Gene therapy for the fetus: is there a future?

Gene therapy uses the intracellular delivery of genetic material for the treatment of disease. A wide range of diseases - including cancer, vascular and neurodegenerative disorders and inherited genetic diseases - are being considered as targets for this therapy in adults. There are particular reasons why fetal application might prove better than application in the adult for treatment, or even prevention of early-onset genetic disorders such as cystic fibrosis and Duchenne muscular dystrophy. Research shows that gene transfer to the developing fetus targets rapidly expanding populations of stem cells, which are inaccessible after birth, and indicates that the use of integrating vector systems results in permanent gene transfer. In animal models of congenital disease such as haemophilia, studies show that the functionally immature fetal immune system does not respond to the product of the introduced gene, and therefore immune tolerance can be induced. This means that treatment could be repeated after birth, if that was necessary to continue to correct the disease. For clinicians and parents, fetal gene therapy would give a third choice following prenatal diagnosis of inherited disease, where termination of pregnancy or acceptance of an affected child are currently the only options. Application of this therapy in the fetus must be safe, reliable and cost-effective. Recent developments in the understanding of genetic disease, vector design, and minimally invasive delivery techniques have brought fetal gene therapy closer to clinical practice. However more research needs to be done in before it can be introduced as a therapy.     

Single umbilical artery: what does it mean for the fetus?

Single umbilical artery (SUA) is the most common anomaly of the umbilical cord which affects between 0.5 and 2.5% of all pregnancies. AIM: Our purpose was to determine whether there was a significant relationship between SUA and other anatomical anomalies. MATERIAL AND METHODS: All cases of fetal single umbilical artery identified in our hospital between 2002-2005 were reviewed for other ultrasound detected abnormalities. RESULTS: 18 cases of single umbilical artery were diagnosed on the basis of initial sonograms. 17 cases formed the study population (in 10 cases the left artery and in 7 the right artery was absent). In one case we diagnosed an umbilical cord tumor. 33.3% had other anatomical anomalies. The mean of women in the study was 30.5 years, the mean gestational age at examination was 28 weeks. CONCLUSIONS: In most cases the SUA occurs to be an isolated anomaly. In cases of SUA, the detailed ultrasound examination should be performed. Left artery absence is more common and also in these cases other anatomical anomalies are more likely to be observed as well. In our study we did not find a correlation between SUA and IUGR.     

Does the physiological acromegaly of pregnancy benefit the fetus?

Pregnancy is accompanied by notable changes in the secretion of growth hormone (GH) and the insulin-like growth factors (IGFs). A GH variant produced by the placenta is discernible in maternal plasma from early pregnancy, rising exponentially until 37 weeks. Meanwhile, pituitary GH gradually drops to near-undetectable levels. While there might be a modest reduction in circulating IGF-I in early pregnancy, IGF-I increases 2- to 3-fold in the second half, again with a peak at around 37 weeks. Thus, placental GH is believed to replace pituitary GH as the primary stimulus for IGF-I secretion in pregnancy. Several IGF-binding proteins (IGFBPs) including IGFBP-3 are proteolyzed, leading to an elevated free (bioavailable) IGF-I fraction. IGF-II concentrations also appear to show a modest (20-25%) increase in the course of pregnancy. The possible clinical manifestations include edema of face and forearms and carpal tunnel symptoms, reminiscent of the symptoms of acromegaly and the side effects of GH/IGF-I treatment. Neither placental GH nor the maternal IGFs cross the placental barrier, yet evidence from preclinical models is accumulating that they promote trophoblast invasion, placenta growth and maturation, transplacental nutrient transport and, ultimately, fetal growth. The ensemble data strongly suggest that 'gestational acromegaly' develops in order to foster fetoplacental growth.     

A symposium on obstetrical ultrasound: is all this safe for the fetus?

Diagnostic ultrasound is a form of energy that has the potential for effects in tissues (bioeffects). The 2 most likely mechanisms are heating and cavitation. The thermal index (TI) expresses the potential for rise in temperature. The MI indicates the potential for the ultrasound to induce inertial cavitation. Scarce data exist regarding instrument's acoustic output for routine ultrasound examinations. Data collected during routine ultrasound examinations (first trimester for viability, nuchal translucency, anatomy surveys including 3-dimensional/4-dimensional studies and growth studies) show that "gray-scale" B-mode ultrasound is associated with a negligible rise in TI. However, Doppler studies show significantly higher levels of TI, which can reach 1.5 and above.     

