gastroenteritis, which was proposed by Ohtsuka et al. It causes hematochezia as a result of eosinophilia, in neonates who have not yet started to receive enteral nutrition, although the whole-body status of the infant is in fact relatively good. To date, there have been no reports of this disease in which abnormalities were noted during gestation, and the clinical phenomena surrounding it, along with any complications, are not yet clear. We encountered a suspected case of NTEC causing respiratory distress with aspiration of hematochezia, in which dilated bowel was noted during gestation. This case indicates that NTEC may occur at the fetal stage and be complicated by respiratory distress.

Efficacy of bronchial fiberscope in esophageal fistula caused by necrotizing bronchitis.

Neonatal necrotizing bronchitis is a disease that occurs in premature and low-birthweight infants who are subject to artificial respiratory management, and which has a poor prognosis, because it progresses suddenly and can result in death. There have been no reports of survival to date in cases of tracheo-esophageal fistula caused by necrotizing bronchitis, and no swift and effective management method has yet been reported. This report describes a case in which the use of a bronchial fiberscope in making an early diagnosis facilitated appropriate management and survival. The proactive use of a bronchial fiberscope in regard to this disease, which has a high fatality rate, may save lives.