Chromosomal Microarray Analysis in Fetuses With Ultrasonographic Soft Markers: A Meta-Analysis of the Current Evidence.

BACKGROUND: Ultrasonographic soft markers are normal variants, rather than fetal abnormalities, and guidelines recommend a detailed survey of fetal anatomy to determine the necessity of antenatal karyotyping. Anecdotal reports have described cases with ultrasonographic soft markers in which chromosomal microarray analysis (CMA) revealed pathogenic copy number variants (CNVs) despite normal results on conventional karyotyping, but CMA for ultrasonographic soft markers remains a matter of debate. In this systematic review, we evaluated the clinical significance of CMA for pregnancies with isolated ultrasonographic soft markers and a normal fetal karyotype. METHODS: An electronic search was conducted by an experienced librarian through the MEDLINE, Embase, and Cochrane CENTRAL databases. We reviewed 3,338 articles (3,325 identified by database searching and 13 by a hand search) about isolated ultrasonographic soft markers, and seven ultrasonographic markers (choroid plexus cysts, echogenic bowel, echogenic intracardiac focus, hypoplastic nasal bone, short femur [SF], single umbilical artery, and urinary tract dilatation) were included for this study. RESULTS: Seven eligible articles were included in the final review. Pathogenic or likely pathogenic CNVs were found in fetuses with isolated ultrasonographic soft markers and a normal karyotype. The overall prevalence of pathogenic or likely pathogenic CNVs was 2.0% (41 of 2,048). The diagnostic yield of CMA was highest in fetuses with isolated SF (9 of 225, 3.9%). CONCLUSION: CMA could aid in risk assessment and pregnancy counseling in pregnancies where the fetus has isolated ultrasonographic soft markers along with a normal karyotype.

Genome-wide polygenic risk scores for hypertensive disease during pregnancy can also predict the risk for long-term cardiovascular disease.

BACKGROUND: Hypertensive disorders during pregnancy are associated with the risk of long-term cardiovascular disease after pregnancy, but it has not yet been determined whether genetic predisposition for hypertensive disorders during pregnancy can predict the risk for long-term cardiovascular disease. OBJECTIVE: This study aimed to evaluate the risk for long-term atherosclerotic cardiovascular disease according to polygenic risk scores for hypertensive disorders during pregnancy. STUDY DESIGN: Among UK Biobank participants, we included European-descent women (n=164,575) with at least 1 live birth. Participants were divided according to genetic risk categorized by polygenic risk scores for hypertensive disorders during pregnancy (low risk, score ≤25th percentile; medium risk, score 25th∼75th percentile; high risk, score >75th percentile), and were evaluated for incident atherosclerotic cardiovascular disease, defined as the new occurrence of one of the following: coronary artery disease, myocardial infarction, ischemic stroke, or peripheral artery disease. RESULTS: Among the study population, 2427 (1.5%) had a history of hypertensive disorders during pregnancy, and 8942 (5.6%) developed incident atherosclerotic cardiovascular disease after enrollment. Women with high genetic risk for hypertensive disorders during pregnancy had a higher prevalence of hypertension at enrollment. After enrollment, women with high genetic risk for hypertensive disorders during pregnancy had an increased risk for incident atherosclerotic cardiovascular disease, including coronary artery disease, myocardial infarction, and peripheral artery disease, compared with those with low genetic risk, even after adjustment for history of hypertensive disorders during pregnancy. CONCLUSION: High genetic risk for hypertensive disorders during pregnancy was associated with increased risk for atherosclerotic cardiovascular disease. This study provides evidence on the informative value of polygenic risk scores for hypertensive disorders during pregnancy in prediction of long-term cardiovascular outcomes later in life.

Long-term adverse neurodevelopmental outcomes of discordant twins delivered at term: A nationwide population-based study.

