Fetal Malformation Rate Research Articles

Risk factors analysis and prediction model construction of major adverse cardiovascular events in pregnant women with valvular heart disease

Objective: To analysis the risk factors for major adverse cardiovascular event (MACE) in pregnant women with valvular heart disease (VHD) and to construct a risk prediction model. Methods: The clinical data of 245 pregnant women with VHD who were hospitalized in Beijing Anzhen Hospital from January 1, 2012, to June 1, 2023 were retrospectively analyzed, including general information, pre-pregnancy and pregnancy-associated cardiac conditions, and MACE. Univariate analysis and logistic regression models were employed to identify risk factors for MACE during pregnancy among pregnant women with VHD. Furthermore, a predictive model was constructed and internal validation was conducted using bootstrap techniques. Results: (1) Among 245 pregnant women with VHD, the incidence of MACE was 18.0% (44/245), and the most common MACE was heart failure (61.4%, 27/44). The mitral valve was the most frequently affected valve (64.9%, 159/245). Prior to pregnancy, the most common type of valve surgery undertaken was mechanical valve replacement, representing 31.4% (77/245) of surgeries. In contrast, among those pregnant women who did not undergo valve surgery before pregnancy, the most common lesion type was mitral regurgitation (17.6%, 43/245). (2) Comparing the maternal and infant outcomes of warfarin, low molecular weight heparin (LMWH) and LMWH sequential with warfarin, the fetal loss rate (36%, 15/42) and malformation rate (7%, 3/42) were the highest, but the MACE rate (12%, 5/42) was the lowest in warfarin group. The fetal loss rate (1/19), malformation rate (1/19) and artificial valve thrombosis rate (0) of LMWH sequential with warfarin were the lowest, and the fetal loss rate and artificial valve thrombosis rate of the three anticoagulation methods were statistically significant (all P<0.05). (3) There were no significant differences in gestational age, age of diagnosis of heart disease, weight at delivery, pre-pregnancy body mass index, proportion of multiparous women and chronic medical history between women with MACE and those without MACE (all P>0.05). (4) Binary logistic regression analysis identified the following as risk factors for MACE during the second trimester of pregnancy among pregnant women with VHD: pre-pregnancy cardiac symptoms, history of corrective surgery for congenital heart disease, pregnancy risk grade Ⅴ, anticoagulation with LMWH during pregnancy, and arrhythmia (all P<0.05). Based on the results of multivariate analysis, a receiver operating characteristic curve was constructed, with an area under the curve of 0.837, indicating good discriminative ability. The calibration plot demonstrated a close alignment between the standard curve and the calibration prediction curve, suggesting excellent calibration of the model. Conclusions: Pregnant women with VHD are at a high risk of experiencing MACE during gestation. Five risk factors, including pre-pregnancy cardiac symptoms, history of corrective surgery for congenital heart disease, pregnancy risk grade Ⅴ, anticoagulation with LMWH, and arrhythmia, could aid in identifying high-risk pregnant women.

Ethical Principles Do Not Support Mandatory Preanesthesia Pregnancy Screening Tests: A Narrative Review

(Anesth Analg. October 6, 2023. doi: 10.1213/ANE.0000000000006669. Online ahead of print) The process of informed consent upholds the principle of patient autonomy, rooted in US constitutional principles of privacy and noninterference. It has been legally required in the United States since 1914, ensuring that individuals have the right to determine what happens to their bodies, as Schloendorff v. New York Society Hospital ruled. The recent US Supreme Court decision on abortion has raised concerns about maternal-fetal conflicts and the rights of pregnant patients to undergo elective anesthesia and surgery. Ethical and legal requirements for informed consent in medical testing vary, with challenges in addressing routine laboratory testing. Not all medical tests carry the same ethical implications, but they should all consider beneficence, nonmaleficence, and patient autonomy. Focusing on the need for preanesthesia pregnancy testing remains a concern in anesthesia and surgery practices. The primary premise is preventing harm to the fetus, but this must be supported by medical evidence and adhere to ethical standards. No study conclusively demonstrates that anesthetic agents significantly increase rates of early human fetal loss or malformations. There is no evidence that anesthetic drugs are generally teratogenic or pose a significant risk of harm to the fetus. While such risks are small, they cannot be guaranteed to be absent.

The comparison between fixed versus degressive doses of medroxyprogesterone acetate combined with letrozole in patients of progestin-primed ovarian stimulation protocol: a propensity score-matched study.

