Pregnancy-related comorbidities and labor induction — the effectiveness and safety of dinoprostone compared to misoprostol

Objectives: The aim of the study was to evaluate whether the presence of the disease in pregnancy influences the effectiveness and safety of delivery preinduction with prostaglandins: misoprostol vaginal insert and dinoprostone vaginal gel.Material and methods: This is a retrospective cohort study conducted of 560 pregnant women. The concomitant diseases mainly recorded were diabetes mellitus, hypertensive diseases, intrahepatic cholestasis of pregnancy, asthma, thrombocytopenia, and hypothyroidism. The primary study outcome was a successful vaginal delivery. The study above others evaluates the time from treatment implementation to the beginning of a labor and to a final delivery, the rate of Cesarean sections, and the presence of delivery complications.Results: Among women with a concomitant disease, Caesarean section was observed more frequently in the misoprostol group. In the dinoprostone group, mothers with the concomitant disease as compared to healthy mothers required more time to the delivery and to achieve the beginning of labor. There were no differences in postpartum complications regardless of the prostaglandins, comorbidities or mothers’ age. Neonates of mothers ≥ 35 years old with concomitant disease had lower average Apgar scores.Conclusions: Our study showed that comorbidities seem to increase the caesarean section risk in the misoprostol preinduction group but in the dinoprostone group they prolong the time needed to achieve an active labour phase and a delivery

The novel P330L pathogenic variant of aromatic amino acid decarboxylase maps on the catalytic flexible loop underlying its crucial role

Aromatic amino acid decarboxylase (AADC) deficiency is a rare monogenic disease, often fatal in the first decade, causing severe intellectual disability, movement disorders and autonomic dysfunction. It is due to mutations in the gene coding for the AADC enzyme responsible for the synthesis of dopamine and serotonin. Using whole exome sequencing, we have identified a novel homozygous c.989C > T (p.Pro330Leu) variant of AADC causing AADC deficiency. Pro330 is part of an essential structural and functional element: the flexible catalytic loop suggested to cover the active site as a lid and properly position the catalytic residues. Our investigations provide evidence that Pro330 concurs in the achievement of an optimal catalytic competence. Through a combination of bioinformatic approaches, dynamic light scattering measurements, limited proteolysis experiments, spectroscopic and in solution analyses, we demonstrate that the substitution of Pro330 with Leu, although not determining gross conformational changes, results in an enzymatic species that is highly affected in catalysis with a decarboxylase catalytic efficiency decreased by 674- and 194-fold for the two aromatic substrates. This defect does not lead to active site structural disassembling, nor to the inability to bind the pyridoxal 5'-phosphate (PLP) cofactor. The molecular basis for the pathogenic effect of this variant is rather due to a mispositioning of the catalytically competent external aldimine intermediate, as corroborated by spectroscopic analyses and pH dependence of the kinetic parameters. Altogether, we determined the structural basis for the severity of the manifestation of AADC deficiency in this patient and discussed the rationale for a precision therapy

Prevalence of DDC genotypes in patients with aromatic L-amino acid decarboxylase (AADC) deficiency and in silico prediction of structural protein changes

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive genetic disorder affecting the biosynthesis of dopamine, a precursor of both norepinephrine and epinephrine, and serotonin. Diagnosis is based on the analysis of CSF or plasma metabolites, AADC activity in plasma and genetic testing for variants in the DDC gene. The exact prevalence of AADC deficiency, the number of patients, and the variant and genotype prevalence are not known. Here, we present the DDC variant (n = 143) and genotype (n = 151) prevalence of 348 patients with AADC deficiency, 121 of whom were previously not reported. In addition, we report 26 new DDC variants, classify them according to the ACMG/AMP/ACGS recommendations for pathogenicity and score them based on the predicted structural effect. The splice variant c.714+4A>T, with a founder effect in Taiwan and China, was the most common variant (allele frequency = 32.4%), and c.[714+4A>T];[714+4A>T] was the most common genotype (genotype frequency = 21.3%). Approximately 90% of genotypes had variants classified as pathogenic or likely pathogenic, while 7% had one VUS allele and 3% had two VUS alleles. Only one benign variant was reported. Homozygous and compound heterozygous genotypes were interpreted in terms of AADC protein and categorized as: i) devoid of full-length AADC, ii) bearing one type of AADC homodimeric variant or iii) producing an AADC protein population composed of two homodimeric and one heterodimeric variant. Based on structural features, a score was attributed for all homodimers, and a tentative prediction was advanced for the heterodimer. Almost all AADC protein variants were pathogenic or likely pathogenic

