Roland Devlieger

VEGF pathway genetic variants as biomarkers of treatment outcome with bevacizumab: an analysis of data from the AViTA and AVOREN randomised trials

BACKGROUND No biomarkers that could guide patient selection for treatment with the anti-VEGF monoclonal antibody bevacizumab have been identified. We assessed whether genetic variants in the VEGF pathway could act as biomarkers for bevacizumab treatment outcome. METHODS We investigated DNA from white patients from two phase 3 randomised studies. In AViTA, patients with metastatic pancreatic adenocarcinoma were randomly assigned to receive gemcitabine and erlotinib plus either bevacizumab or placebo. In AVOREN, patients with metastatic renal-cell carcinoma were randomly assigned to receive interferon alfa-2a plus either bevacizumab or placebo. We assessed the correlation of 138 SNPs in the VEGF pathway with progression-free survival and overall survival in a subpopulation of patients from AViTA. Significant findings were confirmed in a subpopulation of patients from AVOREN and functionally studied at the molecular level. FINDINGS We investigated DNA of 154 patients from AViTA, of whom 77 received bevacizumab, and 110 patients from AVOREN, of whom 59 received bevacizumab. Only rs9582036, a SNP in VEGF receptor 1 (VEGFR1 or FLT1), was significantly associated with overall survival in the bevacizumab group of AViTA after correction for multiplicity (per-allele hazard ratio [HR] 2·1, 95% CI 1·45-3·06, p=0·00014). This SNP was also associated with progression-free survival (per-allele HR 1·89, 1·31-2·71, p=0·00081) in bevacizumab-treated patients from AViTA. AC and CC carriers of this SNP exhibited HRs for overall survival of 2·0 (1·19-3·36; p=0·0091) and 4·72 (2·08-10·68; p=0·0002) relative to AA carriers. No effects were seen in placebo-treated patients and a significant genotype by treatment interaction (p=0·041) was recorded, indicating that the VEGFR1 locus containing this SNP serves as a predictive marker for bevacizumab treatment outcome in AViTA. Fine-mapping experiments of this locus identified rs7993418, a synonymous SNP affecting tyrosine 1213 in the VEGFR1 tyrosine-kinase domain, as the functional variant underlying the association. This SNP causes a shift in codon usage, leading to increased VEGFR1 expression and downstream VEGFR1 signalling. This VEGFR1 locus correlated significantly with progression-free survival (HR 1·81, 1·08-3·05; p=0·033) but not overall survival (HR 0·91, 0·45-1·82, p=0·78) in the bevacizumab group in AVOREN. INTERPRETATION A locus in VEGFR1 correlates with increased VEGFR1 expression and poor outcome of bevacizumab treatment. Prospective assessment is underway to validate the predictive value of this novel biomarker. FUNDING F Hoffmann-La Roche.

Fetoscopic laser coagulation of the vascular equator versus selective coagulation for twin-to-twin transfusion syndrome: an open-label randomised controlled trial

BACKGROUND Monochorionic twin pregnancies complicated by twin-to-twin transfusion syndrome are typically treated with fetoscopic laser coagulation. Postoperative complications can occur due to residual vascular anastomoses on the placenta. We aimed to assess the efficacy and safety of a novel surgery technique that uses laser coagulation of the entire vascular equator (Solomon technique). METHODS We undertook an open-label, international, multicentre, randomised controlled trial at five European tertiary referral centres. Women with twin-to-twin transfusion syndrome were randomly assigned by online randomisation (1:1) with permuted blocks to the Solomon technique or standard laser coagulation. The primary outcome was a composite of incidence of twin anaemia polycythaemia sequence, recurrence of twin-to-twin transfusion syndrome, perinatal mortality, or severe neonatal morbidity. Analyses were by intention to treat, with results expressed as odds ratios (ORs) and 95% CIs. This trial is registered with the Dutch Trial Registry, number NTR1245. FINDINGS Between March 11, 2008, and July 12, 2012, 274 women were randomly assigned to either the Solomon group (n=139) or the standard treatment group (n=135). The primary outcome occurred in 94 (34%) of 274 fetuses in the Solomon group versus 133 (49%) of 270 in the standard treatment group (OR 0·54; 95% CI 0·35-0·82). The Solomon technique was associated with a reduction in twin anaemia polycythaemia sequence (3% vs 16% for the standard treatment; OR 0·16, 95% CI 0·05-0·49) and recurrence of twin-to-twin transfusion syndrome (1% vs 7%; 0·21, 0·04-0·98). Perinatal mortality and severe neonatal morbidity did not differ significantly between the two groups. Outside of the common and well-known complications of twin-to-twin transfusion syndrome and its treatment, no serious adverse events occurred. INTERPRETATION Fetoscopic laser coagulation of the entire vascular equator reduces postoperative fetal morbidity in severe twin-to-twin transfusion syndrome. We recommend that fetoscopic surgeons consider adopting this strategy for treatment of women with twin-to-twin transfusion syndrome. FUNDING Netherlands Organization for the Health Research and Development (ZonMw 92003545).

