Fetal Diagnosis and Therapy

Small fetuses are defined as those with an ultrasound estimated weight below a threshold, most commonly the 10th centile. The first clinically relevant step is the distinction of ‘true' fetal growth restriction (FGR), associated with signs of abnormal fetoplacental function and poorer perinatal outcome, from constitutional small-for-gestational age, with a near-normal perinatal outcome. Nowadays such a distinction should not be based solely on umbilical artery Doppler, since this index detects only early-onset severe forms. FGR should be diagnosed in the presence of any of the factors associated with a poorer perinatal outcome, including Doppler cerebroplacental ratio, uterine artery Doppler, a growth centile below the 3rd centile, and, possibly in the near future, maternal angiogenic factors. Once the diagnosis is established, differentiating into early- and late-onset FGR is useful mainly for research purposes, because it distinguishes two clear phenotypes with differences in severity, association with preeclampsia, and the natural history of fetal deterioration. As a second clinically relevant step, management of FGR and the decision to deliver aims at an optimal balance between minimizing fetal injury or death versus the risks of iatrogenic preterm delivery. We propose a protocol that integrates current evidence to classify stages of fetal deterioration and establishes follow-up intervals and optimal delivery timings, which may facilitate decisions and reduce practice variability in this complex clinical condition.

Objective: To develop models for prediction of preeclampsia (PE) based on maternal characteristics, biophysical and biochemical markers at 11–13 weeks’ gestation in which the gestation at the time of delivery for PE is treated as a continuous variable. Methods: This was a screening study of singleton pregnancies at 11–13 weeks including 1,426 (2.4%) that subsequently developed PE and 57,458 that were unaffected by PE. We developed a survival time model for the time of delivery for PE in which Bayes’ theorem was used to combine the prior information from maternal characteristics with uterine artery pulsatility index (PI), mean arterial pressure (MAP), serum pregnancy-associated plasma protein-A (PAPP-A) and placental growth factor (PLGF) multiple of the median (MoM) values. Results: In pregnancies with PE, there was a linear correlation between MoM values of uterine artery PI, MAP, PAPP-A and PLGF with gestational age at delivery and therefore the deviation from normal was greater for early than late PE for all four biomarkers. Screening by maternal characteristics, biophysical and biochemical markers detected 96% of cases of PE requiring delivery before 34 weeks and 54% of all cases of PE at a fixed false-positive rate of 10%. Conclusions: A new model has been developed for effective first-trimester screening for PE.

<b><i>Objective:</i></b> To compare the effect of early administration of aspirin on the risk of preterm and term preeclampsia. <b><i>Method:</i></b> A systematic review and meta-analysis of randomized controlled trials were performed. Women who were randomized to low-dose aspirin or placebo/no treatment at or before 16 weeks of gestation were included. The outcomes of interest were preterm preeclampsia (delivery <37 weeks) and term preeclampsia. Pooled relative risks (RR) with their 95% confidence intervals (CI) were computed. <b><i>Results:</i></b> The search identified 7,941 citations but only five trials on a combined total of 556 women fulfilled the inclusion criteria. When compared to controls, aspirin initiated ≤16 weeks of gestation was associated with a major reduction of the risk of preterm preeclampsia (RR 0.11, 95% CI 0.04–0.33) but had no significant effect on term preeclampsia (RR 0.98, 95% CI 0.42–2.33). <b><i>Conclusion:</i></b> Low-dose aspirin administrated at or before 16 weeks of gestation reduces the risk of preterm but not term preeclampsia.

<i>Objective:</i> To determine maternal serum placental protein 13 (PP13) in normal pregnancy and preeclampsia. <i>Methods:</i> A prospective, longitudinal study with 41 normal pregnant women, 18 cases with preterm delivery or cervix insufficiency and 4 with developing late-onset preeclampsia. Six hundred and sixty-six maternal blood samples were obtained every 2–4 weeks starting at 5–8 weeks gestation (10–12 samples/patient) and tested for serum PP13 by ELISA. <i>Results:</i> In normal pregnant women delivering at term, median maternal serum PP13 levels were growing from 166 to 202 pg/ml and 382 pg/ml in the first, second and third trimester, respectively. Preeclamptic women had significantly reduced PP13 levels in the first trimester (multiples of median of 0.14 at 7–8 weeks; p = 0.005 compared to normal). PP13 in the third trimester was significantly higher compared to normal at 35–36 weeks with PP13 multiples of median of 1.79. <i>Conclusion:</i> This preliminary study indicates that low levels of PP13 in early pregnancy identify at-risk pregnancies, whereas high levels precede the syndrome in late pregnancy and suggest syncytiotrophoblast necrosis.

