Total pregnancy loss after chorionic villus sampling and amniocentesis: a cohort study.

OBJECTIVES: To identify maternal-, operator- and procedure-related variables that affect procedure-related pregnancy loss after transcervical (TC) and transabdominal (TA) chorionic villus sampling (CVS) and amniocentesis and to estimate the rates of spontaneous and procedure-related loss in comparable subgroups of women. METHODS: This was a retrospective cohort study conducted at the University Medical Center Groningen and the Academic Medical Center, The Netherlands. Databases of both centers were searched to identify singleton pregnancies that had undergone a combined test and/or anomaly scan at around 20 weeks' gestation, or an invasive procedure (CVS and/or amniocentesis) between January 2001 and December 2011. Maternal characteristics, obstetric history, technical aspects of the invasive procedure, ultrasound examinations and fetal and neonatal outcomes were available for 29 201 cases. Women were categorized, according to the type of examination they had received, into the following five groups: first-trimester combined test (and 20-week anomaly scan); 20-week anomaly scan only; CVS; amniocentesis; amniocentesis after unsuccessful CVS. Rates of fetal loss were compared between groups. RESULTS: Variables significantly associated with a higher rate of fetal loss were, for CVS, repeat attempts during the procedure, use of TC cannula instead of biopsy forceps, gestational age at procedure ≥ 13 weeks and a pregnancy after assisted reproductive techniques, and, for amniocentesis, if indication was fetal anomaly or family history of anomalies and repeat attempts during the procedure. In women aged ≥ 36 years who did not undergo an invasive procedure, spontaneous fetal loss rate (FLR) after first-trimester combined test was 1.40%, whereas after CVS, FLR was 2.76% and 2.43% for a TC and TA approach, respectively. The additional risk of fetal loss with TC-CVS was therefore 1.36% (1 : 74), which varied according to the instrument used (0.27% for forceps and 3.12% for cannula), and with TA-CVS was 1.03% (1 : 97). In women aged ≥ 36 years who underwent a 20-week anomaly scan only, spontaneous FLR was 0.63%. In women who underwent amniocentesis solely because of advanced maternal age, FLR was 1.11%. The additional risk of fetal loss with amniocentesis was 0.48% (1 : 208). CONCLUSION: The total rate of procedure-related fetal loss after TA- and TC-CVS and amniocentesis appears lower than the risks on which women are currently counseled. There was a trend for a decrease in risk when the level of experience of the operator increased. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Prenatal Evidence of Persistent Notochord and Absent Sacrum Caused by a Mutation in the T (Brachyury) Gene.

Caudal regression syndrome (CRS) is a rare congenital disorder characterized by developmental abnormalities of caudal spinal segments. To date, the etiology of CRS is unclear; sporadic cases are strongly associated with maternal diabetes, while familiar recurrence is infrequent. We describe in detail the prenatal clinical and sonographic findings of a recently described hereditary caudal regression syndrome, in four fetuses reported to be homozygous for a mutation in the T (brachyury) gene. The syndrome occurred in three consanguineous, but unrelated families, originating from the same geographical area. All affected fetuses had persistence of the notochord in association with abnormal vertebral ossification, sacral agenesis, and bilateral clubfoot. These findings suggest that, in case of prenatal diagnosis of sacral agenesis, an advanced ultrasound examination should assess the vertebral ossification and the rare persistence of the notochord, in order to rule the involvement of the T gene.

Low-resistance hepatic artery flow in first-trimester fetuses: an ominous sign.

OBJECTIVE: Low-resistance hepatic artery (HA) flow has been reported in severely growth-restricted fetuses. The same finding has been incidentally observed in first-trimester fetuses with enlarged nuchal translucency (NT). The aim of this study was to investigate HA flow in first-trimester fetuses. METHODS: Crown-rump length (CRL), NT, ductus venosus (DV) pulsatility index for veins (PIV) and HA pulsatility index (PI) were measured prospectively in fetuses at increased risk on first-trimester assessment for aneuploidy and in a control group of low-risk fetuses. Outcome of pregnancy was known in all cases. Independent sample t-test was used for intergroup comparison. RESULTS: NT, DV-PIV and HA-PI were measured prospectively in 59 fetuses. Thirty-four had an enlarged NT and underwent karyotyping, which was abnormal in 16 cases (trisomy 21, n = 12; trisomy 18, n = 3; 47,XXY, n = 1). Two pregnancies were terminated in view of fetal anomalies. In three other infants an abnormality was confirmed after birth (Noonan syndrome, unspecified genetic syndrome and cardiac defect). The remaining 13 fetuses with enlarged NT and the 25 with normal NT had an uneventful pregnancy outcome. HA-PI was significantly and inversely correlated with NT and DV-PIV. Mean HA-PI was significantly lower in fetuses with adverse outcome (chromosomal anomalies 1.60; chromosomally normal fetuses with adverse outcome 1.66) than in controls (2.03). CONCLUSIONS: Low-resistance HA flow can be observed in first-trimester fetuses and, based on its association with adverse outcome, it can be regarded as an ominous sign.