To explore the cycle characteristics and pregnancy outcomes of progestin-primed ovarian stimulation (PPOS) using fixed versus degressive doses of medroxyprogesterone acetate (MPA) in conjunction with letrozole (LE) in infertile women by propensity score matching (PSM) analysis. A retrospective cohort study. Tertiary-care academic medical center. A total of 3173 infertile women undergoing their first in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) treatment within the period from January 2017 to December 2020. A total of 1068 and 783 patients who underwent a fixed dose of MPA combined with LE and a degressive dose of MPA combined with LE protocols, respectively, were enrolled in this study. The freeze-all approach and later frozen-thawed embryo transfer (FET) were performed in both groups. Propensity score matching (1:1) was performed. The primary outcomes were the dosage of MPA and the incidence of premature luteinizing hormone (LH) surges. The secondary outcomes were the number of oocytes retrieved, the cumulative live birth rate (CLBR) and the fetal malformation rate. We created a perfect match of 478 patients in each group. The dosage of MPA, the LH serum level on the eighth day of stimulation, progesterone (P) level and LH level on the hCG trigger day were significantly higher in the LE + fixed MPA group than in the LE + degressive MPA group (52.1 ± 13.1 mg vs. 44.9 ± 12.5 mg; 5.0 ± 2.7 IU/L vs. 3.7 ± 1.7 IU/L; 0.9 ± 0.5 ng/ml vs. 0.8 ± 0.5 ng/ml; 3.3 ± 2.4 IU/L vs. 2.8 ± 1.9 IU/L; P < 0.01). The duration of Gn, the number of follicles with diameter more than 16mm on trigger day, the estradiol (E2) level on the hCG trigger day were lower in the LE + fixed MPA group than in the LE + degressive MPA group (9.7 ± 1.7 days vs. 10.3 ± 1.5 days; 5.6 ± 3.0 vs. 6.3 ± 3.0; 1752.5 ± 1120.8 pg/ml vs. 1997.2 ± 1108.5 pg/ml; P < 0.001). No significant difference was found in the incidence of premature LH surge, the number of oocytes retrieved, the number of top-quality embryos, clinical pregnancy rate (CPR), CLBR or fetal malformation rate between the two groups. The combination of a degressive MPA dose with LE proved effective in reducing the total MPA dosage with comparable premature LH surge and pregnancy outcomes in women undergoing the PPOS protocol.

Early Abortions and Congenital Malformations: A Comparison Between Agricultural and Nonagricultural Areas in the State of São Paulo/Brazil.

Areas with higher agricultural production have higher rates of abortion and malformation, probable related to pesticides. To compare the rates of early abortion and fetal malformation in agricultural and nonagricultural areas. A survey was carried out on fetal deaths in children weighing less than 500 g or gestational age less than 22 weeks and fetal malformations in live births. From 1996 to 2018, there was an increase in the rates of abortion and, albeit to a lesser extent, malformation. The areas of greater agricultural production have higher rates of fetal mortality and malformation than the others. The study suggests that areas with higher use of pesticides have higher rates of abortion and fetal malformations than the others, requiring further observational studies, reducing confounders inherent to the ecological study.

Artificial oocyte activation using Ca2+ ionophores following intracytoplasmic sperm injection for low fertilization rate.

This large multi-center retrospective study examined whether artificial oocyte activation (AOA) using Ca2+ ionophore following ICSI improves the live birth rate for couples with previous ICSI cycles of unexplained low fertilization rate. In this large-scale multi-center retrospective study conducted in Japan, data were collected from Keio University and 17 collaborating institutions of the Japanese Institution for Standardizing Assisted Reproductive Technology. Between January 2015 and December 2019, 198 couples were included in this study. Oocytes for both the intervention and control groups were procured from the same pool of couples. Oocytes obtained from ICSI cycles with no or low fertilization rate (<50%) with unknown causes were included in the control (conventional ICSI) group while oocytes procured from ICSI cycles followed by performing AOA were assigned to the intervention (ICSI-AOA) group. Those fertilized with surgically retrieved sperm were excluded. ICSI-AOA efficacy and safety were evaluated by comparing these two groups. Live birth rate was the primary outcome. The ICSI-AOA group (2,920 oocytes) showed a significantly higher live birth per embryo transfer rate (18.0% [57/316]) compared to that of the conventional ICSI group with no or low fertilization rate (1,973 oocytes; 4.7% [4/85]) (odds ratio 4.5, 95% confidence interval 1.6-12.6; P<0.05). A higher live birth rate was observed in younger patients without a history of oocyte retrieval. Miscarriage, preterm delivery, and fetal congenital malformation rates were similar between the two groups. ICSI-AOA may reduce fertilization failure without increasing risks during the perinatal period. AOA may be offered to couples with an ICSI fertilization rate < 50%.