OBJECTIVE: To evaluate long-term adverse neurodevelopmental outcomes of discordant twins delivered at term. DESIGN: Retrospective cohort study. SETTING: Nationwide (Republic of Korea). POPULATION: All twin children delivered at term between 2007 and 2010. METHODS: The study population was divided into two groups according to inter-twin birthweight discordancy: the 'concordant twin group', twin pairs with inter-twin birthweight discordancy less than 20%; and the 'discordant twin group', twin pairs with inter-twin birthweight discordancy of 20% or more. The risk of long-term adverse neurodevelopmental outcomes was compared between the concordant twin group and the discordant twin group. Long-term adverse neurodevelopmental outcomes between smaller and larger twin children within twin pairs were further analysed. The composite adverse neurodevelopmental outcome was defined as the presence of at least one of the following: motor developmental delay, cognitive developmental delay, autism spectrum disorders/attention deficit hyperactivity disorders, tics/stereotypical behaviour or epileptic/febrile seizure. MAIN OUTCOME MEASURES: Long-term adverse neurodevelopmental outcome. RESULTS: Of 22 468 twin children (11 234 pairs) included, 3412 (15.19%) twin children were discordant. The risk of composite adverse neurodevelopmental outcome was higher in the discordant twin group than in the concordant twin group (adjusted hazard ratio [HR] 1.13, 95% CI 1.03-1.24). The long-term adverse neurodevelopmental outcomes were not significantly different between smaller and larger twin children in discordant twin pairs (adjusted HR 1.01, 95% CI 0.81-1.28). CONCLUSION: In twin pairs delivered at term, an inter-twin birthweight discordancy of 20% or greater was associated with long-term adverse neurodevelopmental outcomes; and long-term adverse neurodevelopmental outcomes were not significantly different in smaller or larger twin children in discordant twin pairs.

Management of the smaller twin with impending compromise in twin pregnancies complicated by selective fetal growth restriction: a questionnaire-based study of clinical practice patterns.

BACKGROUND: In twin pregnancies complicated by selective fetal growth restriction (sFGR), if the smaller twin is in the state of impending intra-uterine death (IUD), immediate delivery will reduce the risk of IUD of the smaller twin while exposing the larger twin to iatrogenic preterm birth (PTB). Therefore, the management options would either be to maintain pregnancy for the maturation of the larger twin despite the risk of IUD of the smaller twin or immediate delivery to prevent IUD of the smaller twin. However, the optimal gestational age of management transition from maintaining pregnancy to immediate delivery has not been established. The objective of this study was to evaluate the physician's perspective on the optimal timing of immediate delivery in twin pregnancies complicated by sFGR. METHODS: An online cross-sectional survey was performed with obstetricians and gynecologists (OBGYN) in South Korea. The questionnaire asked the following: (1) whether participants would maintain or immediately deliver a twin pregnancy complicated by sFGR with signs of impending IUD of the smaller twin; (2) the optimal gestational age of management transition from maintaining pregnancy to immediate delivery in a twin pregnancy with impending IUD of the smaller twin; and (3) the limit of viability and intact survival in general preterm neonates. RESULTS: A total of 156 OBGYN answered the questionnaires. In a clinical scenario of dichorionic (DC) twin pregnancy complicated by sFGR with signs of impending IUD of the smaller twin, 57.1% of the participants answered that they would immediately deliver the twin pregnancy. However, 90.4% answered that they would immediately deliver the pregnancy in the same scenario for monochorionic (MC) twin pregnancy. The participants designated 30 weeks for DC twin and 28 weeks for MC twin pregnancies as the optimal gestational age of management transition from maintaining pregnancy to immediate delivery. The participants regarded 24 weeks as the limit of viability and 30 weeks as the limit of intact survival in general preterm neonates. The optimal gestational age of management transition for DC twin pregnancy was correlated with the limit of intact survival in general preterm neonates (p < 0.001), but not with the limit of viability. However, the optimal gestational age of management transition for MC twin pregnancy was associated with both the limit of intact survival (p = 0.012) and viability with marginal significance (p = 0.062). CONCLUSIONS: Participants preferred to immediately deliver twin pregnancies complicated by sFGR with impending IUD of the smaller twin at the limit of intact survival (30 weeks) for DC twin pregnancies and at the midway between the limit of intact survival and viability (28 weeks) for MC twin pregnancies. More research is needed to establish guidelines regarding the optimal delivery timing for twin pregnancies complicated by sFGR.

The Effect of Vanishing Twin on First- and Second-Trimester Maternal Serum Markers and Nuchal Translucency: A Multicenter Prospective Cohort Study.

