Pregnancy Outcomes in Women with Thyroid Diseases.

Introduction: Overt hyperthyroidism and hypothyroidism are associated with pregnancy complications; however, most women with these conditions are diagnosed before conception and are under treatment during pregnancy, especially in high-income countries. The purpose of this study was to investigate pregnancy complications among these women. Methods: A retrospective cohort study was conducted, and data on pregnant women who gave birth to a singleton at Nagoya University Hospital in Japan in 2005-2014 was collected. The pregnancy outcomes were divided and compared among three groups: the control group (n = 3531), the hyperthyroidism group (n = 48), and the hypothyroidism group (n = 61). Additionally, risk factors for placental abruption were evaluated by multivariable logistic regression analysis. Moreover, in hyperthyroidism, thyroid function at the placentation period was compared between placental-related diseases and nonplacental-related disease groups, and the latter group included placental abruption and preeclampsia. Results: The incidence of placental abruption was higher in hyperthyroidism than in control and hypothyroidism groups. Hyperthyroidism was independently associated with an increased risk of placental abruption (adjusted odds ratio, aOR = 8.21, 95% confidence interval, CI: 1.76-38.34), as well as preeclampsia (aOR = 4.10, 95% CI: 1.13-14.76) and preterm labor (aOR = 3.38, 95% CI: 1.19-9.64). Additionally, thyroid-stimulating hormone (TSH) at the placentation period was significantly lower in the placental-related disease group than in the nonplacental-related disease group (p < 0.05). Conclusions: Pregnancy outcomes in women with hyperthyroidism and hypothyroidism would be comparable with those without thyroid disease. Hyperthyroidism was an independent risk factor for placental abruption as well as preterm labor and preeclampsia. However, its frequency was extremely low, and further research is required to validate our findings.

Assessment of myocardial performance index in late-onset fetal growth restriction.

The aim of this study is to determine whether the myocardial performance index (MPI) is increased in fetal growth restriction (FGR) fetuses and if increased MPI is related to adverse outcomes of FGR. This is a prospective cross-sectional study. Seventy-three late-onset FGR fetuses and 97 gestational-age matched control fetuses were enrolled in this study. Fetal blood flow parameters including MPI values were measured and compared between the two groups. For the effect of severity of growth restriction on MPI value, they were also compared with < 3rd and 3rd - 10th centile groups. FGR fetuses were divided into two groups by favorable and adverse outcome and ultrasound parameters were compared between these two groups. Moreover, significant factors related to adverse outcomes by univariate analysis were analyzed by multivariate logistic regression analysis. Pulsatility index of umbilical arterial flow (UA-PI), MPI and amniotic fluid index in the FGR were significantly different from the control fetuses. However, no significant difference between < 3rd and 3rd - 10th centile groups was detected in MPI and UA-PI. The increased levels of MPI and UA-PI were independently related with adverse outcome of late-onset FGR pregnancy. In conclusion, MPI values were increased in late-onset FGR pregnancy, and the higher level of MPI could predict adverse outcome as well as the measurement of UA-PI. Clinicians should consider cardiac dysfunction in FGR through increased MPI.

Vitamin D improves pulmonary function in a rat model for congenital diaphragmatic hernia.

A congenital diaphragmatic hernia (CDH) is an anomaly caused by defects in the diaphragm; the resulting limited thorax cavity in turn restricts lung growth (pulmonary hypoplasia). This condition is related to pulmonary hypertension. Despite advances in neonatal CDH therapy, the mortality for severe pulmonary hypoplasia remains high. Therefore, it is essential to establish prenatal therapeutic interventions. Vitamin D was reported to have beneficial effects on adult pulmonary hypertension. This study aims to evaluate the efficacy of prenatal vitamin D administration for CDH. First, serum 25-hydroxyvitamin D [25(OH)D] levels in umbilical cord blood were evaluated among CDH newborns. Second, Sprague Dawley rat CDH models were exposed to nitrofen on embryo day 9 (E9). Randomly selected rats in the nitrofen-treated group were infused with calcitriol from E9 to E21. Samples from CDH pups diagnosed after birth were used for lung weight measurements, blood gas analysis, and immunohistochemical analysis. Third, microarray analysis was performed to examine the effect of vitamin D on gene expression profiles in CDH pulmonary arterial tissues. Serum 25(OH)D levels in the umbilical cord blood of newborns who did not survive were significantly lower than those who were successfully discharged. Prenatal vitamin D showed no significant effect on CDH incidence or lung weight but attenuated alveolarization and pulmonary artery remodeling accompanied the improved blood gas parameters. Vitamin D inhibited several gene expression pathways in the pulmonary arteries of CDH rats. Our results suggest that prenatal vitamin D administration attenuates pulmonary vascular remodeling by influencing several gene pathways in CDH.

