Abstract

Objective:

To determine prospectively the prognostic value of maternal plasma concentrations of placental growth factor (PlGF), soluble endoglin (sEng) and soluble vascular endothelial growth factor receptors-1 and -2 (sVEGFR-1 and -2) in identifying patients with suspected preeclampsia (PE) who require preterm delivery (PTD) or develop adverse outcomes.

Study design:

This prospective cohort study included 85 consecutive patients who presented to the obstetrical triage area at 20-36 weeks with a diagnosis of 'rule out PE'. Patients were classified into: 1) those who remained stable until term (n=37); and 2) those who developed severe PE and required PTD (n=48). Plasma concentrations of PlGF, sEng and sVEGFR-1 and -2 were determined by ELISA.

Results:

Patients with PlGF/sVEGFR-1 ≤0.05 multiples of the median (MoM) or PlGF/sEng ≤0.07 MoM were more likely to deliver preterm due to PE [adjusted odd ratio (aOR) 7.4 and 8.8], and to develop maternal (aOR 3.7 and 2.4) or neonatal complications (aOR 10.0 and 10.1). Among patients who presented <34 weeks of gestation, PlGF/sVEGFR-1 < 0.035 MoM or PlGF/sEng ≤0.05 MoM had a sensitivity of 89% (16/18), specificity of 96% (24/25) and likelihood ratio for a positive test of 22 to identify patients who delivered within two weeks. The addition of the PlGF/sVEGFR-1 ratio to standard clinical tests improved the sensitivity at a fixed false-positive rate of 3% (p=0.004) for the identification of patients who were delivered due to PE within two weeks. Among patients who had a plasma concentration of PlGF/sVEGFR-1 ratio ≤ 0.035 MoM, 0.036-0.34 MoM and ≥ 0.35 MoM, the rates of PTD < 34 weeks were 94%, 27% and 7%, respectively.

Conclusions:

The determination of angiogenic/anti-angiogenic factors has prognostic value in patients presenting to the obstetrical triage area with suspected preeclampsia for the identification of those requiring preterm delivery and at risk for adverse maternal/ neonatal outcomes.

Metal orthopedic implant debris-induced osteolysis of hip bone is a major problem in patients with prosthetic-hips. Although macrophages are the principal targets for implant-wear debris, the receptor(s) and mechanisms underlying these responses are not fully elucidated. We examined whether the TLR4 pathway mediates immune response to metal-on-metal (MoM) implant-generated wear particles. Human monocytes (THP-1) were exposed to Co-alloy particles at increasing particle:cell ratio for 24h. Challenge with particles caused up-regulation of IL-1β, TNF-α and IL-8, and mediated degradation of cytosolic I-κB and nuclear translocation of NF-κB. Blocking antibodies against TLR4 or gene silencing of MyD88 and IRAK-1 prevented particle-induced I-κB/NF-κB activation response and markedly inhibited IL-8 release. Particle-mediated IL-8 response was not observed in TLR4-negative HEK293T cells; whereas transfection-based TLR4-overexpression in HEK293T enabled particle-sensitivity, as observed by I-κB degradation and IL-8 expression in response to particles. Results demonstrate that Co-alloy particles trigger immune response via the TLR4-MyD88-dependent signaling pathway.

Soft tissue reactions following metal-on-metal (MoM) arthroplasty of the hip have been under considerable discussion. These reactions are seen following both hip resurfacing and MoM total hip arthroplasty (THA). The phenomenon may arise owing to shedding of metal particles in high wear states, hypersensitivity with normal metal wear rates or a combination of the two.Three patients were identified who had developed a soft tissue reaction (pseudotumour) following MoM hip resurfacing procedures. The prostheses were revised to ceramic-on-ceramic (CoC) THA with only minimal debridement of the pseudotumour. Pre and postoperative magnetic resonance imaging was performed to assess the size of the lesions.Progressive and satisfactory resolution of the associated pseudotumours was identified following revision of the prostheses to CoC THA.In the early stages of pseudotumour formation following MoM hip resurfacing, this potentially devastating condition can be managed adequately with revision to a CoC bearing THA with minimal soft tissue excision.

BACKGROUND:

Screening at 11-13 weeks with ultrasound biparietal diameter (BPD) can detect half of open spina bifida cases. Maternal serum α-fetoprotein (AFP) levels at 15-19 weeks are increased 3-4 fold, in open spina bifida. We assessed whether combined screening using BPD, AFP and other serum markers at 11-13 weeks would increase detection. POPULATION AND

METHODS:

Maternal AFP levels were measured on serum stored at 11-13 weeks' in 44 open spina bifida and 182 unaffected pregnancies, and results were expressed in multiples of the median for gestational age (MoM). All samples had been measured for free β-human chorionic gonadotropin (hCG) and pregnancy associated plasma protein (PAPP)-A. A multivariate Gaussian model was used to predict screening performance from the serum data and BPD measurements on 80 cases, including 36 previously published.

