PTEN, a tumor suppressor phosphatase, is important in the regulation of cell migration and invasion. Physiological regulation of PTEN phosphatase and tensin homolog deleted on chromosome 10 by cell surface receptors has not been described. Inactivation of the PTEN gene is frequently observed in many human malignancies, including cancer of the breast, prostate, brain, and gastrointestinal tract 3 — 5. Although the importance of the PTEN enzyme is appreciated, our knowledge of how this phosphatase is regulated under physiological conditions and how it is aberrantly regulated in pathology is limited.
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In August , the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institutes of Health Office of Rare Diseases, the American College of Obstetricians and Gynecologists, and the American Academy of Pediatrics cosponsored a 2-day workshop to reassess the body of evidence supporting antepartum assessment of fetal well-being, identify key gaps in the evidence, and formulate recommendations for further research.
Participants included experts in obstetrics and fetal physiology, and representatives from relevant stakeholder groups and organizations. This article is a summary of the discussions at the workshop, including synopses of oral presentations on the epidemiology of stillbirth and fetal neurological injury, fetal physiology, techniques for antenatal monitoring, and maternal and fetal indications for monitoring.
Finally, a synthesis of recommendations for further research compiled from three breakout workgroups is presented. Since the development of technologies for electronic fetal heart rate monitoring in the s, and with increasing sophistication of ultrasound and Doppler imaging, an array of techniques for antenatal assessment of fetal well being have been introduced into clinical practice.
The primary goal of antenatal testing is to identify fetuses at risk for intrauterine injury or death, so that these adverse outcomes can be prevented. Despite widespread use of these technologies, however, there is limited evidence to guide their appropriate application, or to demonstrate their effectiveness at improving perinatal outcomes. Experts were invited to summarize the current state of the art in antenatal testing methodology and indications, and to identify pressing research needs.
Evidence for a number of important issues was reviewed, including the extent to which antenatal testing decreases fetal death and long term neurological disability and how antenatal testing impacts gestational age at delivery and mode of delivery. This manuscript is an executive summary of the proceedings of the workshop. Detailed manuscripts by the individual attendees, based on their presentations, were collectively published in a recent issue of Seminars in Perinatology 1.
The ultimate goal of antepartum fetal monitoring is to improve perinatal outcome, specifically by decreasing stillbirth and longer term neurologic impairments such as injury to the fetal central nervous system. The rate of stillbirth is 6. Injury to the fetal central nervous system CNS is expressed after delivery in a number of clinical entities and syndromes with cerebral palsy the most common.
In contrast to stillbirth, where rates have declined, rates of cerebral palsy have been increasing, primarily due to increased survival of low birth weight and premature infants 3.
Both stillbirth and cerebral palsy have been associated with extremes of maternal age and parity, maternal obesity, African American race, prenatal smoking, maternal medical disease, use of assisted reproductive technologies, previously affected pregnancy, fetal anomalies, multiple pregnancy, fetal growth restriction, and male fetal sex 6. These similarities in risk factors suggest that fetal CNS injury and stillbirth may share a common pathway.
Some authors have postulated that observed trends in decreasing stillbirth rates may be contributing to increasing cerebral palsy rates, i. Fetal hypoxia and acidosis represent the final common pathway to fetal injury and death in many high risk pregnancies 7. The basis for antepartum testing relies on the premise that the fetus whose oxygenation in utero is challenged will respond with a series of detectable physiologic adaptive or decompensatory signs as hypoxemia or frank metabolic acidemia develop.
In one adaptive response to hypoxemia, blood flow is redirected to the brain, heart, and adrenals with subsequent decreased renal perfusion and fetal urine production, which may result in decreased amniotic fluid volume.
Fetal movement is an indirect indicator of central nervous system integrity and function 8. During acute hypoxemia, fetal movements decrease, as the fetus attempts to conserve energy. Loss of fetal movement raises concern for ongoing central nervous system hypoxia and injury. A chemoreceptor response to hypoxemia leads to vagally-mediated reflex slowing of the fetal heart rate FHR , which may appear clinically as late decelerations associated with uterine contractions. A number of investigators have described sequences of measurable changes in fetal blood flow and biophysical parameters that occur as placental insufficiency worsens and fetal hypoxemia and acidemia develop 9 ; Although the precise sequences of observed characteristics differ slightly in these reports, a general pattern of fetal response to intrauterine challenge emerges Figure 1.