BACKGROUND: The purpose of this study was to evaluate the effect of vanishing twin (VT) on maternal serum marker concentrations and nuchal translucency (NT). METHODS: This is a secondary analysis of a multicenter prospective cohort study in 12 institutions. Serum concentrations of pregnancy-associated plasma protein-A in the first trimester and alpha-fetoprotein (AFP), total human chorionic gonadotrophin, unconjugated estriol, and inhibin A in the second trimester were measured, and NT was measured between 10 and 14 weeks of gestation. RESULTS: Among 6,793 pregnant women, 5,381 women were measured for serum markers in the first or second trimester, including 65 cases in the VT group and 5,316 cases in the normal singleton group. The cases in the VT group had a higher median multiple of the median value of AFP and inhibin A than the normal singleton group. The values of other serum markers and NT were not different between the two groups. After the permutation test with adjustment, AFP and inhibin A remained significant differences. The frequency of abnormally increased AFP was also higher in the VT group than in the normal singleton group. CONCLUSION: VT can be considered as an adjustment factor for risk assessment in the second-trimester serum screening test.

Metabolic Dysfunction-Associated Fatty Liver Disease and Subsequent Development of Adverse Pregnancy Outcomes.

BACKGROUND & AIMS: Recently, metabolic dysfunction-associated fatty liver disease (MAFLD), rather than nonalcoholic fatty liver disease (NAFLD), was proposed to better describe liver disease associated with metabolic dysfunction (MD). In this study, we attempted to investigate the impact of MAFLD on pregnancy complications. METHODS: The current study is a secondary analysis of a multicenter prospective cohort designed to examine the risk of NAFLD during pregnancy. In the first trimester, enrolled pregnant women were evaluated for hepatic steatosis by liver ultrasonography, and blood samples were collected for biochemical measurements. The study population was divided into 3 groups: no NAFLD, hepatic steatosis but without metabolic dysfunction (non-MD NAFLD), and MAFLD. The primary outcome was the subsequent development of adverse pregnancy outcomes, including gestational diabetes mellitus, pregnancy-associated hypertension, preterm birth, and fetal growth abnormalities. RESULTS: The study population consisted of 1744 pregnant women, including 1523 with no NAFLD, 43 with non-MD NAFLD, and 178 with MAFLD. The risk of subsequent development of adverse pregnancy outcomes was higher in MAFLD than in non-MD NAFLD (adjusted odds ratio, 4.03; 95% CI, 1.68-9.67), whereas the risk was not significantly different between no NAFLD and non-MD NAFLD. Among women with no NAFLD, the presence of MD increased the risk of adverse pregnancy outcomes. However, women with MAFLD were at higher risk for adverse pregnancy outcomes than women with no NAFLD without MD or those with no NAFLD with MD. CONCLUSIONS: In pregnant women, MAFLD may be associated with an increased risk of subsequent adverse pregnancy outcomes.

Long-term cardiovascular outcomes of gestational diabetes mellitus: a prospective UK Biobank study.

BACKGROUND: Previous studies showed that gestational diabetes mellitus (GDM) can be a risk factor for subsequent atherosclerotic cardiovascular disease. However, there is a paucity of information regarding diverse cardiovascular outcomes in elderly women after GDM. In the current study, we examined whether women with a history of GDM have an increased risk for long-term overall cardiovascular outcomes. METHODS: Among the UK participants, we included 219,330 women aged 40 to 69 years who reported at least one live birth. The new incidence of diverse cardiovascular outcomes was compared according to GDM history by multivariable Cox proportional hazard models. In addition, causal mediation analysis was performed to examine the contribution of well-known risk factors to observed risk. RESULTS: After enrollment, 13,094 women (6.0%) developed new overall cardiovascular outcomes. Women with GDM history had an increased risk for overall cardiovascular outcomes [adjusted HR (aHR) 1.36 (95% CI 1.18-1.55)], including coronary artery disease [aHR 1.31 (1.08-1.59)], myocardial infarction [aHR 1.65 (1.27-2.15)], ischemic stroke [aHR 1.68 (1.18-2.39)], peripheral artery disease [aHR 1.69 (1.14-2.51)], heart failure [aHR 1.41 (1.06-1.87)], mitral regurgitation [aHR 2.25 (1.51-3.34)], and atrial fibrillation/flutter [aHR 1.47 (1.18-1.84)], after adjustment for age, race, BMI, smoking, early menopause, hysterectomy, prevalent disease, and medication. In mediation analysis, overt diabetes explained 23%, hypertension explained 11%, and dyslipidemia explained 10% of the association between GDM and overall cardiovascular outcome. CONCLUSIONS: GDM was associated with more diverse cardiovascular outcomes than previously considered, and conventional risk factors such as diabetes, hypertension, and dyslipidemia partially contributed to this relationship.

Pre-pregnancy blood pressure and pregnancy outcomes: a nationwide population-based study.