Ligands of the antiestrogen-binding site induce active cell death and autophagy in human breast cancer cells through the modulation of cholesterol metabolism.

We have recently reported that cytostatic concentrations of the microsomal antiestrogen-binding site (AEBS) ligands, such as PBPE (N-pyrrolidino-(phenylmethyphenoxy)-ethanamine,HCl) and tamoxifen, induced differentiation characteristics in breast cancer cells through the accumulation of post-lanosterol intermediates of cholesterol biosynthesis. We show here that exposure of MCF-7 (human breast adenocarcinoma cell line) cells to higher concentrations of AEBS ligands triggered active cell death and macroautophagy. Apoptosis was characterized by Annexin V binding, chromatin condensation, DNA laddering and disruption of the mitochondrial functions. We determined that cell death was sterol- and reactive oxygen species-dependent and was prevented by the antioxidant vitamin E. Macroautophagy was characterized by the accumulation of autophagic vacuoles, an increase in the expression of Beclin-1 and the stimulation of autophagic flux. We established that macroautophagy was sterol- and Beclin-1-dependent and was associated with cell survival rather than with cytotoxicity, as blockage of macroautophagy sensitized cells to AEBS ligands. These results show that the accumulation of sterols by AEBS ligands in MCF-7 cells induces apoptosis and macroautophagy. Collectively, these data support a therapeutic potential for selective AEBS ligands in breast cancer management and shows a mechanism that explains the induction of autophagy in MCF-7 cells by tamoxifen and other selective estrogen receptor modulators.

Synthesis of the first stable phosphonamide transition state analogue.

Three methods were selected for the one-pot synthesis of the fully protected beta-fluoroaminophosphonic acids, using the readily accessible N-protected beta-fluoroaminals. These were activated by acylation leading, by beta-elimination, to a transient N-acylimine immediately trapped by reactive forms of dialkyl phosphites. Avoiding basic conditions, the complete or partial deprotection of these N-protected beta-fluoroaminophosphonic esters allowed the synthesis of the free amino acids, their esters, and a racemic beta-trifluorophosphonamidic acid. The latter, which represents a transition state analogue formed by the bacterial transpeptidase, is perfectly stable at pH 4.7, contrary to the nonfluorinated compounds.

Fetal behaviour does not differ between boys and girls.

INTRODUCTION: Little is known about sex differences in human fetal heart and behaviour. PATIENTS AND METHODS: One hundred twenty-three nulliparous healthy women carrying a male (n=56) or female (n=67) fetus participated in this study. All pregnancies remained uncomplicated and delivery was uneventful. Ultrasound observation of fetal general movements (GM) was performed for 1 h at 15-17 (T1) and 27-28 (T2) weeks of gestation and for 2 h at 37-39 weeks (T3). Fetal heart rate (FHR) monitoring occurred simultaneously with fetal ultrasound observations at T2 and T3. The incidence of GM (percentage of time), FHR and its variability, and the incidences of fetal heart rate patterns (HRP) A-D and behavioural states 1F-4F were compared between boys and girls. RESULTS: There were no significant differences between males and females in the distribution of HRP A-D, overall behavioural state distribution, and basal FHR, FHR variability or the presence of GM during quiet and active sleep (or during HRP A and HRP B, respectively). A TimeXSex interaction effect for GM assessed for total record length and a higher %GM in male fetuses at term age were the only significant findings. However, these observations lost statistical significance after adjustment for the effects of fetal wakefulness, which occurred to a higher extent in male than in female fetuses. CONCLUSION: Our data do not provide evidence for a difference in fetal functional development or maturation between the two sexes.

La rinitis a la luz de los consensos internacionales / Rhinitis in the light of international consensuses

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Prenatal maternal stress: effects on pregnancy and the (unborn) child.