Is an atherogenic lipoprotein profile in the fetus a prerequisite for placental vascular disease?

Objective To measure the blood apolipoprotein A-1 and apolipoprotein B in the fetal circulation in normal pregnancy and in pregnancy with evidence of vascular disease in the fetal umbilical placental circulation defined in the antenatal period by Doppler ultrasound study.
Design An observational study to compare fetal plasma apolipoprotein levels in normal and complicated pregnancy.
Setting A university hospital tertiary referral obstetric unit.
Samples Umbilical vein blood was collected at delivery from 22 normal fetuses delivered by elective caesarean section for non fetal reasons and 30 fetuses with evidence of umbilical placental vascular disease identified antenatally by Doppler ultrasound study.
Methods Plasma apolipoprotein A-1 and B were determined using an enzyme-linked immunosorbent assay (ELISA) methods.
Main outcome measures Fetal plasma levels of apolipoprotein A-1 and B were measured.
Results There was a significantly lower level of fetal plasma apolipoprotein A-1 in placental insufficiency [placental insufficiency vs normal pregnancy, median 0.30 g/L (interquartile range 0.24, 0.39 g/L) vs 0.35 g/L (0.31, 0.42 g/L),   P = 0.045  ]. In contrast, the levels of fetal plasma apolipoprotein B in placental insufficiency [0.20 g/L (0.17, 0.26 g/L)] were significantly increased compared with normal pregnancy [0.16 g/L (0.14, 0.20 g/L),   P = 0.03  ]. The ratio of fetal plasma apolipoprotein B to A-1 was also substantially higher in placental insufficiency [0.68 (0.55, 0.83)] than in normal pregnancy [0.45 (0.36, 0.60),   P = 0.0003  ].
Conclusions Our study has demonstrated that levels of fetal plasma apolipoprotein A-1, apolipoprotein B and the ratio of apolipoprotein B to A-1 were altered in the fetuses who are victims of umbilical placental insufficiency in the same direction as in adults associated with a high risk of atherogenesis.     

Post mortem brain MRI: an alternative for pathology examination in Bourneville tuberous sclerosis of the fetus?

Antenatal discovery of cardiac rhabdomyomes evokes the diagnosis of Bourneville's disease. Antenatal brain exploration with ultrasonography and magnetic resonance imaging (MRI) can highlight cerebral localizations. In the event of termination of pregnancy, confirmation of the cerebral lesions can be achieved with post mortem MRI as well as pathology examination. MRI can be usefully employed in the event pathology examination is not feasible.     

Is the liver of the fetus the 4th preferential organ for arterial blood supply besides brain, heart, and adrenal glands?

In this study we compared the distribution of blood flow to the liver in growth-retarded fetuses whose estimated weight was < 5th centile with normal-weight fetuses. As expected, the relative venous blood flow to the liver was reduced, with blood flowing preferentially through the ductus venosus. However, the total blood supply seemed to be maintained by a concomitant, significant increase in arterial blood flow through the hepatic artery. Absolute flow velocities such as the peak, minimum diastolic and temporal average velocities were changed, as was the flow waveform. Effectively, the deficiency in venous supply was made up for by an increase in arterial blood flow. This compensatory effect may be crucial for maintaining liver function in times of low portal venous blood supply. It thus makes sense to regard the liver as the fourth preferential organ for arterial blood supply in the compromised fetus, besides heart, brain, and adrenals.     

Is fetus able to feel pain?

On the basis of fetal hormonal and hemodynamic responses to pain related stimuli, neuroanatomy and observations of preterm babies, it was concluded that human fetus is able to feel pain after 24 weeks gestation. However it is possible that the fetus may feel pain even before that time. With the development of intrauterine diagnostic and therapeutic procedures, it is crucial to provide fetuses undergoing painful procedures not only with anesthesia but also analgesia. The article presents fetal pain research history and its implications for medicine.     