BACKGROUND: Hypertension has been known to increase the risk of obstetric complications. Recently, the American College of Cardiology endorsed lower thresholds for hypertension as systolic blood pressure of 130-139 mmHg or diastolic blood pressure 80-89 mmHg. However, there is a paucity of information regarding the impact of pre-pregnancy blood pressure on pregnancy outcomes. We aimed to evaluate the effect of pre-pregnancy blood pressure on maternal and neonatal complications. METHODS: In this nationwide, population based study, pregnant women without history of hypertension and pre-pregnancy blood pressure < 140/90 mmHg were enrolled. The primary outcome of composite morbidity was defined as any of the followings: preeclampsia, placental abruption, stillbirth, preterm birth, or low birth weight. RESULTS: A total of 375,305 pregnant women were included. After adjusting for covariates, the risk of composite morbidity was greater in those with stage I hypertension in comparison with the normotensive group (systolic blood pressure, odds ratio = 1.68, 95% CI: 1.59 - 1.78; diastolic blood pressure, odds ratio = 1.56, 95% CI: 1.42 - 1.72). There was a linear association between pre-pregnancy blood pressure and the primary outcome, with risk maximizing at newly defined stage I hypertension and with risk decreasing at lower blood pressure ranges. CONCLUSIONS: 'The lower, the better' phenomenon was still valid for both maternal and neonatal outcomes. Our results suggest that the recent changes in diagnostic thresholds for hypertension may also apply to pregnant women. Therefore, women with stage I hypertension prior to pregnancy should be carefully observed for adverse outcomes.

Ultrasonographic evaluation of ovarian mass for predicting malignancy in pregnant women.

OBJECTIVE: The purpose of this study is to compare ultrasonographic ovarian mass scoring systems in pregnant women. STUDY DESIGN: This multicenter study included women with an ovarian mass during pregnancy who were evaluated using ultrasound and underwent surgery in 11 referral hospitals. The ovarian mass was evaluated and scored using three different scoring systems(International Ovarian Tumor Analysis Assessment of Different NEoplasias in the adnexa[IOTA ADNEX], Sassone, and Lerner). The final diagnosis was made histopathologically. Receiver operating characteristic(ROC) curves were generated for each scoring system. RESULTS: During the study period, 236 pregnant women underwent surgery for an ovarian mass, including 223 women(94.5%) with a benign ovarian mass and 13 women(5.5%) with a malignant ovarian mass. Among 10 ultrasound image findings, six findings were different between benign and ovarian masses(maximal diameter of mass, maximal diameter of solid mass, wall thickness of mass, inner wall structure, thickness of septations, and papillarity). In all three scoring systems, the ovarian mass scores were significantly higher in malignant masses than in benign masses, with the highest area under the ROC curve(AUROC) in the Sassone scoring system(AUROC: 0.831 for Sassone, 0.710 for Lerner vs 0.709 for IOTA ADNEX; p < 0.05, between the Sassone and Lerner/ IOTA ADNEX). A combined model was developed with the six different ultrasound findings, and the AUROC of the combined model was 0.883(p = not significant between the combined model and Sassone). CONCLUSION: In pregnant women, malignant ovarian tumors can be predicted with high accuracy using either the Sassone scoring system or the combined model.

Self-reported pain scores as a predictor of preterm birth in symptomatic twin pregnancy: a retrospective study.

BACKGROUND: To evaluate the self-reported pain scores as a predictor of preterm birth (PTB) in symptomatic twin pregnancy and to develop a nomogram for the prediction model. METHODS: We conducted a retrospective study of 148 cases of symptomatic twin pregnancies before 34 weeks of gestation visited at Seoul national university hospital from 2013 to 2018. With other clinical factors, self-reported pain score was evaluated by the numerical rating scale (NRS) pain scores for pain intensity. By multivariate analyses and logistic regression, we developed a prediction model for PTB within 7 days. Using the Cox proportional hazards model, the curves were plotted to show the predictability of the PTB according to NRS pain score, while adjusting the other covariates. RESULTS: Twenty-three patients (15.5 %) delivered preterm within 7 days. By a logistic regression analysis, higher NRS pain score (OR 1.558, 95 % CI 1.093-2.221, P < 0.05), shorter cervical length (OR 3.164, 95 % CI 1.262-7.936, P < 0.05) and positive fibronectin results (OR 8.799, 95 % CI 1.101-70.330, P < 0.05) affect PTB within 7 days. Using the variables, the area under the receiver operating characteristic curve (AUROC) of the prediction model was 0.917. In addition, we developed a nomogram for the prediction of PTB within 7 days. CONCLUSIONS: Self-reported pain scores combined with cervical length and fetal fibronectin are useful in predicting impending PTB in symptomatic twin pregnancy.

