A Novel Method for Determining Fibrin/Fibrinogen Degradation Products and Fibrinogen Threshold Criteria via Artificial Intelligence in Massive Hemorrhage during Delivery with Hematuria.

(1) Background: Although the diagnostic criteria for massive hemorrhage with organ dysfunction, such as disseminated intravascular coagulation associated with delivery, have been empirically established based on clinical findings, strict logic has yet to be used to establish numerical criteria. (2) Methods: A dataset of 107 deliveries with >2000 mL of blood loss, among 13,368 deliveries, was obtained from nine national perinatal centers in Japan between 2020 and 2023. Twenty-three patients had fibrinogen levels <170 mg/dL, which is the initiation of coagulation system failure, according to our previous reports. Three of these patients had hematuria. We used six machine learning methods to identify the borderline criteria dividing the fibrinogen/fibrin/fibrinogen degradation product (FDP) planes, using 15 coagulation fibrinolytic factors. (3) Results: The boundaries of hematuria development on a two-dimensional plane of fibrinogen and FDP were obtained. A positive FDP-fibrinogen/3-60 (mg/dL) value indicates hematuria; otherwise, the case is nonhematuria, as demonstrated by the support vector machine method that seemed the most appropriate. (4) Conclusions: Using artificial intelligence, the borderline criterion was obtained, which divides the fibrinogen/FDP plane for patients with hematuria that could be considered organ dysfunction in massive hemorrhage during delivery; this method appears to be useful.

Fetal Cerebellar Growth Curves Based on Biomathematics in Normally Developing Japanese Fetuses and Fetuses with Trisomy 18.

We used biomathematics to describe and compare cerebellar growth in normally developing and trisomy 18 Japanese fetuses. This retrospective study included 407 singleton pregnancies with fetuses at 14-39 weeks of gestation and 33 fetuses with trisomy 18 at 17-35 weeks. We used ultrasonography to measure fetal transverse cerebellar diameter (TCD) and anteroposterior cerebellar diameter (APCD). We hypothesized that cerebellar growth is proportional to cerebellar length at any given time point. We determined the formula L(t) ≒Keat+r, where e is Napier's number, t is time, L is cerebellar length, and a, K, and r are constants. We then obtained regression functions for each TCD and APCD in all fetuses. The regression equations for TCD and APCD values in normal fetuses, expressed as exponential functions, were TCD(t)=27.85e0.02788t-28.62 (mm) (adjusted R2=0.997), and APCD(t)=324.29e0.00286t-322.62 (mm) (adjusted R2=0.995). These functions indicated that TCD and APCD grew at constant rates of 2.788%/week and 0.286%/week, respectively, throughout gestation. TCD (0.0153%/week) and APCD (0.000430%/week) grew more slowly in trisomy 18 fetuses. This study demonstrates the potential of biomathematics in clinical research and may aid in biological understanding of fetal cerebellar growth.

The Optimal Prepregnancy Body Mass Index for Lactation in Japanese Women with Neonatal Separation as Analyzed by a Differential Equation.

We used a differential equation to identify the biological relationship between the maternal prepregnancy body mass index (BMI) and lactation on postpartum day 4 in Japanese women with neonatal separation. This retro-spective observational study included 252 mothers (135 primiparas, 117 multiparas) whose singleton neonates were admitted to a neonatal ICU. We formulated hypotheses based on breast anatomy to analyze the relation-ship between the expressed milk obtained on postpartum day 4 and the maternal prepregnancy BMI with the following differential equation: y'(x) = k y(x)/x, where k is the constant, x is the prepregnancy BMI, and y is the expressed milk volume. The formula was then obtained as y(x) = axk, where a is the constant. The Akaike information criterion (AIC) was used to estimate the regression equation with the maximum likelihood for primiparas and multiparas. The best criteria for BMI determined by the AIC were 20.89 kg/m2 in primiparas and 20.19 kg/m2 in multiparas. These were the optimal BMI values for lactation, coinciding with the median prepregnancy BMI in the study population (20.78 kg/m2 in primiparas and 20.06 kg/m2 in multiparas). The formula based on biomathematics might help establish the biological relationship between prepregnancy BMI and breastmilk volume.