BACKGROUND: Animal experiments have convincingly demonstrated that prenatal maternal stress affects pregnancy outcome and results in early programming of brain functions with permanent changes in neuroendocrine regulation and behaviour in offspring. AIM: To evaluate the existing evidence of comparable effects of prenatal stress on human pregnancy and child development. STUDY DESIGN: Data sources used included a computerized literature search of PUBMED (1966-2001); Psychlit (1987-2001); and manual search of bibliographies of pertinent articles. RESULTS: Recent well-controlled human studies indicate that pregnant women with high stress and anxiety levels are at increased risk for spontaneous abortion and preterm labour and for having a malformed or growth-retarded baby (reduced head circumference in particular). Evidence of long-term functional disorders after prenatal exposure to stress is limited, but retrospective studies and two prospective studies support the possibility of such effects. A comprehensive model of putative interrelationships between maternal, placental, and fetal factors is presented. CONCLUSIONS: Apart from the well-known negative effects of biomedical risks, maternal psychological factors may significantly contribute to pregnancy complications and unfavourable development of the (unborn) child. These problems might be reduced by specific stress reduction in high anxious pregnant women, although much more research is needed.

Salivary cortisol levels and anxiety are not increased in women destined to develop preeclampsia.

OBJECTIVE: To compare salivary cortisol levels and maternal anxiety (general and pregnancy-specific) in the early and late second trimester of pregnancy between women who developed preeclampsia (PE) and women who remained normotensive. DESIGN: Nested case-referent study. In a prospectively studied cohort of 250 pregnant women, nine women developed PE in late pregnancy. These nine patients were matched and compared with nine controls. Diurnal cortisol levels were obtained by collecting saliva samples at 17-18 and 27-28 weeks gestation. Salivary cortisol levels were determined by radioimmunoassay. Maternal anxiety was determined by Spielberger's State-Trait Anxiety Inventory (STAI) and a pregnancy-specific stress questionnaire. RESULTS: For both patients and controls, a similar pattern of salivary cortisol excretion was observed. Salivary cortisol levels and anxiety scores (general and pregnancy-specific) did not differ significantly between patients and controls. CONCLUSIONS: Our findings do not lend support to a role for maternal anxiety or second trimester increases in circulating stress hormones in the pathogenesis of PE.

Synthesis, binding and structure-affinity studies of new ligands for the microsomal anti-estrogen binding site (AEBS).

New compounds have been synthesized based on the structure of the anti-tumoral drug tamoxifen and its diphenylmethane derivative, N,N-diethyl-2-[(4-phenyl-methyl)-phenoxy]-ethanamine, HCl (DPPE). These new compounds have no affinity for the estrogen receptor (ER) and bind with various affinity to the anti-estrogen binding site (AEBS). Compounds 2, 10, 12, 13, 20a, 20b, 23a, 23b, 29 exhibited 1.1-69.5 higher affinity than DPPE, and compounds 23a and 23b have 1.2 and 3.5 higher affinity than tamoxifen. Three-dimensional structure analysis, performed using the intersection of the van der Waals volume occupied by tamoxifen in its crystallographic state and the van der Waals volume of these new compounds in their calculated minimal energy conformation, correlated well with their pKi for AEBS (r = 0.84, P<0.0001, n = 18). This is the first structure-affinity relationship (SAR) ever reported for AEBS ligands. Moreover in this study we have reported the synthesis of new compounds of higher affinity than the lead compounds and that are highly specific for AEBS. Since these compounds do not bind ER they will be helpful to study AEBS mediated cytotoxicity. Moreover our study shows that our strategy is a new useful guide to design high affinity and selective ligands for AEBS.

A study of the immediate cutaneous response. Influencing factors.

Precision in the calculation of the size of the wheal caused by the cutaneous response is faced with the problem derived from the variability of such response. The possibility of creating dose-response curves and posterior regression line, allow a comparison of these lines by means of an analysis of covariance. With this method we have analysed different factors which may influence this response. With a sample of 138 healthy subjects we have shown that factors such as: age, sex and time the skin test is carried out, have a significant influence on the size of the wheal. In the same way and with a group of 22 patients with allergy to house dust mites, we have shown that factors such as: age, sex, disease (rhinitis-asthma) or time the skin test is carried out, have no influence on the size of the cutaneous response. We have also shown that the average size of the wheal is smaller in healthy subjects than in allergic patients, presenting regression lines with different slope which allow no further comparison.