Leo R. Leader

MATERNAL STRESS AND OBSTETRIC AND INFANT OUTCOMES: EPIDEMIOLOGICAL FINDINGS AND NEUROENDOCRINE MECHANISMS

This review examines the associations between antenatal maternal stress and obstetric and infant outcomes using preterm delivery as the key outcome indicator. This was done by means of a Medline search focusing predominantly on prospective, controlled studies which investigated both the associated epidemiological factors and putative neuroendocrine mechanisms.

Diagnosis of and Screening for Cytomegalovirus Infection in Pregnant Women

ABSTRACT No single diagnostic test for cytomegalovirus (CMV) infection is currently available for pregnant women at all stages of gestation. Improved accuracy in estimating the timing of primary infections can be used to identify women at higher risk of giving birth to congenitally infected infants. A diagnostic algorithm utilizing immunoglobulin G (IgG), IgM, and IgG avidity was used to prospectively screen serum from 600 pregnant women enrolled from two groups: ≤20 weeks gestation (n = 396) or >20 weeks gestation (n = 204). PCR testing of urine and/or blood was performed on all seropositive women (n = 341). The majority (56.8%) of women were CMV IgG seropositive, with 5.5% being also CMV IgM positive. In the IgM-positive women, 1.2% had a low-avidity IgG, indicating a primary CMV infection and a high risk of intrauterine transmission. Two infants with asymptomatic CMV infection were born of mothers who had seroconverted in the second trimester of pregnancy. Baseline, age-stratified CMV serostatus was established from 1,018 blood donors. Baseline seropositivity from a blood donor population increased with age from 34.9% seroprevalence at less than 20 years of age to 72% seroprevalence at 50 years of age. Women at high risk of intrauterine transmission of CMV were identified at all stages of gestation. Women infected with CMV during late gestation may be more likely to transmit the virus, so failure to detect seroconversions in late gestation may result in failure to detect infected neonates.

The assessment and significance of habituation to a repeated stimulus by the human fetus

Habituation is the progressive decrease in response by an organism when it is stimulated repeatedly. This process is a basic form of learning and a normal pattern may be one indication of intact central nervous system function. This study assessed habituation of a behavioral response by the human fetus to repeated vibrotactile stimuli. Of the 40 normal fetuses studied 37 habituated after 10 to 50 stimuli. The gestational age at which the fetus first responded to the stimulus ranged from 22 to 30 weeks. Female fetuses responded 2 weeks earlier than males. The possible value of this assessment in obstetrical practice is presented.

Fetal habituation in high-risk pregnancies.

Summary. Habituation is a basic form of learning and probably requires an intact central nervous system. Habituation in the behavioural response to vibration in 40 normal human fetuses was compared with that in a group of high‐risk pregnancies with an increased risk of fetal neurological damage. Highly significant differences in habituation patterns between the high‐risk groups and normal control subjects were found. This test may offer a method of assessing the integrity of the fetal central nervous system.

Fetal Responses to Vibrotactile Stimulation, A Possible Predictor of Fetal and Neonatal Outcome

Summary: This study measured the antenatal fetal heart rate changes in response to a single vibrotactile stimulus. In a group of 11 normal patients, this resulted in a significant change in the fetal heart rate (P < 0.001). Sixty‐eight high risk patients were also tested. In the group of 25 patients whose fetuses showed no response to the stimulus, there were 4 stillbirths and 4 neonatal deaths; 23 of these 25 infants were small for gestational age (SGA) compared to only 15 of the 43 that showed a response to the stimulus.

Vaginal Delivery After Caesarean Section

EDITORIAL COMMENT: This prospective study reports excellent results although the 64% vaginal delivery rate for those having a trial of scar is less than the other reported series quoted by the authors (table 5). The 1 case of uterine rupture occurring in the 125 women who had a trial of labour may have been called a ‘dehiscence’ by many since there was no bleeding or haematoma, and importantly no harm to fetus or mother. We respectfully disagree with the authors final comment that ‘most women with a previous Caesarean section can safely deliver vaginally’ since this study showed that only 64% (80 of 125) of those having a trial of labour, or 25% (80 of 318) of consecutive women with a previous Caesarean scar could safely deliver vaginally. It seemed to our reviewer that an unmentioned takeaway message was that good clinical judgement was required to select the 61% (193 of 318) of women for elective repeat Caesarean section, as well as providing superior care during labour to those who elected to do so.

Regulator of G protein signaling 5 is a determinant of gestational hypertension and preeclampsia

Reduction of vascular RGS5 causes hypertension and preeclampsia, which can be reversed by PPAR agonist treatment in mouse models. Drugs may play a PPARt against preeclampsia Preeclampsia is a vascular disorder of pregnancy, with symptoms including hypertension and loss of protein in the urine. The underlying causes of preeclampsia are not yet understood, and the only effective treatment is preterm delivery of the infant, which poses many risks for the child. Holobotovskyy et al. determined that a vascular protein called RGS5 plays an important role in the regulation of blood pressure during pregnancy and that a lack of this protein causes a preeclampsia-like syndrome in mouse models. These mice could be effectively treated with drugs called PPAR agonists, some of which are already approved for diabetes in humans, suggesting a potential therapeutic approach for preeclampsia. Preeclampsia is a systemic vascular disorder of pregnancy and is associated with increased sensitivity to angiotensin II (AngII) and hypertension. The cause of preeclampsia remains unknown. We identified the role of regulator of G protein (heterotrimeric guanine nucleotide–binding protein) signaling 5 (RGS5) in blood pressure regulation during pregnancy and preeclampsia. RGS5 expression in human myometrial vessels is markedly suppressed in gestational hypertension and/or preeclampsia. In pregnant RGS5-deficient mice, reduced vascular RGS5 expression causes gestational hypertension by enhancing vascular sensitivity to AngII. Further challenge by increasing AngII results in preeclampsia-like symptoms, namely, more severe hypertension, proteinuria, placental pathology, and reduced birth weight. In pregnant heterozygote null mice, treatment with peroxisome proliferator–activated receptor (PPAR) agonists normalizes vascular function and blood pressure through effects on RGS5. These findings highlight a key role of RGS5 at the interface between AngII and PPAR signaling. Because preeclampsia is refractory to current standard therapies, our study opens an unrecognized and urgently needed opportunity for treatment of gestational hypertension and preeclampsia.

