Ceramides during Pregnancy and Obstetrical Adverse Outcomes.

Ceramides are a group of sphingolipids located in the external plasma membrane layer and act as messengers in cellular pathways such as inflammatory processes and apoptosis. Plasma ceramides are biomarkers of cardiovascular disease, type 2 diabetes mellitus, Alzheimer's disease, various autoimmune conditions and cancer. During pregnancy, ceramides play an important role as stress mediators, especially during implantation, delivery and lactation. Based on the current literature, plasma ceramides could be potential biomarkers of obstetrical adverse outcomes, although their role in metabolic pathways under such conditions remains unclear. This review aims to present current studies that examine the role of ceramides during pregnancy and obstetrical adverse outcomes, such as pre-eclampsia, gestational diabetes mellitus and other complications.

Plasma Ceramide Concentrations in Full-Term Pregnancies Complicated with Gestational Diabetes Mellitus: A Case-Control Study.

Ceramides, a sphingolipid group that acts as a messenger in cellular differentiation, proliferation, apoptosis and senescence, have been associated with cardiovascular disease and type 2 diabetes. The evidence for an association between ceramides and gestational diabetes mellitus (GDM) is scarce. This case-control study aimed to compare women with GDM with healthy, pregnant women in terms of plasma ceramide concentrations at the time of delivery. Ninety-two pregnant women were included in this case-control study, 29 in the GDM group and 63 in the control group. All women were admitted to a tertiary academic hospital for a full-term delivery. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was applied for the quantification of four molecular ceramides, namely Cer d18:1/16:0 (Cer16:0), Cer d18:1/18:0 (Cer18:0), Cer d18:1/24:0 (Cer24:0) and Cer d18:1/24:1 (Cer24:1) in plasma samples. The raw chromatographic data obtained from the LC-MS/MS analysis were processed using Analyst SCIEX (AB Sciex Pte. Ltd., USA). In a univariate statistical analysis, Cer24:0 concentration was significantly lower in the GDM group compared with the control group (p = 0.01). The present study demonstrated lower Cer24:0 concentrations in pregnancies complicated by GDM. Further prospective studies are required to enhance the results of this study.

Characterizing neonatal vitamin D deficiency in the modern era: A maternal-neonatal birth cohort from Southern Europe.

Absence of adequate maternal vitamin D supplementation and decreased maternal ultraviolet exposure during pregnancy are key determinants for the manifestation of neonatal hypovitaminosis D at birth. These parameters may vary, according to country-specific dietary patterns, health policies and sunshine exposure. We aimed to investigate differences in calcium metabolism and anthropometric profiles according to neonatal vitamin D status at birth, in a sunny region of Northern Greece. A secondary aim was to identify maternal parameters as risk factors for developing neonatal vitamin D deficiency at birth. A total of 129 mother-neonate pairs were included in the study and classified into three groups, according to neonatal 25-hydroxy-D [25(OH)D)] concentrations at birth [deficiency (<30 nmol/l), insufficiency (30-50 nmol/l) and sufficiency (>50 nmol/l)]. Neonatal biochemical and anthropometric profiles and maternal demographic, social, dietary and biochemical profiles were comparatively evaluated between the three groups. Univariate and multivariate logistic regression was performed to identify independent associations of maternal factors with neonatal vitamin D status. Vitamin D deficient-neonates manifested higher parathyroid hormone (7.20 ± 2.60 vs 5.50 ± 1.50 pg/ml, p = 0.01) and lower corrected calcium (10.70 ± 0.70 vs 11.30 ± 1.30 mg/dl, p = 0.02) concentrations compared with vitamin d-insufficient neonates. Mothers of vitamin D deficient and insufficient neonates had a lower total of 25(OH)D (31.7 ± 19.2 and 36.5 ± 22.3 vs 53.3 ± 39.0 nmol/l, p < 0.01) and 25(OH)D3 (27.4 ± 17.5 and 33.3 ± 19.9 vs 47.3 ± 36.7 nmol/l, p < 0.01 and p = 0.04, respectively) concentrations respectively, compared with those of vitamin D-sufficient neonates. Maternal use of alcohol during pregnancy was associated with a 5.57-fold higher risk for neonatal vitamin D deficiency at birth (OR 5.57, 95 % CI1.17-26.56, p = 0.03). Newborns with vitamin D deficiency presented a 6.89-fold higher risk of having been given birth by vitamin D deficient mothers (OR 6.89, 95 % CI 3.09-15.38, p < 0.01). In conclusion, neonatal vitamin D deficiency is associated with maternal 25(OH)D concentrations at birth and maternal alcohol use. Further studies are required to replicate these findings in other regions and populations.

An observational study reveals that neonatal vitamin D is primarily determined by maternal contributions: implications of a new assay on the roles of vitamin D forms.