Environmental and Genetic Risk Factors of Congenital Anomalies: an Umbrella Review of Systematic Reviews and Meta-Analyses.

BACKGROUND: The prevalence of congenital anomalies in newborns in South Korea was 272.9 per 100,000 in 2005, and 314.7 per 100,000 in 2006. In other studies, the prevalence of congenital anomalies in South Korea was equivalent to 286.9 per 10,000 livebirths in 2006, while it was estimated 446.3 per 10,000 births during the period from 2008 to 2014. Several systematic reviews and meta-analyses analyzing the factors contributing to congenital anomalies have been reported, but comprehensive umbrella reviews are lacking. METHODS: We searched PubMed, Google Scholar, Cochrane, and EMBASE databases up to July 1, 2019, for systematic reviews and meta-analyses that investigated the effects of environmental and genetic factors on any type of congenital anomalies. We categorized 8 subgroups of congenital anomalies classified according to the 10th revision of the International Statistical Classification of Diseases (ICD-10). Two researchers independently searched the literature, retrieved the data, and evaluated the quality of each study. RESULTS: We reviewed 66 systematic reviews and meta-analyses that investigated the association between non-genetic or genetic risk factors and congenital anomalies. Overall, 269 associations and 128 associations were considered for environmental and genetic risk factors, respectively. Congenital anomalies based on congenital heart diseases, cleft lip and palate, and others were associated with environmental risk factors based on maternal exposure to environmental exposures (air pollution, toxic chemicals), parental smoking, maternal history (infectious diseases during pregnancy, pregestational and gestational diabetes mellitus, and gestational diabetes mellitus), maternal obesity, maternal drug intake, pregnancy through artificial reproductive technologies, and socioeconomic factors. The association of maternal alcohol or coffee consumption with congenital anomalies was not significant, and maternal folic acid supplementation had a preventive effect on congenital heart defects. Genes or genetic loci associated with congenital anomalies included MTHFR, MTRR and MTR, GATA4, NKX2-5, SRD5A2, CFTR, and 1p22 and 20q12 anomalies. CONCLUSION: This study provides a wide perspective on the distribution of environmental and genetic risk factors of congenital anomalies, thus suggesting future studies and providing health policy implications.

An evaluation of obstetric ultrasound education program in Nepal using the RE-AIM framework.

BACKGROUND: Nepal has a high prevalence of congenital anomaly contributing to high infant mortality. Ultrasound, an important tool to detect congenital anomalies and manage maternity-related risk factors, is not properly used in Nepal because Nepali doctors have limited opportunities for learning ultrasound techniques. Hence, we developed and implemented an ultrasound education program from 2016 to 2018. The objective of this study is to evaluate the education program using the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework. METHODS: We conducted a mixed-method study to evaluate each component of RE-AIM. The team collected quantitative data from administrative records, tests, surveys, and an online follow-up survey. Qualitative data were collected from individual in-depth interviews at least a year after the program. The proportions, means, and t-tests were used for quantitative data, and thematic coding for qualitative data. RESULTS: A total of 228 healthcare workers representing 27.3% of the districts of Nepal were reached from 2016 to 2018. The program improved participants' knowledge (29.3, 8.7, and 23.8 increases out of 100, each year, p< 0.001, n=85) and self-confidence (0.6, 0.3, 1.3 increases out of 4.0, p< 0.01, n=111). The participants were highly satisfied with the program (4.2, 4.1, and 4.0 out of 5.0, n=162). Among the respondents of the online follow-up survey (n=28), 60.7% had used ultrasound in their daily practice after the education program, and a medical institution established an ultrasound training center. The absence of clear accreditation and practical guidelines in ultrasound use were presented as barriers for adoption and maintenance. CONCLUSION: The program was successful in improving participant's knowledge and self-confidence in ultrasound techniques and showed great potential for the adoption and maintenance of the techniques in their practice. Continuous implementation of the program and institutional policy changes to facilitate ultrasound use may increase the ultrasound use and improve ultrasound service quality in Nepal.

