Tullia Todros

International standards for fetal growth based on serial ultrasound measurements: the Fetal Growth Longitudinal Study of the INTERGROWTH-21st Project

BACKGROUND In 2006, WHO produced international growth standards for infants and children up to age 5 years on the basis of recommendations from a WHO expert committee. Using the same methods and conceptual approach, the Fetal Growth Longitudinal Study (FGLS), part of the INTERGROWTH-21(st) Project, aimed to develop international growth and size standards for fetuses. METHODS The multicentre, population-based FGLS assessed fetal growth in geographically defined urban populations in eight countries, in which most of the health and nutritional needs of mothers were met and adequate antenatal care was provided. We used ultrasound to take fetal anthropometric measurements prospectively from 14 weeks and 0 days of gestation until birth in a cohort of women with adequate health and nutritional status who were at low risk of intrauterine growth restriction. All women had a reliable estimate of gestational age confirmed by ultrasound measurement of fetal crown-rump length in the first trimester. The five primary ultrasound measures of fetal growth--head circumference, biparietal diameter, occipitofrontal diameter, abdominal circumference, and femur length--were obtained every 5 weeks (within 1 week either side) from 14 weeks to 42 weeks of gestation. The best fitting curves for the five measures were selected using second-degree fractional polynomials and further modelled in a multilevel framework to account for the longitudinal design of the study. FINDINGS We screened 13,108 women commencing antenatal care at less than 14 weeks and 0 days of gestation, of whom 4607 (35%) were eligible. 4321 (94%) eligible women had pregnancies without major complications and delivered live singletons without congenital malformations (the analysis population). We documented very low maternal and perinatal mortality and morbidity, confirming that the participants were at low risk of adverse outcomes. For each of the five fetal growth measures, the mean differences between the observed and smoothed centiles for the 3rd, 50th, and 97th centiles, respectively, were small: 2·25 mm (SD 3·0), 0·02 mm (3·0), and -2·69 mm (3·2) for head circumference; 0·83 mm (0·9), -0·05 mm (0·8), and -0·84 mm (1·0) for biparietal diameter; 0·63 mm (1·2), 0·04 mm (1·1), and -1·05 mm (1·3) for occipitofrontal diameter; 2·99 mm (3·1), 0·25 mm (3·2), and -4·22 mm (3·7) for abdominal circumference; and 0·62 mm (0·8), 0·03 mm (0·8), and -0·65 mm (0·8) for femur length. We calculated the 3rd, 5th 10th, 50th, 90th, 95th and 97th centile curves according to gestational age for these ultrasound measures, representing the international standards for fetal growth. INTERPRETATION We recommend these international fetal growth standards for the clinical interpretation of routinely taken ultrasound measurements and for comparisons across populations. FUNDING Bill & Melinda Gates Foundation.

Fetal cerebral ventriculomegaly: outcome in 176 cases

To evaluate the outcome of fetuses affected by different degrees of ventriculomegaly.

Umbilical doppler waveforms and placental villous angiogenesis in pregnancies complicated by fetal growth restriction

OBJECTIVE To test the hypothesis that the characteristics of umbilical artery Doppler flow velocity waveforms in growth-restricted fetuses indicate angiogenesis within placental stem and gas-exchanging villi. METHODS We examined 18 placentas from singleton fetuses that were normal structurally and chromosomally but were growth-restricted, preterm, and complicated by preeclampsia. Ten cases with positive end-diastolic flow and eight with absent or reverse end-diastolic flow were compared with six gestational age-matched controls. Sections of villous placenta were examined to determine structural composition (percentage of fibrinoid, intervillous space, and villous tissue), relative proportion of villous types (stem, immature intermediate, and gas-exchanging villi), and the frequency distribution of stem arterial vessel calibers and their branching pattern. RESULTS Placentas with positive end-diastolic flow had a significantly (P < .05) higher percentage of gas-exchanging villi (median 69.6%, range 62.5-80.8%) than those with absent or reverse end-diastolic flow (58.3%, 29.9-71.9%) or controls (60.8%, 43.1-65.6%). The gas-exchanging villi from placentas with absent or reverse end-diastolic flow were slender, elongated, poorly branched, and poorly capillarized. There was a progressive trend toward reduced branching of the stem arteries from the controls (median 22%, range 2-38%), through the positive end-diastolic group (17%, 11-20%), to the absent or reverse end-diastolic group (13%, 4-23%). CONCLUSION Compared with absent or reverse end-diastolic flow, the placentas from growth-restricted fetuses with positive end-diastolic flow showed a normal pattern of stem artery development, accompanied by increased capillary angiogenesis and terminal villous development. These features suggest an adaptive pathway for the placenta in the face of uteroplacental ischemia.