In spite of active perinatal management, twin-twin transfusion syndrome (TTTS) remains a severe disease with a high risk of neonatal mortality and morbidity. TTTS initially results from an unbalanced blood flow from a donor to a recipient twin. However, its pathogenesis remains unclear, although cardiovascular disturbances and regulation of fetal volemia and diuresis seem central in this syndrome. Previously, we demonstrated that the renin-angiotensin system (RAS) was up-regulated in donor twins as a consequence of hypovolemia, and down-regulated in recipients. This was the first evidence of the implication of the RAS in TTTS. We hypothesize that the RAS plays a key role in the pathogenesis of TTTS. In the donor, RAS up-regulation aggravates oligohydramnios and may increase arterial resistance, which could contribute to placental dysfunction leading to intrauterine growth restriction. In the recipient, paradoxical RAS activation, due to transfer of effectors such as angiotensin II through placental shunts, could explain fetal vascular disturbances and cardiomyopathy. According to our hypothesis, TTTS would appear similar to the classical model of hypertension referred to as ‘2 kidneys-1 clip’ with a donor twin, comparable to the clipped kidney, intoxicating its cotwin, comparable to the normal kidney.

<i>Background:</i> OK-432, a lyophilised incubation mixture of group A <i>Streptococcus pyogenes</i> of human origin, was used as a sclerosant for the involution of a giant cervical cystic hygroma in a newborn. <i>Results:</i> There were no systemic side effects. Blood tests and double immune diffusion tests showed no systemic infection or generalised inflammatory response, or antibody production. Cellular and cytokine-induced localised inflammatory reaction within the cystic hygroma, was observed on analysis of the intracystic fluid. <i>Conclusions:</i> The leucocytosis induced and activated by OK-432 probably increases the endothelial permeability of the lymphatics. This probably accelerated lymph drainage leading to involution of the cystic hygroma. Intralesional injection of OK-432 was safe and effective therapy for cystic hygroma in this newborn as its inflammatory reaction was localised.

<b><i>Introduction:</i></b> Fetal amniotic membranes (FM) have been shown to preserve spinal cord histology in the fetal sheep model of myelomeningocele (MMC). This study compares the effectiveness of placenta-derived mesenchymal stromal cells (PMSCs) from early-gestation versus term-gestation placenta to augment FM repair to improve distal motor function in a sheep model. <b><i>Methods:</i></b> Fetal lambs (n = 4) underwent surgical MMC creation followed by repair with FM patch with term-gestation PMSCs (n = 1), FM with early-gestation PMSCs (n = 1), FM only (n = 1), and skin closure only (n = 1). Histopathology and motor assessment was performed. <b><i>Results:</i></b> Histopathologic analysis demonstrated increased preservation of spinal cord architecture and large neurons in the lamb repaired with early-gestation cells compared to all others. Lambs repaired with skin closure only, FM alone, and term-gestation PMSCs exhibited extremely limited distal motor function; the lamb repaired with early-gestation PMSCs was capable of normal ambulation. <b><i>Discussion:</i></b> This pilot study is the first in vivo comparison of different gestational-age placenta-derived stromal cells for repair in the fetal sheep MMC model. The preservation of large neurons and markedly improved motor function in the lamb repaired with early-gestation cells suggest that early-gestation placental stromal cells may exhibit unique properties that augment in utero MMC repair to improve paralysis.

<i>Objective:</i> Spectral analysis was conducted on fetal heart rate fluctuations for the purpose of investigating the change in gestational age and examining the usefulness as a method of estimating fetal blood gas. <i>Study Design:</i> Five hundred and twenty-nine pregnant women with a single normal fetus and 26 women with intrauterine growth restriction (IUGR) were studied during the 20th to 38th gestational weeks. In cases of IUGR, fetal blood gas levels were evaluated with percutaneous umbilical blood sampling. A time series of fetal heart rate fluctuation was obtained with a 1.15-MHz ultrasonic transducer, and power spectral analysis of 200 consecutive stable beats was performed with an autoregression method. Integrated areas of 0.025–0.125 cycles/beat were defined as low-frequency areas (LFAs) and were examined in normal fetuses. In addition, the relation between LFA and fetal blood gas values was studied. <i>Results:</i> As pregnancy progressed, LFA increased with a cubic regression equation (Y = 6.484 – 0.764X + 0.029X² – 0.00034X³). The correlation coefficient was 0.625 (p < 0.05). In the cases of IUGR, ΔLFA was highly correlated with ΔpO₂ and ΔpH (correlation coefficient, 0.650 and 0.618, respectively). <i>Conclusions:</i> Measurement of LFA provides insight into the development of fetal autonomic function and also may serve as a quantitative index of fetal well-being in mid-pregnancy.