Mother v fetus: who wins?

This article examines the right of pregnant women to determine what will happen to their own bodies and whether their right to autonomy is absolute when refusing treatment which may be consider in their best interests and/or their fetuses'. A theoretical framework is used supported by relevant legal cases to argue that in some instance the rights of women to refuse treatment, most notably caesarean section have been overridden in favour of the fetus. The conclusion from the legal cases is that despite the consequences a woman's rights should not be overridden in favour of the fetus.     

Are histopathologic chorioamnionitis and funisitis associated with metabolic acidosis in the preterm fetus?

OBJECTIVE: Perinatal infection increases the risk of neonatal neurologic injury. Our objective is to determine whether histologically confirmed chorioamnionitis and funisitis is associated with fetal metabolic acidosis. STUDY DESIGN: This is a retrospective cohort study of all infants 34 weeks or less born at a single tertiary hospital admitted to the neonatal intensive care unit (NICU) between April 1999 and September 2002. Maternal and neonatal records and placental pathology reports were reviewed. RESULTS: There were 392 infants at 23 to 34 weeks' gestational age admitted to the NICU during this period of whom 354 had placental pathology reported; 259 infants had umbilical cord gases available. These neonates were placed into 3 groups: group 1 (208 infants) had no signs of placental infection, group 2 (59 infants) had isolated chorioamnionitis, and group 3 (87 infants) had both chorioamnionitis and funisitis. The gestational age (30.2 +/- 2.8, 28.3 +/- 3.4, 27.8 +/- 2.8 weeks, P < .01) and birth weight (1358 +/- 520, 1242 +/- 547, 1103 +/- 381 g, P < .01) were significantly higher in group 1. There was an increase in neurologic morbidity in groups 2 and 3 (25.2%, 34.4%, 43.7%), which was not significant when corrected for gestational age. Groups 2 and 3 had a small but significant increase in umbilical arterial pH (7.25 +/- 0.10, 7.29 +/- 0.10, 7.30 +/- 0.08, P < .01) and base excess (-3.5 +/- 3.6, -2.2 +/- 3.6, -2.3 +/- 2.7 mmol/L, P = .02). When a single pathologist reviewed all placentas with any inflammation and staged them on the basis of the degree of the fetal inflammatory response, no relationship was found between the degree of fetal inflammation and umbilical arterial pH (stage 1, 7.27 +/- 0.09; stage 2, 7.30 +/- 0.09; stage 3, 7.30 +/- 0.08; P = .41) or base excess (stage 1, -2.82 +/- 3.47 mmol/L; stage 2, -1.95 +/- 3.17 mmol/L; stage 3, -2.23 +/- 3.07 mmol/L; P = .62). When stepwise multiple linear regression was performed, neither histologic chorioamnionitis nor histologic funisitis were associated with a change in umbilical cord pH or base excess. CONCLUSION: Intrauterine infection, as confirmed by histologic chorioamnionitis and funisitis, is not associated with fetal metabolic acidosis. Intrauterine infection may represent a nonhypoxic form of encephalopathy that produces neurologic morbidity by a mechanism independent of hypoxia-ischemia leading to metabolic acidosis.     

Clinical usefulness of pulse oximetry in the fetus with non-reassuring heart rate pattern?