Epidemiology of Adverse Outcomes in Teenage Pregnancy-A Northeastern Romanian Tertiary Referral Center.

Background: Despite being a very well-documented subject in the literature, there are still conflicting results regarding teenage pregnancies and their fetal outcomes. Methods: We conducted a retrospective, comparative cohort study that included 1082 mothers aged less than 18 years, compared to 41,998 mothers aged over 18 years, who delivered in our tertiary referral center between January 2015 and December 2021. To check for significant differences between the two groups, the chi-qquared or Fisher’s test for categorical variables were used. Results: We detected statistically significant higher rates of fetal malformation, premature birth, FGR and SGA fetal growth conditions, preeclampsia, condylomatosis and vaginal infection with E. coli in our cohort of teenagers. In this subpopulation of teenagers, the rate for premature birth at less than 32 weeks of gestation was 3.26-fold higher and 3.25-fold higher for condylomatosis, and these results referred to the cohort of adult patients (>18 years old) that gave birth in the same interval of time. Conclusions: Teenage pregnancies still remain a major health problem that burdens all countries worldwide regardless of their income. It needs solutions initially to prevent pregnancy in this young age segment and last but not least to improve both maternal and fetal outcomes.

Effect of Evidence-Based Diet Nursing on Intestinal Flora and Maternal and Infant Prognosis in Patients with Gestational Diabetes.

Background Gestational diabetes mellitus (GDM) refers to the diabetes first discovered or occurring during pregnancy. The incidence of gestational diabetes in China is about 1%–5%, with an increasing trend in recent years. Objective To observe the effect of evidence-based diet nursing on intestinal flora and maternal and infant prognosis in patients with gestational diabetes. Methods One hundred and thirty patients with GDM admitted to our hospital from January 2020 to January 2022 were selected and divided into two groups according to the intervention method, with 65 cases in each group. The control group was given routine nursing plus diet nursing, while the observation group was given evidence-based nursing plus diet nursing. The changes of blood glucose index and intestinal flora before and after intervention in the two groups were detected, and the compliance behavior, pregnancy outcome, and perinatal outcome in the two groups were statistically analyzed. Results After the intervention, the fasting blood glucose, 2 h postprandial blood glucose, and HbA1c in the two groups gradually decreased (P < 0.05). Further comparison between the groups showed that the fasting blood glucose, 2 h postprandial blood glucose, and HbA1c in the observation group were lower than those in the control group (P < 0.05). After intervention, the ratios of Bifidobacterium, Lactobacillus, and Bifidobacterium to E. coli in the two groups gradually increased (P < 0.05). Furthermore, comparison between the groups showed that the ratios of Bifidobacterium, Lactobacillus, and Bifidobacterium to E. coli in the observation group were higher than those in the control group (P < 0.05). The blood glucose rate, regular prenatal examination rate, and diet control rate of the observation group were 100.00%, 100.00%, and 95.38%, respectively, which were higher than 89.23%, 92.31%, and 84.62% of the control group, and the difference was significant (P < 0.05). The pregnancy infection rate and cesarean section rate in the observation group were 0.00% and 33.85%, respectively, which were lower than 6.15% and 60.00% in the control group, and the difference was significant (P < 0.05).The premature delivery rate and polyhydramnios rate in the observation group were 3.08% and 1.54%, respectively, which were not significantly different from 6.15% to 7.69% in the control group (P > 0.05). The rates of macrosomia, neonatal hypoglycemia, and neonatal hyperbilirubinemia in the observation group were 1.54%, 3.08%, and 9.23%, respectively, which were lower than those in the control group (10.77%, 13.85%, and 23.08%), and the differences were significant (P < 0.05). The fetal malformation rate and neonatal asphyxia rate in the observation group were 0.00% and 1.54%, respectively, which were not significantly different from 1.54% to 7.69% in the control group (P > 0.05). Conclusion The application of evidence-based care combined with dietary care in GDM patients can improve intestinal flora, control blood glucose, improve patient compliance behavior, and improve maternal and infant outcomes.