Stepwise Treatment for Abnormally Invasive Placenta with Placenta Previa.

Placenta accreta spectrum (PAS) disorder often causes a large amount of intraoperative bleeding in a short period which makes maternal circulation unstable and threatens life. As a countermeasure, two-stage surgery combined with selective uterine arterial embolization (UAE), named "stepwise treatment" was introduced in 2003. At a cesarean section (CS), only the baby is delivered and the placenta is left in situ. The transcatheter angiographic UAE is performed on the operation day, followed by the total hysterectomy on 5 to 7 days after CS. The difficulty in the operative procedures for hysterectomy and the amount of bleeding can be reduced by the added effect of the blood flow interruption by UAE and the uterine involution. Although there are not many indication cases, this is the prudent operation that should be considered for the most severe PAS case such as total placenta increta/percreta with placenta previa. In this article, the practical procedures and tips of stepwise treatment are described.

Joint Degree Program for Graduate Students at the Nagoya University Graduate School of Medicine.

In a world of increasing academic mobility, most universities seek to give their students opportunities to experience education in different countries, which is especially true for senior research students. The Nagoya University Graduate School of Medicine started a joint degree program (JDP) for PhD students with the University of Adelaide, Faculty of Health Science (Australia) in 2015 and with Lund University Faculty of Medicine (Sweden) in 2017. Furthermore, we have started a new JDP with the University of Freiburg, Faculty of Medicine (Germany) in 2018. This article reports the issues specific to counterpart medical schools, including student's recruitment, the curriculum, and the general differences between each schools. JDPs are not only important for educational collaboration, but also as a strategy to encourage international research collaboration, which is a core criterion to a university's world-ranking reputation. Acquiring knowledge about educational strategies that are implemented in different foreign medical schools represents a unique opportunity to improve our own curriculum.

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.

Possible Association between Cathepsin V and the Development of Placenta Accreta Spectrum Disorders.

BACKGROUND/AIMS: The study aimed to evaluate molecular changes related to trophoblast adhesion in placenta accreta spectrum (PAS) disorders. METHODS: A retrospective analysis of 10 PAS cases in which both the trophoblast adherent site and the non-adherent site were identified was performed in April 2010 and March 2013. Microarray analysis and reverse transcription polymerase chain reaction (RT-PCR) analyses were performed to extract upregulated genes in the adherent site. Gene expression changes were examined by immunohistochemistry. RESULTS: Microarray analysis showed that 157 transcripts were > 3-fold upregulated, including the following: a disintegrin and metalloproteinase-28 (ADAM28), 3.10-fold; cathepsin V (CTSV), 3.73-fold; cathepsin S (CTSS), 3.46-fold; and matrix metalloproteinase-19 (MMP19), 3.41-fold. RT-PCR showed relatively high mRNA expressions. On immunohistochemistry, extravillous trophoblast (EVT) at the non-adherent site showed weak or no CTSV expression, whereas EVT that invaded myometrium at the adherent site showed strong expression (histological score, median [min-max], 115.6 [37.6-153.6] vs. 184.8 [56.4-222.8], p < 0.05). MMP19 showed moderate staining, with no difference between the adherent and non-adherent sites. ADAM28 and CTSS showed weak or no staining. DISCUSSION: This limited study suggests that CTSV may be involved in the pathogenesis of PAS.

The role of E2F8 in the human placenta.