The risk of pregnancy-associated hypertension in women with nonalcoholic fatty liver disease.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) is an independent predictor of cardiovascular disease (CVD) in non-pregnant adults. Although the biological mechanisms underlying this association are not completely understood, metabolic factors, inflammation, and endothelial dysfunction are likely all involved. The association between NAFLD and pregnancy-associated hypertension (HTN) has not been systematically examined. The aim of this study is to assess the risk of pregnancy-associated HTN in pregnant women with NAFLD. METHODS: This is secondary analysis of a prospective study of healthy pregnant women. Liver ultrasonography was performed at 10-14 weeks of gestation and maternal blood was taken for the measurement of selenoprotein P (SeP), a hepatokine independently associated with both NAFLD and CVD. Pregnancy-associated HTN was defined as the development of gestational HTN, preeclampsia, or eclampsia. RESULTS: Among 877 pregnant women, the risk of developing pregnancy-associated HTN was significantly increased in women with NAFLD compared to those without NAFLD. Grade 2-3 steatosis was a significant predictor of pregnancy-associated HTN, even after adjustment for metabolic risk factors. Circulating levels of SeP were significantly higher in women with versus those without NAFLD (P = .001) and was significantly higher also in women who subsequently developed pregnancy-associated HTN compared with those who did not (P < .005). CONCLUSIONS: Sonographic evidence of NAFLD at 10-14 weeks is an independent predictor of pregnancy-associated HTN. Circulating levels of SeP at that same gestational age are significantly increased in pregnant women with NAFLD who subsequently develop pregnancy-associated HTN.

Short- and long-term outcomes of preterm spontaneous twin anemia-polycythemia sequence.

Background In monochorionic twin pregnancy, placental anastomosis and inter-twin blood transfusion can result in specific complications, such as twin-twin transfusion syndrome (TTTS) and twin anemia-polycythemia sequence (TAPS). It is well established that adverse outcomes are increased in TTTS, but reports on the neonatal and long-term outcomes of TAPS are lacking. The objective of this study was to evaluate the neonatal and neurodevelopmental outcomes in spontaneous TAPS. Methods The study population consisted of monochorionic twin pregnancies with preterm birth (24-37 weeks of gestation) between November 2003 and December 2016 and in which cord blood was taken at the time of delivery. According to the result of hemoglobin in cord blood, the study population was divided into two groups: a spontaneous TAPS group and a control group. Neonatal and neurodevelopmental outcomes were compared between the two groups. Results During the study period, 11 cases were diagnosed as spontaneous TAPS (6.4%). The TAPS group had lower gestational age at delivery and had a higher risk for cesarean delivery. However, neonates with TAPS were not at an increased risk for neonatal mortality and significant neonatal morbidity. In addition, the frequency of severe cerebral lesion during the neonatal period and the risk of cerebral palsy at 2 years of age were not different between the two groups. Conclusion The spontaneous TAPS diagnosed by postnatal diagnostic criteria was not associated with the increased risk of adverse neonatal and neurodevelopmental outcomes. Further studies are needed to evaluate the morbidity of antenatally diagnosed TAPS.

Elevated Alanine Aminotransferase in Early Pregnancy and Subsequent Development of Gestational Diabetes and Preeclampsia.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is now considered as a hepatic manifestation of metabolic syndrome and elevated alanine aminotransferase (ALT) is commonly related to NAFLD in the absence of viral hepatitis or alcohol abuse. Previous studies have indicated that elevated ALT is associated with diabetes or metabolic syndrome in adults, but the clinical significance of ALT or NAFLD in pregnancy has not been well determined. The objective of this study was to determine the association between elevated ALT in early pregnancy and the development of gestational diabetes or preeclampsia in late pregnancy. METHODS: In this retrospective cohort study, pregnant women who met the following inclusion criteria were included: 1) singleton pregnancy; 2) ALT levels were measured in antenatal outpatient clinic at 4-20 weeks of gestation; 3) patients were screened for gestational diabetes and delivered in Cheil General Hospital and Women's Healthcare Center. Cases with viral hepatitis or other liver diseases were excluded. The early ALT levels were divided into two groups (normal ALT [≤ 95th percentile] and elevated ALT [> 95th percentile]), and the frequency of gestational diabetes and preeclampsia was compared between the two groups of cases. Gestational diabetes was screened and diagnosed by two-step procedure (50 g oral glucose challenge test and 75 g glucose challenge test with World Health Organization [WHO] criteria). RESULTS: A total of 2,322 women met the inclusion criteria. Cases with elevated early ALT levels (> 95th percentile) had a higher risk of subsequent gestational diabetes and preeclampsia (gestational diabetes by WHO criteria, 2.1% in normal ALT vs. 6.5% in elevated ALT, P < 0.01; preeclampsia, 1.0% in normal ALT vs. 4.1% in elevated ALT, P < 0.05). This relationship between elevated ALT and increased risk of gestational diabetes/preeclampsia remained significant after adjustment for maternal age and pre-pregnancy body mass index. CONCLUSION: Elevated unexplained ALT in early pregnancy is associated with the risk of subsequent development of gestational diabetes and preeclampsia in late pregnancy.