RESULTS:

The median AFP level in cases was 1.201 MoM, significantly higher than in unaffected pregnancies (P<0.01, 1-tail). The median free β-hCG was significantly reduced to 0.820 MoM (P<0.02) but the median PAPP-A was similar in cases and controls. Modelling predicted that: BPD alone would detect 50% of cases for a 5% false-positive rate or 63% for 10%; adding AFP increases detection by 2%; a combined test with BPD, AFP and free β-hCG detects 58% for 5% or 70% for 10%.

DISCUSSION:

Combining AFP and BPD with free β-hCG as part of first trimester aneuploidy screening would also allow early detection about two-thirds of cases with open spina bifida.

STUDY QUESTION: When does a difference in human intrauterine growth of singletons conceived after IVF and embryo culture in two different culture media appear? SUMMARY ANSWER: Differences in fetal development after culture of embryos in one of two IVF media were apparent as early as the second trimester of pregnancy. WHAT IS KNOWN ALREADY: Abnormal fetal growth patterns are a major risk factor for the development of chronic diseases in adult life. Previously, we have shown that the medium used for culturing embryos during the first few days after fertilization significantly affects the birthweight of the resulting human singletons. The exact onset of this growth difference was unknown.

STUDY DESIGN

, SIZE AND DURATION: In this retrospective cohort study, all 294 singleton live births after fresh embryo transfer in the period July 2003 to December 2006 were included. These embryos originated from IVF treatments that were part of a previously described clinical trial. Embryos were allocated to culture in either Vitrolife or Cook commercially available sequential culture media. PARTICIPANTS/MATERIALS, SETTING,

METHODS:

We analysed ultrasound examinations at 8 (n = 290), 12 (n = 83) and 20 weeks' (n = 206) gestation and used first-trimester serum markers [pregnancy-associated plasma protein-A (PAPP-A) and free β-hCG]. Differences between study groups were tested by the Student's t-test, χ(2) test or Fisher's exact test, and linear multivariable regression analysis to adjust for possible confounders (for example, parity, gestational age at the time of ultrasound and fetal gender). MAIN

RESULTS

AND THE ROLE OF CHANCE: A total of 294 singleton pregnancies (Vitrolife group nVL = 168, Cook group: nC = 126) from 294 couples were included. At 8 weeks' gestation, there was no difference between crown-rump length-based and ovum retrieval-based gestational age (ΔGA) (nVL = 163, nC = 122, adjusted mean difference, -0.04 days, P = 0.84). A total of 83 women underwent first-trimester screening at 12 weeks' gestation (nVL = 45, nC = 38). ΔGA, nuchal translucency (multiples of median, MoM) and PAPP-A (MoM) did not differ between the study groups. Free β-hCG (MoM) ± SEM differed significantly (1.55 ± 0.19 in Vitrolife versus 1.06 ± 0.10 in Cook; P = 0.031, Student's t-test). At 20 weeks' gestation, a more advanced GA, reflecting an increased fetal growth, was seen at ultrasound examination in the Vitrolife group (n = 115) when compared with the Cook group (n = 91). After adjustment for confounding factors, both the difference between GA based on three biparietal diameter dating formulas minus the actual (ovum retrieval based) GA (adjusted mean difference + 1.14 days (P = 0.04), +1.14 days (P = 0.04) and +1.36 days (P = 0.048)), as well as head circumference (HC) and trans-cerebellar diameter (TCD) were significantly higher in the Vitrolife group (HCvl 177.3 mm, HCc 175.9 mm, adjusted mean difference 1.8, P = 0.03; TCDvl 20.5 mm, TCDc 20.2 mm, adjusted mean difference 0.4, P = 0.008). LIMITATIONS, REASONS FOR CAUTION: A first trimester (12 weeks) fetal screening was not yet offered routinely during the study period, therefore only 28% of women in our study participated in this elective screening programme. Although all sonographers were experienced and specially trained to perform these ultrasound examinations and were unaware of the randomization procedure, we cannot totally rule out possible intra- and inter-observer variability. Despite being indispensable in daily practice, sonographic weight formulas have a limited accuracy. WIDER IMPLICATIONS OF THE

FINDINGS:

According to the fetal origins hypothesis, many adult diseases originate in utero owing to adaptations made by the fetus to the environment it encounters. This study indicates that the embryonic environment is already important for fetal development. Therefore, our study emphasizes the need to investigate fetal growth patterns after assisted reproduction technologies and long-term health outcomes of IVF children, especially in relation to the culture medium used during the first few days of preimplantation development. TRIAL REGISTRATION NUMBER: Not applicable.

We systematically reviewed the peer-reviewed literature to determine a pooled estimate of the incidence of pseudotumor and acute lymphocytic vasculitis associated lesions (ALVAL) in adult patients with primary metal-on-metal (MoM) total hip arthroplasty or resurfacing. Fourteen eligible articles were identified, with a total of 13,898 MoM hips. The incidence of pseudotumor/ALVAL ranged from 0% to 6.5% of hips with a mean follow-up ranging from 1.7 to 12.3years across the studies. The pooled estimated incidence of pseudotumor/ALVAL is 0.6% (95% CI: 0.3% to 1.2%). The rate of revision for any reason ranged from 0% to 14.3% of hips, with a pooled estimate of 3.9% (95% CI: 2.7% to 5.3%).