New method for determining fibrinogen and FDP threshold criteria by artificial intelligence in cases of massive hemorrhage during delivery.

AIM: To investigate the feasibility of a novel method using artificial intelligence (AI), in which the fibrinogen criterion was determined by the quantitative relation between the distributions of fibrin/fibrinogen degradation products (FDPs) and fibrinogen. METHODS: A dataset of 154 deliveries comprising more than 2000 g of blood lost due to hemorrhage, excluding disseminated intravascular coagulation (DIC), among patients from eight national perinatal centers in Japan from 2011 to 2015 were obtained. The fibrinogen threshold criterion was identified by using the function that best fit the distributions of FDP as determined by AI. FDP production was described by differential equations using a dataset containing fibrinogen levels less than the fibrinogen criterion and solved numerically. RESULTS: A fibrinogen level of 237 mg/dL as the threshold criterion was obtained. The FDP threshold criteria were 2.0 and 8.5 mg/dL for no coagulopathy and a failed coagulation system, respectively. CONCLUSION: The fibrinogen threshold criterion for patients with massive hemorrhage excluding DIC at delivery were obtained by selecting the functions that best fit the distributions of FDP data by using AI.

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.

High-intensity breastfeeding improves insulin sensitivity during early post-partum period in obese women with gestational diabetes.

AIM: To investigate whether high-intensity breastfeeding (HIB) reduces insulin resistance during early post-partum period in women with gestational diabetes (GDM), independent of post-partum weight change (PWC). MATERIALS AND METHODS: In this multicentre prospective study, we included Japanese women with GDM who underwent a 75-g oral glucose tolerance test (OGTT) during early post-partum. We measured plasma insulin during OGTT to obtain a homeostasis model of assessment of insulin resistance (HOMA-IR). We defined the condition in which infants were fed by breastfeeding alone or greater than or equal to 80% of the volume as HIB, and other statuses, including partial and nonbreastfeeding, as non-HIB. We investigated the association between post-partum HOMA-IR and the breastfeeding status after adjusting for confounders including PWC. RESULTS: Among 222 women with GDM who underwent the OGTT at 7.9 ± 2.3 weeks post-partum with a PWC of -7.8 ± 3.4 kg, although the rate of abnormal glucose tolerance (prediabetes and diabetes) did not differ between the groups (33% vs 32%), the HOMA-IR in the HIB women (n = 166) was significantly lower than that in the non-HIB women (n = 56) (1.12 ± 0.85 vs 1.72 ± 1.43, P = 0.0002). The effect of the HIB was independently associated with lower HOMA-IR after adjusting for confounders including PMC. However, the subgroup analysis according to their pre-pregnancy obesity states showed that the effect was seen only in the obese subjects (BMI ≥ 25). CONCLUSIONS: In obese Japanese women with GDM, HIB has a significant effect in reducing insulin resistance during early post-partum, independent of the post-partum weight loss.

Formulae Based on Biomathematics to Estimate the Standard Value of Fetal Growth of Japanese.

We devised biomathematics-based formulae to estimate the standard values of fetal growth of Japanese after 22 weeks' gestation. The growth rates of bi-parietal diameter (BPD), abdominal circumference (AC), femur length (FL), and estimated fetal body weight (EFBW) at the time of gestation were assumed to be proportional to the product of the value at the time and the rest value of an unknown maximum value, respectively. The EFBW was also assumed to follow a multiple logistic function of BPD, AC and FL to fit the standard values of Japanese fetuses published by the Japan Society of Ultrasonics in Medicine. The Mann-Whitney test was used for statistical analysis. The values as a function of gestational day, t, were as follows: BPD(t)=99.6/(1+exp (2.725-0.01837＊t)) (mm); AC(t)=39.7/(1+exp (2.454-0.01379＊t)) (cm); FL(t)=79.6/(1+exp (2.851-0.01710＊t)) (mm); EFBW(t)=8045.1/(1+exp (6.028-0.06582＊BPD(t)-0.1469＊AC(t)+ 0.07377＊FL(t))) (g). EFBW as a function of BPD, AC and FL was as follows: EFBW=8045.1/(1+exp (4.747+ 0.02584＊BPD+0.1010＊AC-0.1416＊FL)) (g). When the BPD, AC and FL were at -2 standard deviation (SD), -1SD, mean and + 2SD, the EFBW values calculated by the formula were statistically closer to the standard values than conventional formulas with p-values of 4.871×10-7, 4.228×10-7, 9.777×10-7 and 0.028, respectively. The formulae based on biomathematics might be useful to estimate the fetal growth standard values.