Monochorionic Diamniotic Twin Pregnancies: Natural History and Risk Stratification

About 30% of monochorionic twin pregnancies are complicated by twin-to-twin transfusion syndrome (TTTS), isolated discordant growth, twin anemia-polycythemia sequence, congenital defects or intrauterine demise. About 15% will be eligible for invasive fetal therapy, either fetoscopic laser treatment for TTTS or fetoscopic or ultrasound-guided umbilical cord coagulation for a severe congenital defect in one twin or severe discordant growth with imminent demise of the growth-restricted twin. Ultrasound examination in the first and early second trimester can differentiate the monochorionic twins at high risk for adverse outcome from those likely to be uneventful, which may be useful for patient counselling and planning of care.

Maternal obesity and breastfeeding intention, initiation, intensity and duration: a systematic review

This systematic review investigates the relationship between maternal obesity and breastfeeding intention, initiation, intensity, duration and milk supply. A comprehensive search was performed through three major databases, including Medline, Cochrane Library and Cumulative Index For Nursing and Allied Health Literature, and by screening reference lists of the relevant publications. Selection criteria were: report of original research, studies on low-risk obese mothers and the comparison with normal weight mothers which met at least two of the following primary outcomes: breastfeeding intention; initiation; intensity; duration and/or milk supply. Furthermore, the included reports had to contain a clear definition of pre-pregnant obesity, use compensation mechanisms for potential confounding factors, have a prospective cohort design and had to have been published between 1997 and 2011 and in English, French or Dutch. Effects of obesity on breastfeeding intention, initiation, intensity, duration and milk supply were analysed, tabulated and summarised in this review. Studies have found that obese women are less likely to intend to breastfeed and that maternal obesity seems to be associated with a decreased initiation of breastfeeding, a shortened duration of breastfeeding, a less adequate milk supply and delayed onset of lactogenesis II, compared with their normal weight counterparts. This systematic review indicates therefore that maternal obesity is an adverse determinant for breastfeeding success.

Effects of lifestyle intervention in obese pregnant women on gestational weight gain and mental health: a randomized controlled trial

Objective:Lifestyle intervention could help obese pregnant women to limit their weight gain during pregnancy and improve their psychological comfort, but has not yet been evaluated in randomized controlled trials. We evaluated whether a targeted antenatal lifestyle intervention programme for obese pregnant women influences gestational weight gain (GWG) and levels of anxiety or depressed mood.Design and subjects:This study used a longitudinal interventional design. Of the 235 eligible obese pregnant women, 205 (mean age (years): 29±4.5; body mass index (BMI, kg m−2): 34.7±4.6) were randomized to a control group, a brochure group receiving written information on healthy lifestyle and an experimental group receiving an additional four antenatal lifestyle intervention sessions by a midwife trained in motivational lifestyle intervention. Anxiety (State and Trait Anxiety Inventory) and feelings of depression (Edinburgh Depression Scale) were measured during the first, second and third trimesters of pregnancy. Socio-demographical, behavioural, psychological and medical variables were used for controlling and correcting outcome variables.Results:We found a significant reduction of GWG in the brochure (9.5 kg) and lifestyle intervention (10.6 kg) group compared with normal care group (13.5 kg) (P=0.007). Furthermore, levels of anxiety significantly decreased in the lifestyle intervention group and increased in the normal care group during pregnancy (P=0.02); no differences were demonstrated in the brochure group. Pre-pregnancy BMI was positively related to levels of anxiety. Obese pregnant women who stopped smoking recently showed a significant higher GWG (β=3.04; P=0.01); those with concurrent gestational diabetes mellitus (GDM) (β=3.54; P=0.03) and those who consumed alcohol on a regular base (β=3.69; P=0.04) showed significant higher levels of state anxiety. No differences in depressed mood or obstetrical/neonatal outcomes were observed between the three groups.Conclusions:A targeted lifestyle intervention programme based on the principles of motivational interviewing reduces GWG and levels of anxiety in obese pregnant women.