Recent studies have reported that E2F transcription factor (E2F) 8, an atypical E2F transcription factor, serves a critical role in promoting the growth and development of the murine placenta. However, the function of E2F8 in the human placenta remains unknown. Invasion of extravillous trophoblasts (EVTs) into the maternal decidua is known to be important for the development of the human placenta. To investigate the role of E2F8 in human placental development, E2F8 localisation was examined in the human placenta and E2F8 mRNA expression was detected in primary cultured EVTs. The human EVT cell line, HTR­8/SVneo, was divided into two groups and treated separately, one with retrovirus expressing short hairpin (sh)­RNA against E2F8 (shE2F8 cells) and the other with non­target control shRNA (shControl cells). The cell functions, including cell cycle, proliferation, invasion and adhesion, were compared between the shE2F8 and shControl cells. A histological examination revealed that E2F8 was localised in the decidua cells, EVTs, and cytotrophoblasts in the placenta. E2F8 mRNA was confirmed to be expressed in cultured primary EVTs. No significant difference was observed in the cell cycle, proliferation or adhesion between the shE2F8 and shControl cells. The invasive ability was ~2­fold higher in the shE2F8 cells when compared with the shControl cells (P<0.01). Production of matrix metalloproteinase­1 was significantly increased in the shE2F8 cells when compared with the shControl cells (P<0.05). Taken together, E2F8 is present in the EVTs of the human placenta, but, unlike murine placenta, it may suppress the invasiveness of EVTs. E2F8 was also present in cytotrophoblasts in cell columns, which have no invasive ability and differentiate into EVTs. In conclusion, E2F8 also exists in the human placenta, and its function may be different from that in the murine placenta, although further investigation is required.

The Current Status and Future Prospects of Oncolytic Viruses in Clinical Trials against Melanoma, Glioma, Pancreatic, and Breast Cancers.

Oncolytic viral therapy has been accepted as a standard immunotherapy since talimogene laherparepvec (T-VEC, Imlygic®) was approved by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) for melanoma treatment in 2015. Various oncolytic viruses (OVs), such as HF10 (Canerpaturev-C-REV) and CVA21 (CAVATAK), are now actively being developed in phase II as monotherapies, or in combination with immune checkpoint inhibitors against melanoma. Moreover, in glioma, several OVs have clearly demonstrated both safety and a promising efficacy in the phase I clinical trials. Additionally, the safety of several OVs, such as pelareorep (Reolysin®), proved their safety and efficacy in combination with paclitaxel in breast cancer patients, but the outcomes of OVs as monotherapy against breast cancer have not provided a clear therapeutic strategy for OVs. The clinical trials of OVs against pancreatic cancer have not yet demonstrated efficacy as either monotherapy or as part of combination therapy. However, there are several oncolytic viruses that have successfully proved their efficacy in different preclinical models. In this review, we mainly focused on the oncolytic viruses that transitioned into clinical trials against melanoma, glioma, pancreatic, and breast cancers. Hence, we described the current status and future prospects of OVs clinical trials against melanoma, glioma, pancreatic, and breast cancers.

The expression of Toll-like receptor 5 in preterm histologic chorioamnionitis.

Spontaneous preterm birth is often caused by chorioamnionitis. Toll-like receptors (TLRs) have a role in the response of the innate immune system. The role of TLR5 in chorioamnionitis remains unclear: however, TLR5 was reported to have a significantly stronger effect on the induction of interleukin (IL)-6 when compared with other TLRs in amniotic epithelial cells. The aim of this study was to investigate TLR5 expression in placentas with preterm histologic chorioamnionitis (HCA). The expression levels of TLR5 were evaluated in the amnions, chorions, deciduae and villi with and without HCA using immunohistochemistry. The co-localization of IL-6 or IL-8 with TLR5 was examined by immunofluorescence. The production of IL-6 was examined in primary tissue cultured fetal membranes treated with and without the TLR5 agonist. The protein expression of TLR5 was significantly increased in amnions with HCA (p<0.05) and showed a trend toward an increase in chorions with HCA, whereas no significant difference was detected in the villi and decidua. TLR5 co-localized with IL-6 and IL-8 in amnions and chorions. IL-6 showed a significant increase (p<0.05) with the TLR5 agonist. These results suggest that TLR5 plays a role in the pathogenesis of preterm HCA and IL-6 production.

Association of serum asymmetric dimethylarginine, homocysteine, and l-arginine concentrations during early pregnancy with hypertensive disorders of pregnancy.