Cover Image, Volume 176A, Number 3, March 2018.

The cover image, by Kei Tamai et al., is based on the Clinical Report Fetal ultrasonographic findings including cerebral hyperechogenicity in a patient with non-lethal form of Raine syndrome, DOI: 10.1002/ajmg.a.38598.

Fetal ultrasonographic findings including cerebral hyperechogenicity in a patient with non-lethal form of Raine syndrome.

Raine syndrome is a rare osteosclerotic bone dysplasia characterized by craniofacial anomalies and intracranial calcification. Most patients with Raine syndrome are of Arab ancestry and die during the neonatal period. We herein report a Japanese patient with non-lethal Raine syndrome who presented with characteristic cerebral hyperechogenicity and a hypoplastic nose by fetal ultrasonography. She was admitted to the NICU due to pyriform aperture stenosis. Craniofacial abnormalities, intracranial calcification, osteosclerosis, chondrodysplasia punctata, and a mutation of FAM20C was identified. She was subsequently discharged without surgical intervention and is now 2 years old with mild neurodevelopmental delays. Images of cerebral hyperechogenicity by fetal ultrasonography in a non-lethal case were described herein for the first time. This patient represents a rare occurrence of a child with Raine syndrome born to Japanese parents and confirms that this syndrome is not always lethal. Even if Raine syndrome is suspected in a fetus due to cerebral hyperechogenicity and a hypoplastic nose, cerebral hyperechogenicity without pulmonary hypoplasia does not always predict lethality or severe neurodevelopmental delays. The information provided herein will be useful for prenatal counseling.

Factor Structure of the Conflict Tactics Scale 1.

BACKGROUND: The Conflict Tactics Scale 1 (CTS1) is a widely used self-report measure of abusive attitudes of parents towards children. The factor structure of the CTS1 still remains to be clarified. The aim of this study was to examine the factor structure of the Japanese version of the CTS1 for postpartum women in community settings. METHOD: The data in this study came from the Okayama and Kumamoto's study. These were part of a larger survey using longitudinal questionnaire studies conducted in Japan from 2001 to 2002 and in 2011, respectively. In both study sites, the participant mothers were asked to fill in the CTS1 one month after delivery when they attended for check-up at the out-patient clinic. RESULTS: A total of 1,150 questionnaires were collected, excluding the participants with missing values in the CTS1. Finally, 1,078 were included in the statistical analyses. Data of 1,078 women were divided into two parts. In the first halved sample (n=578), an exploratory factor analysis was conducted for the CTS1 items after exluding nine items with extremely low prevalence. It revealed 2-factor or 3-factor models. Then, we conducted a model comparison with the second halved sample (n=500), using confirmatory factor analysis. In terms of goodness-of-fit indeces, the 2-factor model was superior. Its subscales were Reasoning and Psycholosical Aggression. CONCLUSION: The 2-factor model of the CTS1 consisting of Reasoning and Psychological Aggression was superior to the 3-factor model. This is not inconsistent with the original authors' theoretical model.

Discrete category of mother-to-infant bonding disorder and its identification by the Mother-to-Infant Bonding Scale: A study in Japanese mothers of a 1-month-old.