Perinatal morbidity and mortality in early‐onset fetal growth restriction: cohort outcomes of the trial of randomized umbilical and fetal flow in Europe (TRUFFLE)

Few data exist for counseling and perinatal management of women after an antenatal diagnosis of early‐onset fetal growth restriction. Yet, the consequences of preterm delivery and its attendant morbidity for both mother and baby are far reaching. The objective of this study was to describe perinatal morbidity and mortality following early‐onset fetal growth restriction based on time of antenatal diagnosis and delivery.

2 year neurodevelopmental and intermediate perinatal outcomes in infants with very preterm fetal growth restriction (TRUFFLE): A randomised trial

BACKGROUND No consensus exists for the best way to monitor and when to trigger delivery in mothers of babies with fetal growth restriction. We aimed to assess whether changes in the fetal ductus venosus Doppler waveform (DV) could be used as indications for delivery instead of cardiotocography short-term variation (STV). METHODS In this prospective, European multicentre, unblinded, randomised study, we included women with singleton fetuses at 26-32 weeks of gestation who had very preterm fetal growth restriction (ie, low abdominal circumference [<10th percentile] and a high umbilical artery Doppler pulsatility index [>95th percentile]). We randomly allocated women 1:1:1, with randomly sized blocks and stratified by participating centre and gestational age (<29 weeks vs ≥29 weeks), to three timing of delivery plans, which differed according to antenatal monitoring strategies: reduced cardiotocograph fetal heart rate STV (CTG STV), early DV changes (pulsatility index >95th percentile; DV p95), or late DV changes (A wave [the deflection within the venous waveform signifying atrial contraction] at or below baseline; DV no A). The primary outcome was survival without cerebral palsy or neurosensory impairment, or a Bayley III developmental score of less than 85, at 2 years of age. We assessed outcomes in surviving infants with known outcomes at 2 years. We did an intention to treat study for all participants for whom we had data. Safety outcomes were deaths in utero and neonatal deaths and were assessed in all randomly allocated women. This study is registered with ISRCTN, number 56204499. FINDINGS Between Jan 1, 2005 and Oct 1, 2010, 503 of 542 eligible women were randomly allocated to monitoring groups (166 to CTG STV, 167 to DV p95, and 170 to DV no A). The median gestational age at delivery was 30·7 weeks (IQR 29·1-32·1) and mean birthweight was 1019 g (SD 322). The proportion of infants surviving without neuroimpairment did not differ between the CTG STV (111 [77%] of 144 infants with known outcome), DV p95 (119 [84%] of 142), and DV no A (133 [85%] of 157) groups (ptrend=0·09). 12 fetuses (2%) died in utero and 27 (6%) neonatal deaths occurred. Of survivors, more infants where women were randomly assigned to delivery according to late ductus changes (133 [95%] of 140, 95%, 95% CI 90-98) were free of neuroimpairment when compared with those randomly assigned to CTG (111 [85%] of 131, 95% CI 78-90; p=0.005), but this was accompanied by a non-significant increase in perinatal and infant mortality. INTERPRETATION Although the difference in the proportion of infants surviving without neuroimpairment was non-significant at the primary endpoint, timing of delivery based on the study protocol using late changes in the DV waveform might produce an improvement in developmental outcomes at 2 years of age. FUNDING ZonMw, The Netherlands and Dr Hans Ludwig Geisenhofer Foundation, Germany.

Is three-dimensional power Doppler ultrasound useful in the assessment of placental perfusion in normal and growth-restricted pregnancies?

To investigate three‐dimensional (3D) power Doppler ultrasound indices in the assessment of placental perfusion and their relationship to gestational age (GA), placental position and umbilical artery Doppler flow velocity waveform (FVW) patterns in normal and intrauterine growth‐restricted (IUGR) pregnancies.