BACKGROUND: Our previous study suggested that a lower l-arginine level (<70µM) at early gestation is associated with pregnancy-induced hypertension. The maternal asymmetric dimethylarginine (ADMA) and homocysteine (Hcy) concentrations also have been reported to be increased in hypertensive disorders of pregnancy (HDP). These molecules have a key role in metabolism of nitric oxide. The aim of this study is to determine the most useful predictor of HDP at early gestation. METHODS: The concentrations of ADMA and Hcy at each of three periods in normal pregnancy were determined, and the values compared between the normal pregnancy and HDP groups. Moreover, the possible risk factors for the development of HDP also were evaluated using a multivariate logistic regression model and propensity score (PS). RESULTS: The maternal ADMA concentration was significantly elevated with advance of gestational age, while Hcy concentration was decreased from early to mid-gestation and increased from mid- to late-gestation in normal pregnancy. The maternal Hcy concentration at early gestation was significantly higher in the HDP group compared to that in the normal group. A higher maternal Hcy level (>7.2µM) in early pregnancy was independently associated with the development of HDP (PS-adjusted odds ratio=4.47, 95% confidence interval=1.51-12.82), as well as pre-pregnancy overweight [body mass index (BMI)>25kg/m2], primipara status, and a lower maternal l-arginine level (<70µM). CONCLUSIONS: The risk factors, such as overweight (BMI>25kg/m2) before pregnancy, primipara status, higher Hcy (>7.2µM), and lower l-arginine (<70µM) concentration in early pregnancy, for development of HDP were detected.

Genomic Signature of the Natural Oncolytic Herpes Simplex Virus HF10 and Its Therapeutic Role in Preclinical and Clinical Trials.

Oncolytic viruses (OVs) are opening new possibilities in cancer therapy with their unique mechanism of selective replication within tumor cells and triggering of antitumor immune responses. HF10 is an oncolytic herpes simplex virus-1 with a unique genomic structure that has non-engineered deletions and insertions accompanied by frame-shift mutations, in contrast to the majority of engineered OVs. At the genetic level, HF10 naturally lacks the expression of UL43, UL49.5, UL55, UL56, and latency-associated transcripts, and overexpresses UL53 and UL54. In preclinical studies, HF10 replicated efficiently within tumor cells with extensive cytolytic effects and induced increased numbers of activated CD4+ and CD8+ T cells and natural killer cells within the tumor, leading to a significant reduction in tumor growth and prolonged survival rates. Investigator-initiated clinical studies of HF10 have been completed in recurrent breast carcinoma, head and neck cancer, and unresectable pancreatic cancer in Japan. Phase I trials were subsequently completed in refractory superficial cancers and melanoma in the United States. HF10 has been demonstrated to have a high safety margin with low frequency of adverse effects in all treated patients. Interestingly, HF10 antigens were detected in pancreatic carcinoma over 300 days after treatment with infiltration of CD4+ and CD8+ T cells, which enhanced the immune response. To date, preliminary results from a Phase II trial have indicated that HF10 in combination with ipilimumab (anti-CTLA-4) is safe and well tolerated, with high antitumor efficacy. Improvement of the effect of ipilimumab was observed in patients with stage IIIb, IIIc, or IV unresectable or metastatic melanoma. This review provides a concise description of the genomic functional organization of HF10 compared with talimogene laherparepvec. Furthermore, this review focuses on HF10 in cancer treatment as monotherapy as well as in combination therapy through a concise description of all preclinical and clinical data. In addition, we will address approaches for future directions in HF10 studies as cancer therapy.

Antenatal Saireito (TJ-114) Can Improve Pulmonary Hypoplasia and Pulmonary Vascular Remodeling in Nitrofen-Induced Congenital Diaphragmatic Hernia.

Congenital diaphragmatic hernia (CDH) can induce lung hypoplasia and pulmonary hypertension and is associated with high mortality. The purpose of this study is to examine the efficacy and safety of antenatal Saireito (TJ-114), a traditional Japanese herbal medicine, in a rat CDH model. Sprague-Dawley rats were exposed to an herbicide (nitrofen, 100 mg) on embryonic day 9 (E9) to induce CDH, and antenatal Saireito (2000 mg/kg/day) was orally administered from E10 to E20. On E21, fetuses were delivered. Antenatal Saireito significantly decreased the incidence of CDH (p < 0.01), increased lung volume (p < 0.01), improved alveolarization and pulmonary artery remodeling using histological analysis, and improved respiratory function using gasometric analysis (pH; p < 0.05, and PCO2 ; p < 0.01). In addition, antenatal Saireito significantly decreased endothelin-1 and endothelin receptor A expression in the pulmonary arteries. Taken together, our results demonstrated that antenatal Saireito can improve fetal pulmonary hypoplasia and pulmonary vascular remodeling and, as a result, can improve respiratory function in a rat CDH model. Copyright © 2016 John Wiley & Sons, Ltd.