BACKGROUND: Difficulty of maternal bonding towards a baby is widely recognised. It is unclear whether this phenomenon is dimensional or categorical. If categorical, an optimal cut-off score of a screening instrument is needed in clinical settings. AIMS: In this study, we investigated whether maternal bonding is dimensional or categorical phenomenon and try to set optimal cut-off score of screening instruments. METHODS: Self-report questionnaire studies were conducted in a general hospital and four antenatal clinics. Two-step cluster analysis was conducted for the Mother-to-Infant Bonding Scale (MIBS) subscale scores in 723 mothers of neonates. ROC curves and optimal cut-off points of the MIBS scores were calculated based on cluster-analysis derived groups. RESULTS: A 2-cluster structure appeared: "normal" (n=619) vs. "pathological maternal bonding" (n=104). Mothers of the latter category scored significantly higher in terms of postnatal depression and neonatal abuse than those of the former category. AUC of the ROC curve by the total MIBS scores both 5days and 1month after childbirth were >0.9. The optimal cut off scores were 3/4 at 5days, and 4/5 at 1month, after childbirth. CONCLUSIONS: There was a group of mothers with high MIBS scores discretely different from those with low MIBS scores. MIBS may be a useful tool to identify mothers with a severe bonding disorder that needs clinical intervention.

Multiple pregnancy, short cervix, part-time worker, steroid use, low educational level and male fetus are risk factors for preterm birth in Japan: a multicenter, prospective study.

AIM: To examine the relationship between preterm birth and socioeconomic factors, past history, cervical length, cervical interleukin-8, bacterial vaginosis, underlying diseases, use of medication, employment status, sex of the fetus and multiple pregnancy. METHODS: In a multicenter, prospective, observational study, 1810 Japanese women registering their future delivery were enrolled at 8⁺° to 12⁺6 weeks of gestation. Data on cervical length and delivery were obtained from 1365 pregnant women. Multivariate logistic regression analysis was performed. RESULTS: Short cervical length, steroid use, multiple pregnancy and male fetus were risk factors for preterm birth before 34 weeks of gestation. Multiple pregnancy, low educational level, short cervical length and part-timer were risk factors for preterm birth before 37 weeks of gestation. CONCLUSION: Multiple pregnancy and cervical shortening at 20-24 weeks of gestation was a stronger risk factor for preterm birth. Any pregnant woman being part-time employee or low educational level, having a male fetus and requiring steroid treatment should be watched for the development of preterm birth.

Utility of maternal 6-thioguanine nucleotide levels in predicting neonatal pancytopenia.

An infant with pancytopenia was born to a mother who used the common immunosuppressant azathioprine (AZA). Maternal and neonatal blood levels of 6-thioguanine nucleotides (6TGN; metabolite of AZA) were 1890 and 1480 pmol/8 × 10(8) red blood cells, respectively. Maternal 6TGN levels could be useful in predicting neonatal pancytopenia.

Folic acid in the prevention of neural tube defects: awareness among laywomen and healthcare providers in Japan.

It is known that neural tube defects are folic acid preventable congenital anomalies. We investigated to what extent this information was disseminated among laywomen and healthcare providers. Questionnaire studies were conducted twice, in 2002 and 2007, for four groups of laywomen and seven groups of healthcare providers in Japan regarding awareness, folic acid supplements and healthy diets. Awareness among laywomen was less than 20%, except for families who had experience with spina bifida in 2002, and 5 years later only pregnant women showed a significant increase in awareness. Awareness among healthcare providers varied from 12 to 76%, depending on their profession, and this proportion increased in five of the seven groups in 2007. The majority of laywomen obtained their information from mass media, while the majority of healthcare providers received information through media for professionals. Laywomen who used folate supplements and healthcare providers who recommended them were initially fewer than 25 and 37%, respectively. Five years later, however, pregnant women who used folic acid supplements increased from 9.1 to 43.1%. As awareness among non-pregnant laywomen and some healthcare providers is considerably low, information should be presented repeatedly to these groups. The difficulty in getting women to consume folic acid supplements is an argument for the government to require folic acid fortification of grains so that the prevention of neural tube defects can be maximized.

[Folic acid reduces the risk of neural tube defects: awareness and folate intake among pregnant women in 2006].