Successful Pregnancy and Delivery with Intracytoplasmic Sperm Injection in HIV-Serodiscordant Couple: the First Case in Korea.

With highly active antiretroviral therapy, human immunodeficiency virus (HIV) infection is considered to be a manageable chronic disease. The improved prognosis increases the desire of individuals with HIV to have biological offspring. With the establishment of washing protocol, no HIV transmission has been reported among more than 11,000 assisted reproduction technology (ART) cycles. Although the Acquired Immunodeficiency Syndrome Prevention Act in Korea prevents the use of HIV-infected blood, organs, tissues and semen, we recently obtained the authentic approval from the Korea Centers for Disease Control and Prevention for the practice of ART in HIV-serodiscordant couples. We report a 32-year-old HIV-seronegative female with her husband who was HIV-1 seropositive. After semen washing was performed by means of a density gradient and the swim-up technique, HIV-1 ribonucleic acid was not detected in the semen. An aliquot of processed semen was cryopreserved before ART. None of 3 cycles of intrauterine insemination was successful. After the third frozen-thawed embryo transfer following two cycles of intracytoplasmic sperm injection, an intrauterine singleton pregnancy was identified. She gave birth to a normal healthy male baby at full term by Cesarean section. She and her baby were tested for HIV during pregnancy and after delivery and the results were negative. Semen washing may be a safe ART method for HIV-serodiscordant couples who desire to have a baby in Korea.

The Amniotic Fluid Proteome Differs Significantly between Donor and Recipient Fetuses in Pregnancies Complicated by Twin-to-Twin Transfusion Syndrome.

BACKGROUND: Twin-to-twin transfusion syndrome (TTTS) is a serious complication of monochorionic twin pregnancies. It results from disproportionate blood supply to each fetus caused by abnormal vascular anastomosis within the placenta. Amniotic fluid (AF) is an indicator reflecting the various conditions of the fetus, and an imbalance in AF volume is essential for the antenatal diagnosis of TTTS by ultrasound. In this study, two different mass spectrometry quantitative approaches were performed to identify differentially expressed proteins (DEPs) within matched pairs of AF samples. METHODS: We characterized the AF proteome in pooled AF samples collected from donor and recipient twin pairs (n = 5 each) with TTTS by a global proteomics profiling approach and then preformed the statistical analysis to determine the DEPs between the two groups. Next, we carried out a targeted proteomic approach (multiple reaction monitoring) with DEPs to achieve high-confident TTTS-associated AF proteins. RESULTS: A total of 103 AF proteins that were significantly altered in their abundances between donor and recipient fetuses. The majority of upregulated proteins identified in the recipient twins (including carbonic anhydrase 1, fibrinogen alpha chain, aminopeptidase N, alpha-fetoprotein, fibrinogen gamma chain, and basement membrane-specific heparan sulfate proteoglycan core protein) have been associated with cardiac or dermatologic disease, which is often seen in recipient twins as a result of volume overload. In contrast, proteins significantly upregulated in AF collected from donor twins (including IgGFc-binding protein, apolipoprotein C-I, complement C1q subcomponent subunit B, apolipoprotein C-III, apolipoprotein A-II, decorin, alpha-2-macroglobulin, apolipoprotein A-I, and fibronectin) were those previously shown to be associated with inflammation, ischemic cardiovascular complications or renal disease. CONCLUSION: In this study, we identified proteomic biomarkers in AF collected from donor and recipient twins in pregnancies complicated by TTTS that appear to reflect underlying functional and pathophysiological challenges faced by each of the fetuses.

Non-alcoholic fatty liver disease in the first trimester and subsequent development of gestational diabetes mellitus.