Efficacy and safety of daikenchuto (TJ-100) in pregnant women with constipation.

OBJECTIVE: Constipation is common and a significant problem in pregnant women. The purpose of this study was to examine the efficacy and the safety of daikenchuto in pregnant women with constipation. MATERIAL AND METHODS: This was a prospective study, and a total of 20 patients were registered between February 2010 and August 2012. The patients received 7.5 g/d of daikenchuto for 28 days from the day of registration. All enrolled patients were asked to complete the constipation assessment scale (CAS) every day. In addition, we measured the aspartate transaminase, alanine transaminase, blood urea nitrogen, and creatinine levels to assess the adverse effects of daikenchuto. RESULTS: The CAS scores were significantly lower at 28 days after daikenchuto treatment (p = 0.019), with a significant effect achieved on Day 1. The impact of the therapy was greatest in the second trimester (p = 0.043). No significant adverse effects of daikenchuto were observed, and the rates of preterm birth and pregnancy-induced hypertension were 10% and 5%, respectively, which are similar to previously reported values. CONCLUSION: We herein demonstrated the efficacy and safety of daikenchuto in pregnant women with constipation. We hope that our findings will aid in the management of constipation in pregnant women.

Relationship between the cortisol levels in umbilical cord blood and neonatal RDS/TTN in twin pregnancies.

OBJECTIVE: Twin neonates have a higher risk of respiratory complications, such as respiratory distress syndrome (RDS) and transient tachypnea of the newborn (TTN), than singleton neonates. The purpose of this study was to evaluate the relationship between the cortisol levels in the umbilical cord and neonatal RDS/TTN in twin pregnancies. METHODS: We analyzed data obtained from 106 neonates (53 twin pairs), comprising 33 dichorionic twin (DCT) and 20 monochorionic twin (MCT) gestations. All infants were delivered via scheduled cesarean section without labor. We measured the cortisol levels in umbilical vein blood using enzyme-linked immunosorbent assay. RESULTS: The cortisol levels in the umbilical vein were significantly lower in the RDS/TTN group than in the no RDS/TTN group (p = 0.004). The umbilical cortisol levels in the TTN group were between the values observed in the RDS group and no RDS/TTN group. We subsequently analyzed the cut-off cortisol values for RDS/TTN and observed higher accuracy in the DCTs than in the MCTs. CONCLUSIONS: Neonates who develop RDS/TTN have significantly lower cortisol levels in the umbilical cord at birth than no RDS/TTN neonates in twin pregnancies. When applying these data in clinical practice, physicians should pay attention to differences based on chorionicity.

Neuroprotective potential of molecular hydrogen against perinatal brain injury via suppression of activated microglia.

Exposure to inflammation in utero is related to perinatal brain injury, which is itself associated with high rates of long-term morbidity and mortality in children. Novel therapeutic interventions during the perinatal period are required to prevent inflammation, but its pathogenesis is incompletely understood. Activated microglia are known to play a central role in brain injury by producing a variety of pro-inflammatory cytokines and releasing oxidative products. The study is aimed to investigate the preventative potential of molecular hydrogen (H2), which is an antioxidant and anti-inflammatory agent without mutagenicity. Pregnant ICR mice were injected with lipopolysaccharide (LPS) intraperitoneally on embryonic day 17 to create a model of perinatal brain injury caused by prenatal inflammation. In this model, the effect of maternal administration of hydrogen water (HW) on pups was also evaluated. The levels of pro-inflammatory cytokines, oxidative damage and activation of microglia were determined in the fetal brains. H2 reduced the LPS-induced expression of pro-inflammatory cytokines, oxidative damage and microglial activation in the fetal brains. Next, we investigated how H2 contributes to neuroprotection, focusing on microglia, using primary cultured microglia and neurons. H2 prevented LPS- or cytokine-induced generation of reactive oxidative species by microglia and reduced LPS-induced microglial neurotoxicity. Finally, we identified several molecules influenced by H2, involved in the process of activating microglia. These results suggested that H2 holds promise for the prevention of inflammation related to perinatal brain injury.