Folic acid plays an important role in proliferating cells and tissues of the fetus. A randomized control trial demonstrated in 1991 that 4 mg of folic acid supplements successfully prevented 72% of recurrence of neural tube defects (NTDs) in women who had had afflicted pregnancy. In 2000, the Japanese Government recommended women of childbearing age to take 400 microgram of folate supplements per day from 4 weeks prior to and 12 weeks after conception. A questionnaire study was performed in pregnant women by post on their awareness of the role folic acid plays, their life style, and folate intake by dietary consumption. Thirty-five percent of 1,251 pregnant women were aware of the important role of folic acid in the critical stage of fetal development and 31% actually took the supplement. Information on folic acid was obtained through mass media in 47% of the women, through the internet in 17%, through healthcare providers in 13% and so forth. The food record analysis revealed that the dietary intake of folic acid averaged 341 microg/day that was 60 microg less than what was recommended by the Government and that 33 of 86 women took the supplement. Overall, a half of pregnant women are required to take 400 microg folate supplement per day. It is to be stressed that primary prevention of NTDs by periconceptional intake of folic acid is a major public health opportunity and that prevention is more important than cure in the management of NTDs.

Evaluation of normal fetal branch pulmonary artery diameters measured by ultrasonography: a comparison with congenital diaphragmatic hernia.

OBJECTIVE: The aim of this study was to examine the size of fetal branch pulmonary artery (PA) diameters in normal growth fetuses. METHOD: Fetal PA diameters were measured in 175 normal fetuses between 18 and 40 weeks of gestation from 2005 to 2006. In addition, 4 fetuses with left-sided congenital diaphragmatic hernia (CDH) from 2001 to 2006 were retrospectively reviewed. Branch PA diameters were measured from a cross-sectional image at the level of the three-vessel view (main PA, ascending aorta and superior vena cava) to demonstrate the long axis of both branch PAs whenever possible. RESULTS: Both the left and right PA diameters were found to correlate strongly with the advancing gestational age (r = 0.78, p < 0.01, respectively). Left pulmonary artery to main pulmonary artery (LPA/MPA) ratio and right pulmonary artery to main pulmonary artery (RPA/MPA) ratio were calculated. These two parameters were almost constant throughout gestation. LPA in fetal left CDH was smaller than control. Both LPA/MPA and RPA/MPA were within the normal range in most cases. CONCLUSIONS: It is important to establish the normal range of branch PA diameters and it appears to be useful to compare the branch PA diameters in normal fetuses with that in cases of pulmonary hypoplasia.

The relationship between Doppler indices from inferior vena cava and hepatic veins in normal human fetuses.

This study was conducted to determine the gestational age-related reference range of the preload index [peak velocity during atrial contraction (A)/peak velocity during ventricular systole (S)] for the inferior vena cava (IVC), the right hepatic vein, the middle hepatic vein and the left hepatic vein. The slope and the intercept of the regression line for each preload index were compared among the 4 veins using analysis of covariance. Doppler measurements were obtained for the 4 veins of 316 normal fetuses at 22-40 weeks of gestation. A and S values were measured from the recorded flow velocity waveform of each vein and the A/S ratio was calculated as the preload index. The regression lines for the preload index of the 4 veins decreased gradually throughout gestation. Analysis of covariance revealed no significant differences in the slopes of the regression lines for the 4 veins. However, the intercepts of the regression lines for all hepatic veins were significantly higher than that of the regression line for the IVC (P<0.0001), with the difference ranging from 0.024 to 0.033. There were no significant differences among the intercepts of the regression lines for different hepatic veins. We concluded that the relationship between the preload index and the duration of gestation was statistically similar for all hepatic veins, and strongly resembled that for the IVC.

Changes in the aortic and pulmonary diameters in a fetus with hypoplastic left heart syndrome.

We diagnosed hypoplastic left heart syndrome in a 26-week-old fetus using fetal echocardiography. Color Doppler ultrasonography was helpful for evaluating the structural abnormalities. The diameters of the aorta and the pulmonary artery were measured periodically from 26 to 38 weeks of gestation. Aortic diameter was below the normal range throughout gestation. The diameter of the pulmonary artery was normal at 26 weeks of gestation but gradually dilated and was abnormally dilated after the 36th week of gestation. Here we discuss the cause of enlarged pulmonary artery in fetal hypoplastic left heart syndrome.