Association of gestational weight gain with maternal and infant outcomes: A systematic review and meta-analysis

Importance Body mass index (BMI) and gestational weight gain are increasing globally. In 2009, the Institute of Medicine (IOM) provided specific recommendations regarding the ideal gestational weight gain. However, the association between gestational weight gain consistent with theIOM guidelines and pregnancy outcomes is unclear. Objective To perform a systematic review, meta-analysis, and metaregression to evaluate associations between gestational weight gain above or below the IOM guidelines (gain of 12.5-18 kg for underweight women [BMI <18.5]; 11.5-16 kg for normal-weight women [BMI 18.5-24.9]; 7-11 kg for overweight women [BMI 25-29.9]; and 5-9 kg for obese women [BMI ≥30]) and maternal and infant outcomes. Data Sources and Study Selection Search of EMBASE, Evidence-Based Medicine Reviews, MEDLINE, and MEDLINE In-Process between January 1, 1999, and February 7, 2017, for observational studies stratified by prepregnancy BMI category and total gestational weight gain. Data Extraction and Synthesis Data were extracted by 2 independent reviewers. Odds ratios (ORs) and absolute risk differences (ARDs) per live birth were calculated using a random-effects model based on a subset of studies with available data. Main Outcomes and Measures Primary outcomes were small for gestational age (SGA), preterm birth, and large for gestational age (LGA). Secondary outcomes were macrosomia, cesarean delivery, and gestational diabetes mellitus. Results Of 5354 identified studies, 23 (n = 1 309 136 women) met inclusion criteria. Gestational weight gain was below or above guidelines in 23% and 47% of pregnancies, respectively. Gestational weight gain below the recommendations was associated with higher risk of SGA (OR, 1.53 [95% CI, 1.44-1.64]; ARD, 5% [95% CI, 4%-6%]) and preterm birth (OR, 1.70 [1.32-2.20]; ARD, 5% [3%-8%]) and lower risk of LGA (OR, 0.59 [0.55-0.64]; ARD, −2% [−10% to −6%]) and macrosomia (OR, 0.60 [0.52-0.68]; ARD, −2% [−3% to −1%]); cesarean delivery showed no significant difference (OR, 0.98 [0.96-1.02]; ARD, 0% [−2% to 1%]). Gestational weight gain above the recommendations was associated with lower risk of SGA (OR, 0.66 [0.63-0.69]; ARD, −3%; [−4% to −2%]) and preterm birth (OR, 0.77 [0.69-0.86]; ARD, −2% [−2% to −1%]) and higher risk of LGA (OR, 1.85 [1.76-1.95]; ARD, 4% [2%-5%]), macrosomia (OR, 1.95 [1.79-2.11]; ARD, 6% [4%-9%]), and cesarean delivery (OR, 1.30 [1.25-1.35]; ARD, 4% [3%-6%]). Gestational diabetes mellitus could not be evaluated because of the nature of available data. Conclusions and Relevance In this systematic review and meta-analysis of more than 1 million pregnant women, 47% had gestational weight gain greater than IOM recommendations and 23% had gestational weight gain less than IOM recommendations. Gestational weight gain greater than or less than guideline recommendations, compared with weight gain within recommended levels, was associated with higher risk of adverse maternal and infant outcomes.