Prevalence of DDC genotypes in patients with aromatic L-amino acid decarboxylase (AADC) deficiency and in silico prediction of structural protein changes

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive genetic disorder affecting the biosynthesis of dopamine, a precursor of both norepinephrine and epinephrine, and serotonin. Diagnosis is based on the analysis of CSF or plasma metabolites, AADC activity in plasma and genetic testing for variants in the DDC gene. The exact prevalence of AADC deficiency, the number of patients, and the variant and genotype prevalence are not known. Here, we present the DDC variant (n = 143) and genotype (n = 151) prevalence of 348 patients with AADC deficiency, 121 of whom were previously not reported. In addition, we report 26 new DDC variants, classify them according to the ACMG/AMP/ACGS recommendations for pathogenicity and score them based on the predicted structural effect. The splice variant c.714+4A>T, with a founder effect in Taiwan and China, was the most common variant (allele frequency = 32.4%), and c.[714+4A>T];[714+4A>T] was the most common genotype (genotype frequency = 21.3%). Approximately 90% of genotypes had variants classified as pathogenic or likely pathogenic, while 7% had one VUS allele and 3% had two VUS alleles. Only one benign variant was reported. Homozygous and compound heterozygous genotypes were interpreted in terms of AADC protein and categorized as: i) devoid of full-length AADC, ii) bearing one type of AADC homodimeric variant or iii) producing an AADC protein population composed of two homodimeric and one heterodimeric variant. Based on structural features, a score was attributed for all homodimers, and a tentative prediction was advanced for the heterodimer. Almost all AADC protein variants were pathogenic or likely pathogenic

Prevalence of DDC genotypes in patients with aromatic L-amino acid decarboxylase (AADC) deficiency and in silico prediction of structural protein changes

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive genetic disorder affecting the biosynthesis of dopamine, a precursor of both norepinephrine and epinephrine, and serotonin. Diagnosis is based on the analysis of CSF or plasma metabolites, AADC activity in plasma and genetic testing for variants in the DDC gene. The exact prevalence of AADC deficiency, the number of patients, and the variant and genotype prevalence are not known. Here, we present the DDC variant (n = 143) and genotype (n = 151) prevalence of 348 patients with AADC deficiency, 121 of whom were previously not reported. In addition, we report 26 new DDC variants, classify them according to the ACMG/AMP/ACGS recommendations for pathogenicity and score them based on the predicted structural effect. The splice variant c.714+4A>T, with a founder effect in Taiwan and China, was the most common variant (allele frequency = 32.4%), and c.[714+4A>T];[714+4A>T] was the most common genotype (genotype frequency = 21.3%). Approximately 90% of genotypes had variants classified as pathogenic or likely pathogenic, while 7% had one VUS allele and 3% had two VUS alleles. Only one benign variant was reported. Homozygous and compound heterozygous genotypes were interpreted in terms of AADC protein and categorized as: i) devoid of full-length AADC, ii) bearing one type of AADC homodimeric variant or iii) producing an AADC protein population composed of two homodimeric and one heterodimeric variant. Based on structural features, a score was attributed for all homodimers, and a tentative prediction was advanced for the heterodimer. Almost all AADC protein variants were pathogenic or likely pathogenic

Pregnancy-related comorbidities and labor induction : the effectiveness and safety of dinoprostone compared to misoprostol