Measurement of fetal responses to vibroacoustic stimuli: Habituation in fetal sheep

Electrocortical (ECoG) and integrated electromyographic (EMG) activity was recorded in 6 chronically prepared fetal sheep (132-145 days). Recording were made in fetuses prior to and during repeated vibroacoustic stimulation. In the undisturbed fetus, two patterns of ECoG activity were apparent; high (HV) and low voltage (LV). The fetus responded to this broad spectrum stimulus during both LV and HV ECoG activity. In 18 of the 20 experiments, repeated stimulation was not associated with a change in the background ECoG activity. All fetuses responded at least once to the stimulus. Habituation of the EMG response was observed during both HV and LV ECoG activity. The rate of habituation was independent of the background ECoG activity and was unchanged when experiments were repeated at intervals of more than 3 days. These results show that fetal sheep also respond to vibroacoustic stimulation and with repetition habituation occurs.

The changes in fetal habituation patterns due to a decrease in inspired maternal oxygen

Summary. Habituation is widely regarded as a basic form of learning. A fully functioning central nervous system is probably required for a normal habituation pattern. Habituation of the behavioural response to vibroacoustic stimulation was studied in 23 normal human fetuses whose gestational age was 36 or more weeks. Eighteen were tested whilst their mothers breathed either air or a 12% oxygen in nitrogen mixture. The test was repeated the following day with the order of the gases reversed. In addition five fetuses were tested while their mothers breathed air on both occasions. Of the 18 fetuses 17 had a normal habituation pattern when tested in air but only two had a normal pattern when their mothers breathed 12% O2. Four of the five fetuses tested both days in air had normal patterns on the second day. Altering the amount of inspired maternal O2 alters the fetal habituation pattern.

Pregnancy-induced remodelling and enhanced endothelium-derived hyperpolarization-type vasodilator activity in rat uterine radial artery: transient receptor potential vanilloid type 4 channels, caveolae and myoendothelial gap junctions

In pregnancy, the vasculature of the uterus undergoes rapid remodelling to increase blood flow and maintain perfusion to the fetus. The present study determines the distribution and density of caveolae, transient receptor potential vanilloid type 4 channels (TRPV4) and myoendothelial gap junctions, and the relative contribution of related endothelium‐dependent vasodilator components in uterine radial arteries of control virgin non‐pregnant and 20‐day late‐pregnant rats. The hypothesis examined is that specific components of endothelium‐dependent vasodilator mechanisms are altered in pregnancy‐related uterine radial artery remodelling. Conventional and serial section electron microscopy were used to determine the morphological characteristics of uterine radial arteries from control and pregnant rats. TRPV4 distribution and expression was examined using conventional confocal immunohistochemistry, and the contribution of endothelial TRPV4, nitric oxide (NO) and endothelium‐derived hyperpolarization (EDH)‐type activity determined using pressure myography with pharmacological intervention. Data show outward hypertrophic remodelling occurs in uterine radial arteries in pregnancy. Further, caveolae density in radial artery endothelium and smooth muscle from pregnant rats was significantly increased by ~94% and ~31%, respectively, compared with control, whereas caveolae density did not differ in endothelium compared with smooth muscle from control. Caveolae density was significantly higher by ~59% on the abluminal compared with the luminal surface of the endothelium in uterine radial artery of pregnant rats but did not differ at those surfaces in control. TRPV4 was present in endothelium and smooth muscle, but not associated with internal elastic lamina hole sites in radial arteries. TRPV4 fluorescence intensity was significantly increased in the endothelium and smooth muscle of radial artery of pregnant compared with control rats by ~2.6‐ and 5.5‐fold, respectively. The TRPV4 signal was significantly higher in the endothelium compared with the smooth muscle in radial artery of both control and pregnant rats, by ~5.7‐ and 2.7‐fold, respectively. Myoendothelial gap junction density was significantly decreased by ~37% in radial artery from pregnant compared with control rats. Pressure myography with pharmacological intervention showed that NO contributes ~80% and ~30%, and the EDH‐type component ~20% and ~70% of the total endothelium‐dependent vasodilator response in radial arteries of control and pregnant rats, respectively. TRPV4 plays a functional role in radial arteries, with a greater contribution in those from pregnant rats. The correlative association of increased TRPV4 and caveolae density and role of EDH‐type activity in uterine radial artery of pregnant rats is suggestive of their causal relationship. The decreased myoendothelial gap junction density and lack of TRPV4 density at such sites is consistent with their having an integral, albeit complex, interactive role in uterine vascular signalling and remodelling in pregnancy.