Fetal malformations in successive pregnancies in Australian women with epilepsy

ObjectivesTo utilize data from the Australian Register of Antiepileptic Drugs in Pregnancy (APR) to determine the hazard of fetal malformation in the subsequent pregnancy or pregnancies in women with epilepsy following a pregnancy associated with a fetal malformation, and to identify factors relevant to the hazard. ResultsThere was a 7.4% initial pregnancy fetal malformation rate. The subsequent pregnancy malformation rate was 4.2% if there was no initial pregnancy malformation, but 21.2% if there was an initial pregnancy malformation (O.R. = 6.1448, 95% C.I. 2.3396, 16.1386). For pregnancies where antiseizure medication (ASM) therapy was unchanged between pregnancies (N = 196), the initial pregnancy malformation rate was 10.2%, but 30.0% in the subsequent pregnancy if there was a malformation in the initial pregnancy, and 2.35% if there was none (O.R. = 17.7857, 95% C.I. 4.4847, 70.5361). A cohort comprising 24% of the women with fetal malformations in their initial pregnancies seemed to be intrinsically vulnerable to fetal malformation during successive pregnancies: when their seizure disorder type had been recorded all had genetic generalized epilepsies, compared with a 45.8% generalized epilepsy rate in women with initial but not subsequent pregnancy malformations (P = 0.0121). ConclusionsIf fetal malformation had occurred in an initial ASM-treated pregnancy there was a significantly increased hazard of fetal malformation in the subsequent pregnancy, particularly if the woman involved had a genetic generalized epilepsy.

Diagnostic Value and High-Risk Factors of Two-Dimensional Ultrasonography Combined with Four-Dimensional Ultrasonography in Prenatal Ultrasound Screening of Fetal Congenital Malformations.

Objective This study mainly analyzes the diagnostic value of two-dimensional ultrasonography (2D-US) combined with four-dimensional ultrasonography (4D-US) in prenatal ultrasound screening of fetal congenital malformations (CMs) and explores the high-risk factors affecting fetal malformations. Methods The clinical and imaging data of 2247 pregnant women who underwent prenatal fetal malformation screening in the General Hospital of Ningxia Medical University between February 2020 and October 2021 were collected and analyzed, retrospectively. All pregnant women underwent 2D-US, and those with suspected fetal malformations were further inspected by 4D-US. The accuracy of ultrasound examination results relative to actual pregnancy outcomes was analyzed, taking the neonatal malformation after induced labor or actual delivery as the gold standard, and the risk factors influencing the occurrence of fetal malformations were discussed. Results A total of 87 cases (3.87%) of fetal malformations were detected out of the 2247 parturients examined. The accuracy, sensitivity, and specificity of 2D-US diagnosis were 81.40%, 43.68%, and 82.92%, respectively, while the data were 83.67%, 51.72%, and 84.95% for 4D-US, respectively, and 93.59%, 90.80%, and 93.70%, respectively, for 2D-US +4D-US. The combined diagnosis of 2D-US +4D-US achieved statistically higher accuracy, sensitivity, and specificity than either of them alone. One-way analysis of variance and multivariate logistic regression analysis identified that the independent risk factors affecting fetal malformation were age ≥ 35, history of adverse pregnancy and childbirth, medication during pregnancy, toxic exposure during pregnancy, and history of seropositive for TORCH-IgM. Folic acid supplementation was a protective factor. Conclusions Prenatal US is an effective approach for screening fetal malformations. 2D-US +4D-US can effectively improve the diagnostic rate of fetal malformations. For pregnant women with high-risk factors, prevention should be given priority, and prenatal screening and prenatal diagnosis should be standardized to reduce the occurrence of fetal malformations.

P-786 Perinatal outcomes of assisted reproduction technology (ART) pregnancies after transfer of mosaic blastocysts: a single centre matched cohort study