Loss of FHR reactivity and abnormal blood flow in the umbilical artery are often the earliest signs of fetal compromise. Sequential changes in other fetal vessels are detectable next, followed by abnormalities in biophysical parameters such as fetal breathing movements, amniotic fluid levels, fetal body movements, and fetal tone.
Not all fetuses exhibiting the full range of these findings, however, will exhibit significant metabolic acidosis at birth. In a group of 34 liveborn infants with intrauterine growth restriction delivered because of progressive deterioration in Doppler and biophysical parameter assessments, while all had abnormal arterial cord blood pH median 7. Progression of Doppler and biophysical findings in severe fetal growth restriction. NST, nonstress test; absent or reversed end-diastolic flow; MCA, middle cerebral artery; DV, ductus venosus; fetal breathing movements.
The sequence of changes in Doppler and biophysical parameters as severe fetal growth restriction worsens. Ultrasound Obstet Gynecol ; In the normal fetus, fetal movements are first perceptible at 17 — 20 weeks and reach peak frequency at or before 38 weeks.
Fetal movement decreases in response to hypoxemia, making formalized maternal assessment of fetal movements a potentially simple method of monitoring fetal oxygenation and well being. Results of trials of routine fetal movement assessment for reduction of stillbirth have been mixed. The results of these trials are difficult to compare because of methodologic differences, particularly in how women were instructed to count movements and how decreased fetal movement was defined.
Some authors suggest that a more important predictor may be an overall maternal sense that fetal activity is reduced, and that any such report warrants further evaluation A recent systematic review 16 concluded that there is insufficient evidence to recommend routine fetal movement counting to prevent stillbirth.
Equivocal — suspicious: intermittent late decelerations or significant variable decelerations. Equivocal — hyperstimulatory: decelerations with contractions occurring more frequently than q 2 min.
The contraction stress test CST is based on the premise that uterine contractions transiently restrict oxygen delivery to the fetus and that a hypoxic fetus will demonstrate recurrent late decelerations. The rate of antepartum stillbirth within one week of a negative CST i.
Drawbacks to the CST include the need to stimulate contractions and the fact that inducing contractions is contraindicated in a number of conditions e.
A less intensive method, the nonstress test NST , grew from the observations that the presence of two or more fetal heart rate accelerations during a CST most often predicted a negative CST and that absence of accelerations on a baseline FHR tracing was associated with adverse perinatal outcomes The NST false negative rate is about 0.
NSTs should be performed at least twice weekly The risk of fetal death within one week of a normal biophysical assessment is 1 in In a large observational study, the false negative rate was 0. Measurement of blood flow velocities in the maternal and fetal vessels gives information about uteroplacental blood flow and fetal responses to physiologic challenges.
Of all the antenatal assessment methods, Doppler-based tests have been most rigorously evaluated in randomized trials. The information derived from velocity waveforms in different vessels varies according to the specific vessel assessed see Table 2. Failure of adequate trophoblast invasion and remodeling of maternal spiral arteries is characterized by persistent high-pressure uterine circulation and increased impedance to uterine artery blood flow.
A number of investigators have explored the use of UtA Doppler for third trimester fetal assessment among women with complicated pregnancies 32 - 34 , but its role in this setting has not been clearly defined.
Umbilical artery flow velocity waveforms of normally growing fetuses are characterized by high-velocity diastolic flow, while in growth-restricted fetuses, UA diastolic flow is diminished, absent, or even reversed in severe cases This progressive reduction of UA diastolic flow is associated with worsening destruction of placental villous vasculature In the growth restricted fetus, absent or reversed end diastolic flow is associated with fetal hypoxia 37 and increased perinatal morbidity and mortality In a systematic review of 11 randomized trials enrolling approximately high-risk patients, the use of Doppler ultrasound was associated with a trend toward decreased perinatal mortality OR 0.
UA Doppler assessments are considered most useful for monitoring of early-onset growth restriction due to uteroplacental insufficiency Several randomized trials have demonstrated that routine UA Doppler screening of all pregnancies does not improve perinatal outcomes Current American College of Obstetricians and Gynecologists ACOG practice guidelines support the use of UA Doppler assessments only in the management of suspected intrauterine growth restriction, stipulating that decisions regarding the timing of delivery should be based on UA Doppler results in combination with other tests of fetal well-being In the compromised fetus, systemic blood flow is redistributed from the periphery to the brain.
The limited data available currently are mixed. Blood flow in the umbilical vein is continuous in normal pregnancies after 15 weeks gestation. Pathological states, such as FGR, may be associated with pulsatile flow in the umbilical vein, which is a reflection of cardiac dysfunction against increased afterload.