BACKGROUND: Vitamin D concentrations during pregnancy are measured to diagnose states of insufficiency or deficiency. The aim of this study is to apply accurate assays of vitamin D forms [single- hydroxylated [25(OH)D2, 25(OH)D3], double-hydroxylated [1α,25(OH)2D2, 1a25(OH)2D3], epimers [3-epi-25(OH)D2, 3-epi-25(OH)D3] in mothers (serum) and neonates (umbilical cord) to i) explore maternal and neonatal vitamin D biodynamics and ii) to identify maternal predictors of neonatal vitamin D concentrations. METHODS: All vitamin D forms were quantified in 60 mother- neonate paired samples by a novel liquid chromatography -mass spectrometry (LC-MS/MS) assay. Maternal characteristics [age, ultraviolet B exposure, dietary vitamin D intake, calcium, phosphorus and parathyroid hormone] were recorded. Hierarchical linear regression was used to predict neonatal 25(OH)D concentrations. RESULTS: Mothers had similar concentrations of 25(OH)D2 and 25(OH)D3 forms compared to neonates (17.9 ± 13.2 vs. 15.9 ± 13.6 ng/mL, p=0.289) with a ratio of 1:3. The epimer concentrations, which contribute approximately 25% to the total vitamin D levels, were similar in mothers and neonates (4.8 ± 7.8 vs. 4.5 ± 4.7 ng/mL, p=0.556). No correlation was observed in mothers between the levels of the circulating form (25OHD3) and its active form. Neonatal 25(OH)D2 was best predicted by maternal characteristics, whereas 25(OH)D3 was strongly associated to maternal vitamin D forms (R²=0.253 vs. 0.076 and R2=0.109 vs. 0.478, respectively). Maternal characteristics explained 12.2% of the neonatal 25(OH)D, maternal 25(OH)D concentrations explained 32.1%, while epimers contributed an additional 11.9%. CONCLUSIONS: By applying a novel highly specific vitamin D assay, the present study is the first to quantify 3-epi-25(OH)D concentrations in mother-newborn pairs. This accurate assay highlights a considerable proportion of vitamin D exists as epimers and a lack of correlation between the circulating and active forms. These results highlight the need for accurate measurements to appraise vitamin D status. Maternal characteristics and circulating forms of vitamin D, along with their epimers explain 56% of neonate vitamin D concentrations. The roles of active and epimer forms in the maternal-neonatal vitamin D relationship warrant further investigation.

Thyrotropin receptor autoantibodies and early miscarriages in patients with Hashimoto thyroiditis: a case-control study.

We have previously hypothesized that early miscarriage in women with Hashimoto thyroiditis might be the result of a cross-reactivity process, in which blocking autoantibodies against thyrotropin receptor (TSHr-Ab) antagonize hCG action on its receptor on the corpus luteum. To test this hypothesis from the clinical perspective, we investigated the presence of TSHr-Ab in Hashimoto thyroiditis patients with apparently unexplained, first-trimester recurrent miscarriages compared to that in Hashimoto thyroiditis patients with documented normal fertility. A total of 86 subjects (43 cases and 43 age-matched controls) were finally included in a case-control study. No difference in the prevalence of TSHr-Ab positivity was detected between cases and controls (Fisher's exact test, p value = 1.00). In patients with recurrent miscarriages, TSHr-Ab concentrations did not predict the number of miscarriages (univariate linear regression, p value = 0.08). These results were robust in sensitivity analyses, including only cases with full investigation or those with three or more miscarriages. We conclude that no role could be advocated for TSHr-Ab in the aetiology of recurrent miscarriages in women with Hashimoto thyroiditis.

New insights of osmoregulatory system changes in ovarian hyperstimulation syndrome.

This study evaluated the osmoregulatory system changes in 39 patients with severe ovarian hyperstimulation syndrome. Plasma osmolality (Posm) less or more than 280 mOsm/kg body weight were associated with inappropriate antidiuretic hormone secretion syndrome and hypovolemia, respectively.

Acute and chronic Chlamydia pneumoniae infection in pregnancy complicated with preeclampsia.

OBJECTIVE: To investigate whether Chlamydia pneumoniae (Cp) infection is more common in women whose current pregnancy is complicated with preeclampsia (PE) as compared to pregnant women without PE. METHODS: Thirty pregnant women with PE and 30 pregnant women without PE were studied between 29 and 30 weeks of gestation. The presence of an acute or chronic Cp infection was determined by the estimations of serum IgG, IgM, and IgA Cp antibodies. RESULTS: None of the women were diagnosed as having acute Cp infection. Prevalence of chronic Cp infection was 53 and 66% in the PE and control groups, respectively (X(2), p = 0.068). CONCLUSION: Chronic Cp infection is not more common in women whose pregnancy is complicated with PE as compared to pregnant women without PE. Therefore, no association between Cp infection and PE can be established.

Regulatory Τ-cell differentiation between maternal and cord blood samples in pregnancies with spontaneous vaginal delivery and with elective cesarian section.