Abstract Study question Do viable pregnancies after transfer of mosaic blastocysts present different perinatal outcomes as compared to those deriving from transfer of euploid blastocysts? Summary answer Pregnancies from transfer of mosaic vs. euploid blastocysts showed an increased rate of fetal structural malformations and postpartum haemorrhages (PPH). What is known already The incidence of mosaicisms in the trophoectoderm is a relatively frequent event and most true embryo mosaicisms result in spontaneous intrauterine demise. The confirmation of the mosaic aneuploidy in the fetus is related to the type and grade of the aneuploidy with higher risk for chromosomes 13, 14, 15, 16, 18 and 21 and X monosomy. On the other hand, selected mosaic blastocysts have been transferred with subsequent birth of healthy neonates. However, the risk of abnormal obstetric outcomes after transfer of mosaic embryos remains to be completely elucidated. Study design, size, duration Explorative cohort study between 2016 and 2021 including consecutive viable ART pregnancies developing from transfer of mosaic blastocysts (n = 39 cases). Transfer of available mosaic embryos was considered for patients with a poor response to ovarian stimulation or recurrent implantation failures and no available euploid blastocysts, after genetic counselling. Cases were matched for maternal age, parity and body mass index to women with viable pregnancies after transfer of euploid blastocysts (n = 39, controls) and followed-up until delivery. Participants/materials, setting, methods All patients recruited at San Raffaele, Scientific Institute of Milan, underwent a prenatal genetic testing by trophoectoderm biopsy and next-generation sequencing analysis. Patients with a viable fetus at 12 weeks gestation were included and underwent detailed ultrasound assessment at 12, 20 and 32 weeks including fetal biometry and anatomical survey. Frequency of adverse pregnancy and perinatal outcomes including maternal, fetal and delivery complications were compared between patients who received a mosaic versus a euploid blastocyst. Main results and the role of chance No difference in indications to preimplantation diagnosis was found between cases and controls. In the group who transferred mosaic embryos, median rate of mosaicisms was 35% (IQR 30%-40%) and they were characterized by heterogeneous anomalies including complex aneuploidies (n = 12), autosomal monosomies (n = 13), trisomies (n = 8) and duplications/deletions (n = 6). Invasive testing was performed in 62.0% of mosaics (5 chorion villous samplings; 19 amniocenteses; 2 anomalies: confined placental mosaicism trisomy 15 after transfer of mosaic monosomy 6 and fetal microduplication 6p after transfer of mosaic deletion 10p) vs 2.5% of controls (p &amp;lt; 0.001). Structural malformations were observed in 6 neonates in the study group (tanatophoric skeletal dysplasia, complex central nervous system anomaly, congenital diaphragmatic hernia, cerebral arteriovenous fistulae, pyeloureteral junction stenosis, diffuse haemangiomatosis) compared to 1 in controls (pulmonary stenosis) (p = 0.04). One neonate per group was followed-up for future surgery. PPH rate was significantly higher in cases vs controls (15 vs 7; p = 0.04). Neonatal survival at hospital discharge was not different in the two groups (p = 0.30). No significant differences were recorded in rates of preterm birth, small or large for gestational age, fetal growth restriction, miscarriage, preeclampsia and median birthweight centile or gestational age at birth. Limitations, reasons for caution Data from our exploratory study should be interpreted cautiously given the limited sample size which makes it challenging to infer a causal relationship between the association found and transfer of mosaic blastocysts. Wider implications of the findings The higher rates of structural malformations and PPH in ART pregnancies after transfer of mosaic embryos strongly suggest the need for strict monitoring of these patients. First and second trimester ultrasound screening for structural defects, and preventive measures to minimize bleeding at delivery should be implemented. Trial registration number not applicable

Gestational Diabetes Mellitus: Clinical Characteristics and Perinatal Outcomes in a Multiethnic Population of North Italy.

Aim To evaluate clinical characteristics and perinatal outcomes in a heterogeneous population of Caucasians born in Italy and High Migration Pressure Countries (HMPC) women with GDM living in Piedmont, North Italy. Methods We retrospectively analyzed data from 586 women referring to our unit (2015–2020). Epidemiological (age and country of origin) and clinical-metabolic features (height, weight, family history of DM, parity, previous history of GDM, OGTT results, and GDM treatment) were collected. The database of certificates of care at delivery was consulted in relation to neonatal/maternal complications (rates of caesarean sections, APGAR score, fetal malformations, and neonatal anthropometry). Results 43.2% of women came from HMPC; they were younger (p < 0.0001) and required insulin treatment more frequently than Caucasian women born in Italy (χ2 = 17.8, p=0.007). Higher fasting and 120-minute OGTT levels and gestational BMI increased the risk of insulin treatment (OGTT T0: OR = 1.04, CI 95% 1.016–1.060, p=0.005; OGTT T120: OR = 1.01, CI 95% 1.002–1.020, p=0.02; BMI: OR = 1.089, CI 95% 1.051–1.129, p < 0.0001). Moreover, two or more diagnostic OGTT glucose levels doubled the risk of insulin therapy (OR = 2.03, IC 95% 1.145–3.612, p=0.016). We did not find any association between ethnicities and neonatal/maternal complications. Conclusions In our multiethnic GDM population, the need for intensive care and insulin treatment is high in HPMC women although the frequency of adverse peripartum and newborn outcomes does not vary among ethnic groups. The need for insulin therapy should be related to different genetic backgrounds, dietary habits, and Nutrition Transition phenomena. Thus, nutritional intervention and insulin treatment need to be tailored.