Objectives: The aim of the study was to evaluate whether the presence of the disease in pregnancy influences the effectiveness and safety of delivery preinduction with prostaglandins: misoprostol vaginal insert and dinoprostone vaginal gel.Material and methods: This is a retrospective cohort study conducted of 560 pregnant women. The concomitant diseases mainly recorded were diabetes mellitus, hypertensive diseases, intrahepatic cholestasis of pregnancy, asthma, thrombocytopenia, and hypothyroidism. The primary study outcome was a successful vaginal delivery. The study above others evaluates the time from treatment implementation to the beginning of a labor and to a final delivery, the rate of Cesarean sections, and the presence of delivery complications.Results: Among women with a concomitant disease, Caesarean section was observed more frequently in the misoprostol group. In the dinoprostone group, mothers with the concomitant disease as compared to healthy mothers required more time to the delivery and to achieve the beginning of labor. There were no differences in postpartum complications regardless of the prostaglandins, comorbidities or mothers’ age. Neonates of mothers ≥ 35 years old with concomitant disease had lower average Apgar scores.Conclusions: Our study showed that comorbidities seem to increase the caesarean section risk in the misoprostol preinduction group but in the dinoprostone group they prolong the time needed to achieve an active labour phase and a delivery

Comparison of Misoprostol versus Dinoprostone for delivery induction among pregnant women without concomitant disease

Objectives: Induction of labour is a part of an active prenatal care nowadays and the ideal method of that procedure stillremains to be identified. The purpose of this study was to evaluate effectiveness of misoprostol vaginal insert as comparedto dinoprostone gel for delivery induction in pregnant women without any comorbidities.Material and methods: It was a retrospective cohort study of 240 pregnant women. The primary study outcome wassuccessful delivery. Other analysed parameters included time to delivery of a baby, time to the beginning of the first stageof labour, time to vaginal delivery, and duration of all delivery stages. We compared both methods regarding maternalcomplications during and after delivery. We also reviewed neonatal outcomes such as birth weight, birth length and1-minute Apgar scores.Results: The patients’ basic characteristics were similar regarding their age, gravidity, parity, height, weight and Bishopscore. Time to any delivery and to the onset of a labour in the misoprostol group versus in the dinoprostone group was14.5 vs 35.6 h (p < 0.001) and 9.9 h vs 25.3 h (p < 0.001) respectively. The chance of the beginning of labour and the baby’sdelivery over time has been observed to be approximately two times higher for misoprostol as compared to dinoprostone.Conclusions: Our study showed that using misoprostol vaginal insert in comparison to dinoprostone seems to shorten thetime to beginning of the first stage of labour as well as the time to the delivery itself. Some lower Apgar scores observedin the misoprostol group requires further investigation

Factors associated with caesarean section in women referred for preinduction — a nested case-control study in dinoprostone and misoprostol groups

Obj Objectives: Induction of labour is a beneficial perinatal procedure, but may be associated with some risks. The aim of this study was to identify factors associated with the need for Caesarean section in women referred for preinduction with dinoprostone and misoprostol. Material and methods: It was a retrospective cohort study of 560 pregnant women who underwent labour induction for medical reasons. Analyses were performed separately in the dinoprostone and misoprostol group. Above other characteristics, the diameters of the pelvis and abdominal circumference of pregnant women were analysed. Results: There were some mothers’ characteristics like age, weight, BMI, presence of hypothyroidism or diabetes, which were not associated with Caesarean section deliveries. Women in the misoprostol group with gestational age less than 38 weeks had an increased risk of Caesarean section (OR 2.189; p = 0.041).  The analyses of combined effect of mothers age and parity history showed 6.7 (in dinoprostone group) and over 10 times (in misoprostol group) increased the risk of Caesarean section in nulliparous women over 35 years of age. Conclusions: The increased risk of Caesarean delivery in the dinoprostone group was combined with the intertrochanteric dimensions such as the mother’s height measuring less than 165 cm, nulliparity and hypertension. In the misoprostol group, strong risk factors for Caesarean delivery were mothers aged 35 years or more, gestational age less than 38 weeks and  nulliparity and hypertension as in dinoprostone group. The oxytocin infusion had increased the risk of Caesarean section only in the combined dinoprostone and misoprostol group. Further high-quality studies are warranted

Corrigendum to:Prevalence of DDC genotypes in patients with aromatic L-amino acid decarboxylase (AADC) deficiency and in silico prediction of structural protein changes (Molecular Genetics and Metabolism (2023) 139(3), (S1096719223002548), (10.1016/j.ymgme.2023.107624))

The authors regret that the printed version of the above article contained an incomplete list of references, particularly those listed in the Table 1. The changes do not affect the main conclusion of this article. The authors would like to apologize for any inconvenience caused.</p