Accuracy of routine ultrasonography in screening heart disease prenatally

The aim of the present study was to assess the accuracy of the four‐chamber view as a screening test for detection of congenital heart disease (CHD) prenatally in a low‐risk population. A prospective observational study was conducted in 17 ultrasound units of the Piemonte Region, Italy, in pregnancies with no risk factors for CHD. At each routine scan, from 18 weeks of gestational age, the four‐chamber view of the heart was looked for. When an anomaly was suspected, the patients were referred to a specialized unit. Follow‐up of the babies until discharge from the hospital was obtained. 11 232 sonograms were performed on 8299 pregnancies. Cardiac malformations were diagnosed in 40 newborns (4·8/1000). Six of them (15 per cent) had been recognized in utero. The sensitivity, specificity, and positive and negative predictive values were 15, 99·9, 50, and 99·6 per cent, respectively. When malformations that are not associated with an abnormal four‐chamber view were excluded from the analysis, the sensitivity increased to 35·3 per cent. The sensitivity found in this study is low, but it is probably realistic since it is comparable to that reported in other multicentric studies. This type of study should reflect the state of the art of the method applied in the field. Although the sensitivity is low, it would be nil if the test were not performed. Moreover, it will probably increase with better training of the operators and by extending the examination to the ventriculo‐arterial connections.

Prenatal screening for congenital heart disease with four-chamber and outflow-tract views: a multicenter study

Congenital heart diseases (CHD) are the most common congenital anomalies, and most cases occur in the low‐risk population. Prenatal ultrasound screening based on visualization of the four‐chamber view has had disappointing results in detecting these anomalies thus far. The aim of this study was to evaluate the diagnostic accuracy of ultrasound screening based on the combination of the four‐chamber and outflow‐tract views.

The significance of fetal ventriculomegaly: etiology, short- and long-term outcomes

Fetal cerebral ventriculomegaly (VM) is diagnosed when the width of one or both ventricles, measured at the level of the glomus of the choroid plexus (atrium), is ≥ 10 mm. VM can result from different processes: abnormal turnover of the cerebrospinal fluid (CSF), neuronal migration disorders, and destructive processes. In a high percentage of cases, it is associated with structural malformations of the central nervous system (CNS), but also of other organs and systems. The rate of associated malformations is higher (≥60%) in severe VM (>15 mm) and lower (10–50%) in cases of borderline VM (10–15 mm). When malformations are not present, aneuploidies are found in 3–15% of borderline VM; the percentage is lower in severe VM. The neurodevelopmental outcome of isolated VM is normal in > 90% of cases if the measurement of ventricular width is between 10 and 12 mm; it is less favorable when the measurement is > 12 mm. Copyright

Pregnancy in dialysis patients: is the evidence strong enough to lead us to change our counseling policy?

BACKGROUND AND OBJECTIVES Although successful pregnancy is rare, results attained with higher dialysis efficiency and the spread of dialysis to different cultural and religious settings are changing the panorama. In this study, we systematically review the recent literature (2000 through 2008) on pregnancy in dialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Medline on OVID was searched in November 2008, with MESH and free terms on pregnancy and chronic kidney disease or dialysis; limits were human subjects and English-language articles. Case reports were excluded to minimize publication bias. The final selection and extraction of data were performed in duplicate. RESULTS From 2840 references, 241 full-text articles were retrieved; eight fulfilled the selection criteria, and two were added from reference lists. In the 10 studies (nine of 10 monocentric), 90 pregnancies were observed in 78 patients (range of cases five to 15). The studies were heterogeneous for definition of outcomes, duration (2 to 16 yr), period (1988 through 1998 to 2000 through 2006), age (25 to 35 yr), and support and dialysis therapy. Daily dialysis was frequently used; type of treatment, membranes, and flows varied widely. Hypertension and anemia were frequent concerns for the mothers. Intrauterine deaths, hydramnios, and small-for-gestational-age or preterm infants were frequent. The possibility of a healthy offspring ranged from 50 to 100% (overall 76.25%). CONCLUSIONS Evidence on pregnancy in dialysis is heterogeneous; however, the growing number of reports worldwide and the improving results suggest that we should reconsider our counseling policy, which only rarely includes pregnancy in dialysis patients.