CircRNA circVEGFC is Highly Expressed in Gestational Diabetes Mellitus (GDM) and It is Correlated with Multiple Adverse Events.

BackgroundCircular RNA vascular endothelial growth factor C (circVEGFC) is a novel regulator of glucose metabolism, while its role in gestational diabetes mellitus (GDM) is unclear. This study aimed to detect the expression of circVEGFC in GDM and explore its clinical values.MethodsThis study enrolled 220 pregnant women (gestational age less than 5 weeks) with normal blood glucose level on the day of admission. The expression of circVEGFC in plasma samples of these participants was determined by RT-qPCR. The participants were divided into high and low circVEGFC level groups with the median expression level of plasma circVEGFC as the cutoff value. The development of GDM was monitored until delivery. Adverse events were also monitored.ResultsCompared to low circVEGFC level group, GDM-free curve analysis revealed significantly higher incidence of GDM in high circVEGFC level group. In addition, plasma expression levels of circVEGFC were also higher in GDM patients than that in non-GDM patients on the day of admission and at 1 month before and after delivery. ROC curve analysis revealed that high expression levels of circVEGFC on the day of admission showed higher sensitivity and specificity in the early diagnosis of GDM. Moreover, high circVEGFC level group showed higher incidence rates of fetal malformation and hypertension.ConclusionTherefore, circVEGFC is highly expressed in GDM, and it is correlated with multiple adverse events.

Prevalence Rate of Congenital Fetal Malformations in Second Trimester by Ultrasound Scanning in Zagazig University Outpatient Clinic

Background: All pregnancies are at a risk of producing congenital malformations, though only some of them are at a greater risk. Congenital anomalies its problem in which abnormalities of structure, function or body metabolism resulting in physical or mental disability or it may be fatal. Objective: This study aimed for early detection of major fetal anomalies to improve fetal and maternal outcome. Patients and methods: This cross-sectional study that include 422 pregnant females was carried out at the Ultrasound Unit and Obstetrics & Gynecology Department, Faculty of Medicine, Zagazig University during the period from December 2018 to July 2019. Results: Ultrasonography can identify at least 35-50% of major fetal malformations with a specificity of 90-100%. Though other methods of screening like biochemical markers and karyotyping are available, ultrasonography has the advantage of being non- invasive, safe, fast, accurate and reproducible with real time display, causing no discomfort to the patient at any time of gestation. Conclusions: The Prevalence of congenital fetal malformations (CFMF) among the study participants using ultrasonography scanning was 3.6%. The most prevalent anomalies were Hydrops fetalis and CVS anomalies. Therefore screening for congenital anomalies in obstetric sonography is an important component of primary healthcare for maternal and child health.

The contribution of non-drug factors to fetal malformation in anti-seizure-medication-treated pregnancy

PurposeTo assess the possible contribution of factors in additional to intrauterine anti-seizure medication (ASM) exposure in the occurrence of fetal malformation in women with ASM-treated epilepsy. ResultsLogistic regression analysis showed that maternal age over 31 years, family histories of fetal malformation, and conception after assisted fertility treatment, and also dosage of valproate, carbamazepine, and topiramate, made statistically significant (P<0.05) contributions to the fetal malformation rate in 2223 pregnancies in Australian women with epilepsy. The malformation rates were lower in pregnancies where the non-ASM-associated contributory factors were not present: statistically significantly so for all ASM-exposed pregnancies, and those pregnancies exposed to the more potent teratogenic drugs. ConclusionIt is important to consider the possible roles of identified, and also possible non-identified, non-ASM factors in relation to the occurrence of fetal malformations in the pregnancies of women with ASM-treated epilepsy.

Folic acid dose, valproate, and fetal malformations

ObjectiveTo determine whether there is a relationship between folic acid dose and the degree of protection against valproate-associated and other antiepileptic drug (AED)-associated fetal structural malformations in women with AED-treated epilepsy. MethodsStatistical analysis of data from the Raoul Wallenberg Australian Register of Antiepileptic Drugs in Pregnancy involving 2104 folic acid-treated pregnancies in women with epilepsy. ResultsMultiple variable logistic regression failed to demonstrate any statistically significant effect of folic acid dosage in reducing overall fetal malformation rates in women taking folic acid either before and during pregnancy (P = 0.640) or during early pregnancy only (P = 0.801), and in reducing spina bifida occurrence rates (P = 0.409). ConclusionsIn the present state of knowledge, it would seem misguided to hope that a folic acid dose of 5 mg/day taken before and during pregnancy would protect against the occurrence of valproate-associated and other AED-associated fetal structural malformations. Future studies are required to determine whether high-dose periconceptional folate use may decrease the risk of other valproate-associated adverse fetal outcomes, including impaired post-natal neurobehavioral development.