Fetoscopic Laser Surgery in 100 Pregnancies with Severe Twin-to-Twin Transfusion Syndrome in the Netherlands

Objective: In this prospective cohort study, we evaluated the initial results of fetoscopic laser surgery for severe second trimester twin-to-twin transfusion syndrome (TTTS) treated at our centre. Method: A total of 100 consecutive pregnancies with severe second trimester TTTS treated at our centre with selective fetoscopic laser coagulation of vascular anastomoses on the placental surface between August 2000 and November 2004 were included in the study. Perinatal survival was analysed in relation to Quintero stage. Results: Median gestational age was 20 weeks at fetoscopy (range: 16–26) and 33 weeks at delivery (range: 18–40). Perinatal survival rate was 70% (139/200). The treatment resulted in at least one survivor at the age of 4 weeks in 81% of pregnancies. Perinatal survival was significantly higher when treatment was performed in the early Quintero stages (95% in stage 1, 76% in stage 2, 70% in stage 3, 50% in stage 4) (p = 0.02). Conclusion: Results of fetoscopic laser surgery for TTTS in our centre are similar to those in specialised centres in other countries. Diagnosis and treatment in the early Quintero stages resulted in significantly higher perinatal survival.

Prenatal diagnosis, prediction of outcome and in utero therapy of isolated congenital diaphragmatic hernia.

Congenital diaphragmatic hernia (CDH) can be associated with genetic or structural anomalies with poor prognosis. In isolated cases, survival is dependent on the degree of lung hypoplasia and liver position. Cases should be referred in utero to tertiary care centers familiar with this condition both for prediction of outcome as well as timed delivery. The best validated prognostic indicator is the lung area to head circumference ratio. Ultrasound is used to measure the lung area of the index case, which is then expressed as a proportion of what is expected normally (observed/expected LHR). When O/E LHR is < 25% survival chances are < 15%. Prenatal intervention, aiming to stimulate lung growth, can be achieved by temporary fetal endoscopic tracheal occlusion (FETO). A balloon is percutaneously inserted into the trachea at 26–28 weeks, and reversal of occlusion is planned at 34 weeks. Growing experience has demonstrated the feasibility and safety of the technique with a survival rate of about 50%. The lung response to, and outcome after FETO, is dependent on pre‐existing lung size as well gestational age at birth. Early data show that FETO does not increase morbidity in survivors, when compared to historical controls. Several trials are currently under design. Copyright

Validation of the fetal myocardial performance index in the second and third trimesters of gestation

To test the validity of the myocardial performance index (MPI) and its components against the more conventional methods of fetal cardiac function assessment: the ejection fraction (EF) for systolic function and the E/A index (ratio of transmitral flow during early (E) ventricular filling to flow during atrial (A) contraction) for diastolic function, both in a normal population and in a population at risk for cardiac failure because of volume overload (recipient fetuses in cases of twin–twin transfusion syndrome (TTTS)).

Preterm Prelabor Rupture of Membranes and Fetal Survival after Minimally Invasive Fetal Surgery: A Systematic Review of the Literature

Objective: Iatrogenic preterm prelabor rupture of membranes (iPPROM; <37 weeks of gestation) is a major complication of fetal surgery. Little information is available about risk factors and incidence. Methods: We systematically reviewed reported iPPROM rates, gestational age at delivery and fetal survival after representative minimally invasive antenatal procedures. Results: A total of 1,146, 36 and 194 cases with mean iPPROM rates of 27, 31 and 26% were included for placental laser in twin-twin transfusion syndrome, shunting in lower urinary tract obstruction and interventions for twin-reversed arterial perfusion, respectively. In the statistical analysis, the maximum diameter of the instrument predicted iPPROM rate and was significantly related to gestational age at birth as well as fetal survival. Information on duration of the respective procedures was scarce and did not allow for meaningful analysis. Conclusions: iPPROM occurs in about 30% of cases treated by minimally invasive fetal surgery. The maximum diameter of the instrument explains iPPROM rate, gestational age at birth and fetal survival. Great variations in the reporting of iPPROM make data analysis difficult.