PROBLEM: The immunological mechanisms preventing fetal antigenic rejection during normal pregnancy and the extent to which the type of delivery influences lymphocyte reactions are elusive. METHOD OF STUDY: Maternal peripheral blood and neonatal umbilical cord blood (CB) was collected upon labor after vaginal delivery or cesarian section. Leukocytes were analyzed with flow cytometry, focusing on regulatory and γ/δ T-cells. RESULTS: In CB from neonates delivered by vaginal delivery, natural killer cells were increased. On the other hand, in maternal blood, γ/δ T-cells were increased, and activated T-cells (cluster of differentiation [CD]4+/25(dim) /122+ cells) were decreased. Moreover, maternal blood presented increased levels of T regulatory cell subsets like CD4+/25(high) /45RO+, CD4+/25(high) /DR+, CD4+/25(high) /CD38+ and CD4+/25(high) /71+. In CB, CD19+, CD4+/25(high) /45RA+ and CD4+/25(high) /122+ cells were increased. CONCLUSION: The effect of delivery type on lymphocyte immunophenotype was minimal. Mothers' and neonates' lymphocyte subsets differed significantly. Mothers' phenotype comprised significantly of lymphocytes involved in tolerance (memory and activated regulatory T-cells, γ/δ T-cells).

Mosaic ring X chromosome in a case of secondary amenorrhea.

OBJECTIVE: To report an unusual case of secondary amenorrhea in a 17-year-old adolescent with normal sexual development who proved to have a karyotype 46,XX/46,X,+ringX/47,XX,+ringX. DESIGN: Case report. SETTING: Hospital, tertiary level of clinical endocrine care. PATIENT(S): A 17-year-old patient with secondary amenorrhea and normal sexual characteristics with no stigmata of Turner syndrome. INTERVENTION(S): Clinical history, hormonal markers, cytogenetic analysis. MAIN OUTCOME MEASURE(S): Cytogenetic analysis by G-banding technique, multicolor fluorescence in situ hybridization, and multicolor banding analysis on peripheral blood lymphocytes. RESULT(S): The presence of mosaicism in 12% of metaphases indicating a ring X chromosome with one or two normal X chromosomes, forming a karyotype 46,XX/46,X, +ringX/47,XX,+ringX. CONCLUSION(S): Our findings indicate the necessity for cytogenetic studies in certain cases of amenorrhea. This is a very rare karyotype in patients with secondary amenorrhea.

Safety of GnRH agonists and antagonists.

The widespread application of protocols using gonadotropin-releasing hormone (GnRH) agonists or antagonists in assisted reproduction treatment has led to an increasing number of pregnancies exposed to these drugs. This issue has raised scepticism as to the safety of these medications, concerning both pregnant women and their offspring. The main parameters that can be studied to ensure the safety of GnRH analogues include: a) systemic and local reactions to the medication; b) incidence of ovarian hyperstimulation syndrome (OHSS); c) direct effect on oocytes and embryos; and d) the health of those children exposed. So far, no systemic side effects and no major local reactions have been reported following the use of GnRH agonists or third-generation antagonists. On the other hand, the incidence of OHSS seems to be higher with GnRH agonist protocols compared to conventional or GnRH antagonist protocols. The recent cloning of the GnRH receptor has led to the demonstration of GnRH receptor gene expression in the human ovary, although the existence of GnRH receptors per se remains controversial. Similarly, the potential direct effect of GnRH analogues on the follicles and oocytes remains a matter of debate. The incidence of miscarriage and the health of children born as a result of in vitro fertilisation (IVF) treatment do not appear to be influenced by the GnRH agonist treatment. This also seems to be the case for the GnRH antagonists, although the available information on this issue is still limited. Therefore, most of the accumulated data concerning the safety of the GnRH analogues are encouraging, and no serious side effects have been reported. On the other hand, as no definite conclusions about the safety of these drugs can be drawn until now, continued assessment of the aforementioned parameters in long-term follow-up studies is recommended.

Gonadotropin-releasing hormone antagonists: impact of IVF practice and potential non-assisted reproductive technology applications.

PURPOSE OF REVIEW: To provide the clinician with updated knowledge of the most recent findings on the clinical use of gonadotropin-releasing hormone antagonists. RECENT FINDINGS: Gonadotropin-releasing hormone antagonists, which have recently been introduced in clinical practice, cause an immediate suppression of gonadotropin secretion by competitive blocking of pituitary gonadotropin-releasing hormone receptors. Thus, they are effective in preventing the premature luteinizing hormone surges during ovarian stimulation for in-vitro fertilization and may improve the patient's response to lower doses of gonadotropins. Better patient acceptance, shorter treatment cycles and fewer follicles and oocytes are also reported. Data existing so far concerning the necessity of luteal phase support after the use of gonadotropin-releasing hormone antagonists show that it might not be mandatory when used in clomiphene citrate costimulated cycles or in intrauterine insemination cycles. The use of gonadotropin-releasing hormone antagonists seems to be safe for pregnant women and their offspring. All sex-hormone-dependent disorders, currently treated with gonadotropin-releasing hormone agonists, may in future be indications for a gonadotropin-releasing hormone antagonist, including endometriosis, leiomyoma, and breast cancer in women, benign prostatic hypertrophy and prostatic carcinoma in men, and central precocious puberty in children. The vast majority of the available clinical data up till now, however, are in assisted reproduction and prostate cancer. SUMMARY: It is expected that the availability of gonadotropin-releasing hormone antagonist will lead to the use of 'softer' ovarian stimulation protocols, which will be shorter, cheaper and safer compared with the conventional protocols.