The outcome of altering antiepileptic drug therapy before pregnancy

We investigated the outcome of altering antiepileptic drug (AED) therapy in the year before pregnancy on 2233 occasions in Australian women in the 20-year period of functioning of the Raoul Wallenberg Australian Pregnancy Register (APR).Therapy had been altered in 358 instances (16%) in the months prior to the pregnancy (median interval: 18 weeks). Antiepileptic drug doses had been changed in 141 pregnancies (39.4%), being decreased in 94; drugs changed in 151 (42.2%); drugs withdrawn without replacement in 66 (18.4%) but resumed in 40 before pregnancy ended. The main drugs involved were valproate (34%), phenytoin (16.5%), topiramate (12.6%), and carbamazepine (11.4%). Antiepileptic drug doses were increased significantly more often (16.9% vs. 6.4%) when epilepsy before pregnancy was not controlled, and AED treatment ceased significantly less often (13.6% vs. 24.0%). The alterations were more often made in women with generalized epilepsies and in those whose seizure disorders were not fully controlled in the prepregnancy year, suggesting that avoidance of teratogenicity and achieving improved seizure control often motivated the changes.Overall, the alterations did not result in improved rates of seizure freedom during pregnancy, as compared with pregnancies where therapy was unchanged; however, fetal malformation rates were lower 3.6% vs. 5.4%, but this difference did not attain statistical significance. The same trends regarding seizure control and malformations persisted after pregnancies involving valproate exposure were excluded.In conclusion, this analysis of the APR cohort did not demonstrate that altering AEDs before pregnancy produced a significant improvement in seizure control and the reduction in fetal malformation rate that occurred was not statistically significant.

Pregnancy after valproate withdrawal-Fetal malformations and seizure control.

To assess the outcomes in women with epilepsy in relation to fetal malformation and epileptic seizure control during pregnancy when valproate (VPA) intake was ceased, or the drug's dose was reduced before pregnancy. Statistical analysis of data collected in the Australian Pregnancy Register between 1999 and 2018 concerning 580 pregnancies previously treated with VPA, with the VPA dose reduced or the drug withdrawn prior to pregnancy in 158 cases. Although the available data have limitations, fetal malformation rates in the pregnancies studied were lower in the VPA changed pregnancies (4.5%) than in the VPA unchanged comparator pregnancies (10.9%, hazard ratio [HR]0.412, 95% confidence interval [CI] 0.190-0.892), and were only 2.7% where VPA intake was ceased before pregnancy (HR0.262, 95% CI 0.083-0.826). Seizure-affected pregnancies were more frequent in the VPA changed pregnancies than in the VPA unchanged ones (46.2% vs 30.8%, HR1.500, 95% CI 1.203-1.870). Convulsive seizure-affected pregnancies also were increased, but the difference was not statistically significant. Prepregnancy reduction in VPA dosage reduced the hazard of fetal malformations, whereas ceasing intake of the drug decreased the hazard to one similar to that which applies in the general population, but at a cost of decreased control of epileptic seizures during the pregnancies studied. Further investigations are needed to see whether such findings apply more widely in women with epilepsy.

Preexisting illness, fetal malformation, and seizure control rates in pregnant women with epilepsy

Data from 2182 pregnancies in the Australian Register of antiepileptic drugs in pregnancy that were followed to term, with 1965 followed for another year, were analyzed to ascertain whether preexisting illness influenced i. the hazard of fetal malformations, and ii. seizure control during pregnancy. Fetal malformation occurred in 74 of the 842 pregnancies associated with preexisting illness (8.8%) and in 84 of the 1340 comparator pregnancies (6.27%), Relative Risk (R.R.) = 1.402 (95% Confidence Interval (C.I.) = 1.038, 1.893). Logistic regression showed statistically significant effects of preexisting maternal drug-treated psychiatric illness, untreated psychiatric illness, and use of citalopram, carbamazepine, valproate, and topiramate in increasing hazard of fetal malformation. Preexisting nonpsychiatric illness and other antiepileptic drugs and drugs prescribed for psychiatric illness, mainly antidepressants, had no such effect. Seizures occurred during 405 of the 842 pregnancies associated with preexisting illness, and during 593 of 1340 comparison pregnancies (48.1% v 44.3%; R.R. = 1.087; 95% C.I. = 0.991, 1.192). There were no statistically significant relationships between preexisting nonpsychiatric and psychiatric illnesses separately and seizure control during pregnancy.Thus, apart from consequences of antiepileptic drug exposure, preexisting maternal psychiatric illness, in its own right, or when treated with citalopram, appears to be associated with increased hazards of fetal malformation.