Background:

Thyroid disease during pregnancy may be associated with increased risk of various pregnancy complications. It is known that serum thyroid stimulating hormone (TSH) is suppressed by human chorionic gonadotrophin (hCG) in early pregnancy, and that higher hCG levels in twin pregnancies may cause a more pronounced physiologic suppression, this is important to avoid unnecessary concern and facilitate the diagnosis of overt thyroid disease in twin pregnancy. The aim of this study is to establish normal ranges of maternal serum TSH, and free thyroxine (FT4) at 11-13 weeks' gestation in twin pregnancy.

Methods:

This was a case series of 177 dichorionic and 58 monochorionic twin pregnancies with normal outcome and 19 monochorionic pregnancies complicated by severe twin-to-twin transfusion syndrome (TTTS). Maternal serum concentrations of TSH, FT4, anti-thyroperoxidase and anti-thyroglobulin antibodies were measured at 11-13 weeks' gestation. The measured TSH and FT4 were converted to multiple of median (MoM) of normal singleton pregnancy and MoM values in the different groups were compared.

Results:

In the antithyroid antibody negative twin pregnancies with normal outcome, compared to singletons, serum TSH MoM was lower (median 0.62, IQR 0.16-1.18 vs. 1.01, IQR 0.61-1.51; P<0.0001), FT4 MoM was not significantly different (median 0.98, IQR 0.91-1.08 vs. 0.99, IQR 0.91-1.09; P=0.975) and free ß-hCG MoM was higher (median 1.91, IQR 1.33-2.59 vs. 0.98, IQR 0.66-1.50; P<0.0001). In the antibody-positive group (n=37), compared to the negative group (n=198), the median TSH was higher but FT4 and free ß-hCG were not significantly different. In the TTTS group, compared to normal twin pregnancies, TSH, FT4 and free ß-hCG were not significantly different.

Conclusion:

In twins, compared to singleton pregnancies, TSH is lower but FT4 is not significantly different. These normal ranges of thyroid hormones in twins can form the basis for the study of early thyroid function in pathological pregnancies and the investigation of the consequences of overt and subclinical hypothyroidism on twin pregnancy outcome.

Abstract In this study, we investigated whether the concentrations of pregnancy-associated plasma protein-A (PAPP-A) or free β-hCG (fβhCG) in the first trimester can identify women at increased risk of subsequent preterm delivery in the absence of hypertensive disorders. Preterm and early preterm deliveries are defined as those deliveries before completing 37 and 34 weeks, respectively. A total of 868 women were enrolled into this study. According to the level of the markers, the patients were evaluated in three groups: 1 - maternal serum level ≤5th percentile, 2 - between 5th and 95th percentiles, 3 - ≥95th percentile. In the group of patients with a PAPP-A level ≤5th percentile [≤0.35 multiples of the median (MoM)], mean gestational age (GA) at delivery, mean birth weight and the number of the cases with early preterm delivery were significantly lower than the others. Mean level of PAPP-A was significantly lower in cases with early preterm than term deliveries (0.58 ± 0.32 versus1.09 ± 0.69; p = 0.01). Maternal serum level of fβhCG did not show significant difference between these groups (0.84 ± 0.45 versus 1.17 ± 0.77; p = 0.15). Low levels of maternal serum PAPP-A (≤0.35 MoM) (Odds ratio = 7; 95% confidence interval 1.8-27.7; p = 0.0048) significantly predicted early preterm delivery in normotensive pregnancies. Women with low levels of PAPP-A at first trimester have a higher risk of early preterm delivery even in the absence of hypertensive disorders.

Deprotection of a methoxymethyl (MOM) group on an oxindole nitrogen under basic conditions is demonstrated. The mechanisms of both the deprotection and the formation of N-methyloxindole were revealed by using deuterated NaOMe-MeOH in mechanistic studies.

In recent years, metal-on-metal (MOM) arthroplasty has come under fire with reported adverse outcomes of metal hypersensitivity, adverse local tissue reaction (ALTR), and the carcinogenicity concern from systemic metal ions. We present a retrospective analysis of 354 primary total hip arthroplasties from 2 independent centers. Revision data, predicted survival and Harris Hip Scores (HHS) are reported. Nine hips (2.5%) underwent component revision, and 9year predicted survival was 95.8%. One revision had elevated metal ions but no histological evidence of ALTR. Average HHS at a minimum 5year follow up (range 5-10years) improved significantly from 52 pre-operatively to 93 post-operatively. While a 2.5% revision rate and improved clinical outcomes are reported in this study, longer term follow-up is warranted to monitor for late complications.