The ductus venosus regulates oxygenated blood in the fetus 42 and is resistant to alterations in flow except in the most severely growth restricted fetuses. Recent evidence suggests that Doppler evaluation of fetal veins combined with arterial assessments is useful for predicting outcomes in growth restricted fetuses 43 ; As the fetal central nervous system matures, there are distinctive alterations in fetal physiological and behavioral parameters, such as heart rate patterns, motor activity, and sleep-wake cycles.
One important developmental feature is the increased coupling between fetal movement FM and FHR that normally occurs with advancing gestational age and reflects maturation of the parasympathetic and sympathetic components of the fetal autonomic nervous system. The use of a fetal actocardiograph, which electronically records FHR and FM, and novel analytic techniques allow computation of time-dependent cross-correlation coefficients between FHR and FM Aims for direct assessment of fetal cortical and brainstem function.
A specialized apparatus incorporating an array of ultrasensitive magnetic field detectors allows noninvasive, direct continuous recording of fetal electro-cortical signals, and can record fetal brain activity in response to auditory and visual stimuli applied to the maternal abdomen 48 ; This technology may contribute to future clinically important assessments of the CNS status of the fetus.
Historically, insulin-dependent diabetes has been a major contributor to perinatal mortality; however, due to both improved treatment and antepartum monitoring, the stillbirth rate in pregnancies complicated by diabetes now is equivalent to or lower than uncomplicated pregnancies Poorly controlled maternal diabetes is associated with increased perinatal mortality largely related to congenital anomalies and indicated preterm deliveries, but also to sudden unexplained fetal death.
Though observational studies have described the use of the NST 51 , CST 52 , and BPP 53 in management of diabetic pregnancy, no method s have been assessed in well-designed clinical trials and it is not clear which method, if any, is superior. There is no evidence supporting routine antepartum fetal assessment in diet-controlled gestational diabetes Maternal hypertension in pregnancy, whether chronic, pregnancy-induced, or a combination, is a risk factor for perinatal death, and is a common indication for antenatal testing There are insufficient data to recommend one testing modality over another, or to make conclusions about when testing should begin and how frequently it should be repeated.
Some authorities hold that mild to moderate chronic hypertension in the absence of growth restriction or superimposed preeclampsia is not an indication for routine fetal surveillance 55 , and a recent systematic review concluded that benefits and harms of routine antenatal assessment in women with chronic hypertension cannot be determined with current evidence No randomized trials have assessed the best method for antenatal testing in the preeclamptic patient for whom delayed delivery is desired.
If fetal growth restriction or decreased AFV are present, testing is recommended twice weekly. Daily fetal cardiotocographic or ultrasound surveillance may be useful in conservative management of severe preterm preeclampsia FGR is a well-recognized risk factor for fetal death.
Abnormalities in Doppler velocimetry indices may help distinguish between fetal growth restriction due to placental insufficiency, in which impedance indices tend to be increased, and growth restriction from other causes e. There are no data from randomized trials indicating the optimal mode and frequency of antenatal testing of the fetus with growth restriction. Given the limitations in predictive value, timing delivery based on results of antenatal testing in preterm FGR presents a particular problem, as the risks of fetal loss must be balanced against the risks of iatrogenic prematurity.
The greater prevalence of maternal risk factors e. Population based evidence indicates that the lowest risk for intrauterine death in multiple gestations occurs at w Chorionicity is an important consideration in the assessment of risk, with higher rates of adverse outcomes among monochorionic twins. There are scant data to indicate the gestational age at which testing should start; some suggest that fetal surveillance among diamniotic-dichorionic twins with concordant growth may not be needed before 38 weeks.
There is insufficient evidence to support specific recommendations for any antenatal testing strategy in triplets and higher-order multiples. Abnormalities of AFV have long been viewed as risk factors for poor perinatal outcomes 63 ; 64 , although this concept has recently been called into question There is some controversy over whether isolated oligohydramnios 66 or polyhydramnios 67 near term is associated with adverse pregnancy outcomes.
There are few data on which to base recommendations for antenatal testing in pregnancies with abnormalities of AFV.
Preterm premature rupture of membranes PPROM is associated with oligohydramnios and subclinical intrauterine infection. The goal of antenatal testing in this setting is early recognition of chorioamnionitis necessitating delivery.
AFI 22-102, Wall to Wall Counseling
Antenatal Testing – A Reevaluation
PTEN as an effector in the signaling of antimigratory G protein-coupled receptor
PTEN as an effector in the signaling of antimigratory G protein-coupled receptor