Maternal molecular hydrogen administration on lipopolysaccharide-induced mouse fetal brain injury.

Fetal brain injury is often related to prenatal inflammation; however, there is a lack of effective therapy. Recently, molecular hydrogen (H2), a specific antioxidant to hydroxyl radical and peroxynitrite, has been reported to have anti-inflammatory properties. The aim of this study was to investigate whether maternal H2 administration could protect the fetal brain against inflammation. Pregnant C3H/HeN mice received an intraperitoneal injection of lipopolysaccharide (LPS) on gestational day 15.5 and were provided with H2 water for 24 h prior to LPS injection. Pup brain samples were collected on gestational day 16.5, and the levels of apoptosis and oxidative damage were evaluated using immunohistochemistry. Interleukin-6 (IL-6) levels were examined using real-time PCR. The levels of apoptosis and oxidative damage, as well as the levels of IL-6 mRNA, increased significantly when the mother was injected with LPS than that in the control group. However, these levels were significantly reduced when H2 was administered prior to the LPS-injection. Our results suggest that LPS-induced apoptosis, oxidative damage and inflammation in the fetal brain were ameliorated by maternal H2 administration. Antenatal H2 administration might protect the premature brain against maternal inflammation.

Risk assessment for neonatal RDS/TTN using gestational age and the amniotic lamellar body count in twin pregnancies.

BACKGROUND: The amniotic lamellar body count (LBC) is useful for predicting respiratory distress syndrome (RDS) and transient tachypnea of the newborn (TTN) in twin pregnancies. However, the risk of neonatal respiratory complications varies with gestational age (GA). We herein created a model to predict the risk for RDS and TTN using GA and the LBC in twin pregnancies. METHODS: Six hundred thirty-two amniotic fluid samples, comprising 169 dichorionic twin (DCT) and 147 monochorionic twin (MCT) gestations, were obtained at Cesarean section. The samples were analyzed immediately without centrifugation. A logistic regression model including the LBC and GA was used to develop the prediction model for RDS/TTN. RESULTS: There were 101 neonates (16.0%) with RDS/TTN. The GA and LBC were significant independent factors affecting RDS/TTN. According to the logistic regression model, we determined the probability of RDS/TTN given the values of GA and the LBC. The overall diagnostic accuracy for predicting neonatal RDS/TTN using GA and the LBC was higher than the use of the LBC alone. CONCLUSIONS: GA-specific LBC cutoffs for the risk assessment of neonatal RDS/TTN have been considered to be more accurate in twin pregnancies. Our findings provide valuable, new information for the management of twin pregnancies.

Is the serum l-arginine level during early pregnancy a predictor of pregnancy-induced hypertension?

The objective of this study was to determine the concentration of serum l-arginine in healthy pregnant women and infant cord blood and to compare them with those in patients with pregnancy-induced hypertension (PIH). The serum concentration of l-arginine in normal pregnant women at early gestation (n = 186) was determined and analyzed based on maternal factors such as the age, pre-pregnancy body mass index (BMI), smoking and alcohol habits before pregnancy. Similarly, the concentration of cord blood of the newborns (n = 142) was also analyzed. These values were compared with those in the PIH group (n = 21). The potential risk factors for PIH were also estimated. The serum concentration of l-arginine at early gestation in normal pregnant women (88.65 ± 19.96 µM) was not affected by the maternal age and BMI before pregnancy. A lower l-arginine concentration at early gestation (<70 µM) significantly elevated PIH risk [adjusted odds ratio (OR) = 4.26, 95% CI 1.29-14.50]. In addition, either women with large body mass before pregnancy (BMI>25 kg/m(2)) or primipara women also showed a significant association with PIH risk [adjusted OR = 10.55 (2.95-40.68); 5.25 (1.72-19.15), respectively]. In conclusion, a lower l-arginine concentration at early gestation, overweight before pregnancy (BMI>25 kg/m(2)) and primipara could predict to the development of PIH.