Fetal and perinatal outcome associated with small cerebellar diameter based on second- or third-trimester ultrasonography.

To examine the outcome of pregnancy with fetal transverse cerebellar diameter (TCD) below the fifth percentile based on routine second- or third-trimester ultrasonography. We retrospectively analyzed the outcomes of 12344 women according to TCD Z scores based on systematic second- or third-trimester ultrasound examination between 2007 and 2015. Information on major malformations, chromosomal anomalies, intrauterine or neonatal demise, and other abnormal findings were collected. In total, 408 fetuses with small prenatal TCD underwent clinical investigation; 160 major malformations were noted, consisting mainly of neurological or cardiac anomalies (39,2%%). Chromosomal anomalies were reported in 39 (9.5%) and intrauterine or neonatal demise in 41 cases (10%). Major malformations and chromosomal anomalies were found in 46.4% and 10% of fetuses with extremely small TCD (Z score<-2.5), respectively, 31.3% and 12.7% of fetuses with small TCD (Z score between -2.0 and -1.645), and 39.6 % and 7.7% of fetuses with subnormal TCD (Z score between -2.0 and -1.645). Intrauterine or neonatal demise was noted in 22%, 8.8%, and 4.8% of fetuses with extremely small, small, and subnormal TCD, respectively (P<.05). Among intrauterine growth-restricted fetuses, fetal demise or neonatal adverse outcome was reported in 75%, 81.8%, and 18.5%, respectively. Of all the fetuses, 2.2% were lost to follow-up. A small cerebellar diameter below the fifth percentile is a relevant marker to detect associated anomalies during routine ultrasound examination in the second or third trimester. This is related to a high rate of fetal malformations, chromosomal anomalies, and genetic disorders, regardless of the severity of the cerebellar small size. Small TCD seems to be a prognostic factor for fetal growth restriction. Therefore, when facing a TCD below the fifth percentile, patients should be referred for further sonography and fetal karyotyping.

Placental P-glycoprotein inhibition enhances susceptibility to Di-(2-ethylhexyl)-phthalate induced cardiac malformations in mice: A possibly promising target for congenital heart defects prevention.

BackgroundsReducing toxicants transplacental rates could contribute to the prevention of congenital heart defects (CHDs). Placental P-glycoprotein (P-gp) plays a vital role in fetal toxicants exposure and subsequently affects the risk of toxicants-induced birth defects. However, data on the role of placental P-gp in decreasing toxicants-induced cardiac anomalies is extremely limited. This study aimed to explore the protective role of placental P-gp in reducing the risk of Di-(2-ethylhexyl)-phthalate (DEHP) induced cardiac anomalies in mice.MethodsThe C57BL mice were randomly divided into four groups: the vehicle group (corn oil, n = 10), 500mg/Kg DEHP group (n = 15), 3mg/Kg verapamil group (n = 10) and 500mg/Kg DEHP & 3mg/Kg verapamil group (n = 20). Pregnant dams in different group received respective intervention by gavage once daily from E6.5–14.5. Maternal weights were monitored every day and samples were collected at E15.5. HE staining was used to examine fetal cardiac malformations. Real-time quantitative PCR (RT-qPCR) and Western-Blot were applied to detect Nkx2.5/Gata4/Tbx5/Mef2c/Chf1 mRNA and protein expression, respectively. The mRNA expression of peroxisome proliferator-activated receptor γ (PPARγ) was also determined using RT-qPCR.ResultsCo-administration of verapamil and DEHP significantly elevated fetal cardiac malformation rates, in comparison with the DEHP group, the verapamil group and the vehicle group. Different phenotypes of cardiac anomalies, including septal defects and ventricular myocardium noncompaction, were noted both in the DEHP group and the DEHP & verapamil group. The ventricular myocardium noncompaction appeared to be more severe in the DEHP & verapamil group. Fetal cardiac PPARγ mRNA expression was notably increased and Gata4/Mef2c/Chf1 expression was markedly decreased in the DEHP & verapamil group.ConclusionPlacental P-gp inhibition enhances susceptibility to DEHP induced cardiac malformations in mice.