The objective of this study was the evaluation of intrapartum pulse oximetry as an indicator of fetal distress and the condition of the newborn during clinical routine surveillance in an University Perinatal Center. Between 1998 and 1999 pulse oximetry (SpO2) was used additionally to routine fetal monitoring by electronic fetal heart rate tracing (CTG) and fetal blood sampling (FBA) in 128 cases with nonreassuring heart rate pattern. Cut off values were FIGO Score < 8 for the heart rate pattern and for fetal blood sampling during labor results of < 7.25 (preacidosis). The condition of the newborn was defined by the APGAR score with the cut off < 7 at 1 minute, while the biochemical status was evaluated by means of arterial blood sampling of the umbilical artery directly after birth using a pH of < 7.20 to verify acidosis. Predictive values of critically low SpO2 values (< 30%) for at least 10 minutes as well as corresponding sensitivities and specificities were calculated together with 95% confidence intervals to identify fetal distress or a depressed condition of the newborns. Of 128 fetuses included in this study 66 (52%) were born spontaneously, 23 (18%) were born by operative vaginal delivery and 39 (31%) by means of cesarean section. The high rate of cesarean section was due to cephalopelvic disproportion in 29 cases. Fetal outcome was evaluated with a clinical score: mean APGAR score value 8.5 SD +/- 1. The mean value of the pH in the umbilical artery was 7.23 +/- 0.04. During a SpO2 monitoring period of 18,381 minutes we analyzed a contact time of 63%. Comparing SpO2 values of < 30% with preacidosis in the fetal blood sampling, we found a positive predictive value of merely 0.17 (95% CI: 0.00-0.64). Of 9 preacidotic cases during delivery only 1 was indicated by a saturation value below 30% (sensitivity 0.11, 95% CI: 0.00-0.48). The specificity and negative predictive value were calculated as 0.83 (95% CI: 0.65-0.94) and 0.76 (95% CI: 0.58-0.89) respectively. Of eleven cases with acidosis in the blood of the umbilical cord artery, pH < 7.20, only 2 were indicated by a SpO2 values below 30%. Which is equivalent to a sensitivity of 0.18 (95% CI: 0.03-0.52). Results of a receiver operator curve analysis showed no substantial deviation from the diagonal. The area under the curve was 0.62, the 95% CI (0.47-0.76) indicating no significant discrimination. Three of 49 fetuses with SpO2 recording during the last 10 minutes were born in clinical depressed status (APGAR < 7). None was indicated by a SpO2 value below 30%. CONCLUSION: Fetal distress and impaired condition of the newborn are not identified or predicted during routine application of SpO2 monitoring in the fetus during labor with adequate safety.     

What antepartum fetal test should guide the timing of delivery of the preterm growth-restricted fetus? A decision-analysis

OBJECTIVE: The purpose of this study was to use a decision-analytic approach to explore the best strategy for the timing of the delivery of preterm intrauterine growth-restricted fetuses. STUDY DESIGN: We constructed a decision-analysis model that compared 4 antenatal fetal testing strategies The fetal/neonatal states that were compared included live in utero pregnancy; fetal death; neonatal death; disabled neonate, and healthy neonate. Probability estimates for these states and sensitivity and specificity for Doppler velocimetry and biophysical profile were derived from literature review. Sensitivity analyses were performed on the baseline assumptions. RESULTS: Under the baseline assumptions, biophysical profile was the best test to guide decisions on delivery. Sensitivity analyses revealed the model to be sensitive only to the specificity of a biophysical profile <82%. CONCLUSION: Compared with the other options, biophysical profile was the best strategy to guide physicians on the timing of the delivery of the preterm growth-restricted fetus.     

When is a post-mortem skeletal survey of the fetus indicated,and when not?

Objective: Radiography after fetal or perinatal death has become a routine part of post-mortem diagnostics. However, only a selected subset of these babygrams or fetal post-mortem skeletal surveys (FPSSs) provides useful information. We investigated the indication for a FPSS.

Methods: Inclusion consisted of the routinely made FPSS (2002–2012) in our university hospital in cases of fetal or perinatal death up to 7 days after birth. We categorized the diagnostic value of the FPSS as no, minor, major or pathognomonic. Regression analysis was used to determine the selection criteria for a useful FPSS.

Results: Three hundred and thirty-seven FPSS were included. Three hundred and five (91%) FPSS showed no or minor skeletal malformations. Fourteen (4.2%) FPSS had major skeletal malformations. In 18 (5.3%) cases the diagnosis was based on the pathognomonic skeletal malformations on the FPSS. Two cases were false positive after major birth trauma. The presence of multiple skeletal malformations on prenatal ultrasound or at post-mortem external inspection was highly indicative of a diagnostic FPSS (p < 0.001).

Conclusion: The majority of the babygrams/FPSS has no contribution to the diagnostic process. Multiple skeletal malformations on prenatal ultrasound or post-mortem external inspection are indicative for a diagnostic FPSS, and this should be the main selection criterion.