AIMS/HYPOTHESIS: Although there is substantial evidence that non-alcoholic fatty liver disease (NAFLD) is associated with impaired glucose homeostasis, the clinical significance of NAFLD in pregnant women has not been well determined. This study investigates the relationship between NAFLD in the first trimester and the subsequent development of gestational diabetes mellitus (GDM). METHODS: A multicentre, prospective cohort study was conducted in which singleton pregnant Korean women were assessed for NAFLD at 10-14 weeks using liver ultrasound, fatty liver index (FLI) and hepatic steatosis index (HSI). Maternal plasma adiponectin and selenoprotein P concentrations were measured. Participants were screened for GDM using the two-step approach at 24-28 weeks. RESULTS: Six hundred and eight women were included in the final analysis. The prevalence of NAFLD was 18.4% (112/608) and 5.9% (36/608) developed GDM. Participants who developed GDM had a higher prevalence of radiological steatosis (55.6% vs 16.1%; p < 0.001) and higher FLI (40.0 vs 10.7; p < 0.001) and HSI (35.5 vs 29.0; p < 0.001). The risk of developing GDM was significantly increased in participants with NAFLD and was positively correlated with the severity of steatosis. This relationship between NAFLD and GDM remained significant after adjustment for metabolic risk factors, including measures of insulin resistance. Maternal plasma adiponectin and selenoprotein P levels were also correlated with both NAFLD severity and the risk of developing GDM. CONCLUSIONS/INTERPRETATION: NAFLD in early pregnancy is an independent risk factor for GDM. Adiponectin may be a useful biomarker for predicting GDM in pregnant women.

Effects of antenatal corticosteroids in twin neonates with late preterm birth (ACTWIN [Antenatal Corticosteroids in TWIN late preterm neonates] trial): study protocol for a randomized controlled trial.

BACKGROUND: Antenatal corticosteroids have been proven to prevent adverse outcomes including respiratory morbidities in preterm neonates before 34 weeks of gestation. Recently, it has been suggested that antenatal corticosteroids may also be effective in singleton late preterm pregnancies, and guidelines recommend the use of corticosteroids in singleton pregnant women who are at risk for late preterm birth. On the contrary, there is a paucity of information regarding the effectiveness of corticosteroids in twin neonates with late preterm birth. This study aims to determine the effectiveness of antenatal corticosteroids in late preterm twin neonates. METHODS: In this multicentre randomized controlled trial, women who are at risk for late preterm birth will be enrolled at 34 0/7 to 36 5/7 weeks of gestation. The participants will be randomly assigned to receive antenatal corticosteroids (betamethasone 12 mg, 3 mL intramuscularly [IM]) or placebo (normal saline 3 mL IM). The perinatal outcomes will be compared between the two groups of cases. The primary outcome is severe respiratory complications (the use of continuous positive airway pressure or high-flow nasal cannula for at least 12 h, supplemental oxygen administration with a fraction of oxygen 0.3 or more for at least 24 h, mechanical ventilation, or extracorporeal membranes oxygenation) or perinatal death within the first 72 h of delivery. The secondary outcomes are neonatal mortality and/or other neonatal morbidities. DISCUSSION: This study will be the first randomized controlled trial that evaluates the effectiveness of antenatal corticosteroids in late preterm twin neonates. TRIAL REGISTRATION: NCT03547791 (ClinicalTrials.gov), first submitted date: March 29, 2018, first posted date: June 6, 2018 (retrospectively registered).

Fetal Survival Immediate after Fetoscopic Laser Ablation in Twin to Twin Transfusion Syndrome.

BACKGROUND: The purpose of this study was to determine prognostic factors that can affect the fetal survival immediate after fetoscopic laser ablation. METHODS: The study population consisted of consecutive twin pregnant women who underwent fetoscopic laser ablation with the diagnosis of twin to twin transfusion syndrome (TTTS) from 2011 to 2018 in Seoul National University Hospital. Fetal survival immediate after procedure was defined as survival to 48 hours after procedure and neonatal survival was defined as survival to 28 days of life. Clinical characteristics and ultrasound findings were compared according to the fetal survival immediate after procedure. RESULTS: A total of 57 pregnant women with TTTS were included, and the overall fetal survival immediate after procedure was 71.1% (81/114) after fetoscopic laser ablation. Fetuses who survived immediate after procedure had higher gestational age at procedure and lower frequency of abnormal Doppler studies than those did not survive. However, the frequency of hydrops was not different between cases with fetal survival and those with fetal death. The earlier gestational age at procedure and the presence of abnormal Doppler studies were significant risk factors for fetal death even after adjustment. CONCLUSION: Based on this data, the fetal survival immediate after procedure (fetoscopic laser treatment) in TTTS can be affected by the gestational age at procedure and the presence of abnormal Doppler studies.