Vesicoamniotic shunting for fetal megacystis in the first trimester with a Somatex® intrauterine shunt.

PURPOSE: The objective was to evaluate the feasibility of vesicoamniotic shunting (VAS) in the first trimester with the Somatex® intrauterine shunt and report on complications and neonatal outcome. METHODS: Retrospective cohort study of all VAS before 14 weeks at two tertiary fetal medicine centres from 2015 to 2018 using a Somatex® intrauterine shunt. All patients with a first trimester diagnosis of megacystis in male fetuses with a longitudinal bladder diameter of at least 15 mm were offered VAS. All patients that opted for VAS after counselling by prenatal medicine specialists, neonatologists and pediatric nephrologists were included in the study. Charts were reviewed for complications, obstetric and neonatal outcomes. RESULTS: Ten VAS were performed during the study period in male fetuses at a median GA of 13.3 (12.6-13.9) weeks. There were two terminations of pregnancy (TOP) due to additional malformations and one IUFD. Overall there were four shunt dislocations (40%); three of those between 25-30 weeks GA. Seven neonates were born alive at a median GA of 35.1 weeks (31.0-38.9). There was one neonatal death due to pulmonary hypoplasia. Neonatal kidney function was normal in the six neonates surviving the neonatal period. After exclusion of TOP, perinatal survival was 75%, and 85.7% if only live-born children were considered. CONCLUSION: VAS in the first trimester is feasible with the Somatex® Intrauterine shunt with low fetal and maternal complication rates. Neonatal survival rates are high due to a reduction in pulmonary hypoplasia and the rate of renal failure at birth is very low. VAS can be safely offered from the late first trimester using the Somatex® intrauterine shunt.

Uptake of non-invasive prenatal testing (NIPT) and impact on invasive procedures in a tertiary referral center.

PURPOSE: The introduction of non-invasive prenatal testing (NIPT) by isolation of cell-free fetal DNA from maternal blood is a new diagnostic option in prenatal care. The aim of the study was to investigate the algorithm of prenatal testing before and after the introduction of NIPT in a tertiary referral center and to investigate the influence of NIPT on the frequency of invasive procedures. METHODS: Retrospective data analysis was conducted of all singleton pregnancies that presented for first trimester screening 17 months before and after the introduction of NIPT (n = 2271). Women were categorized into three risk groups: low risk for trisomy 21 (<1:1000), intermediate risk (1:101-1:1000) and high risk (≥1:100). The choice of diagnostic testing after FTS was analyzed. RESULTS: 1093 (group 1) presented before and 1178 (group 2) after the introduction of NIPT. The rate of high-risk patients was equal in both groups (14.4 vs. 15.4 %). No differences were found with regard to invasive testing (11.6 vs. 11.3 %). NIPT was chosen by 3.7 % (44/1178) in group 2. Of those with NIPT, 72.7 % had a risk estimate of <1:100, but 90.9 % were ≥35 years old. The rate of NIPT among high-risk patients with a normal ultrasound examination was 25 %. CONCLUSION: At present, NIPT is chosen mainly for reassurance by patients not considered to be at high risk. In the high-risk group, NIPT can be offered if the ultrasound examination is normal and the risk is high due to maternal age or serum screening alone. The rate of invasive testing was not reduced in this selected population.

Conflicting umbilical artery Doppler findings in fetuses with trisomy 21.

OBJECTIVE: To assess differences between fetuses with isolated and non-isolated trisomy 21 in umbilical artery (UA) Doppler findings in the second and third trimester and to correlate those with placental histology. METHODS: Retrospective analysis of UA pulsatility index (PI) in 281 fetuses with trisomy 21. Cases were divided into isolated trisomy 21 (group I, n = 148, 52.7 %) and non-isolated trisomy 21 (group II, n = 133, 47.3 %). UA measurements were evaluated in five different time periods (A-E; <20 + 0 to ≥ 35 + 0 weeks) and were assigned histopathology of the placenta. RESULTS: In 118/281 (42 %) cases, UA measurement was abnormal. The frequency of PI values above the 95th percentile increased significantly with gestational age in both groups (period A 32.9 % vs. period E 63.6 %, p < 0.0001). There was neither a difference in abnormal UA PI values between isolated and non-isolated cases [37.8 % (56/148) vs. 46.6 % (62/133)] nor a correlation to placental findings. CONCLUSIONS: Fetuses with trisomy 21 often present with elevated UA PI in the late second or third trimester, irrespective of small for gestational age growth, malformations or histopathological findings of impaired placentation.

Impact of chorionicity on first-trimester nuchal translucency screening in ART twin pregnancies.

OBJECTIVE: Nuchal translucency (NT) measurement in assisted reproduction treatment (ART) twins is less extensively investigated. Therefore, the present study compared NT measurements of spontaneously conceived twins with ART twins in dichorionic (DC) and monochorionic (MC) pregnancies. METHODS: Retrospective analysis of 706 unaffected twins between 11 + 0 and 13 + 6 weeks conceived either spontaneously (n = 362) or with ART (n = 344). The group with spontaneous conception included 234 DC (64.6%) and 128 MC (35.4%) pregnancies. In the ART group, 326 were DC (94.7%) and 18 were MC (5.3%). NT values were transformed into multiples of median (MoM). RESULTS: In the DC group, no significant differences between ART and spontaneously conceived twins (NT MoM 1.06 ± 0.28 vs 1.03 ± 0.29; p > 0.05) were observed. NT MoM of MC ART twins was higher compared with spontaneous MC twins (1.23 ± 0.82 vs 0.99 ± 0.27; p = 0.011). Although the incidence of twin-to-twin transfusion syndrome (TTTS) was higher among ART twins (11.1% vs 4.7%), inter-twin NT difference was similar between pregnancies with TTTS (0.42 ± 0.21) or without (0.40 ± 0.71). CONCLUSIONS: Measurement of NT thickness in DC ART twins achieves comparable results with twins conceived spontaneously. Conclusions in MC twins are limited; however, higher NT MoM was not related to TTTS or selective intrauterine growth restriction.

Cytokines and parturition: investigating adiponectin, TNF-α, and IL-6 in mother-newborn pairs.

OBJECTIVE: Cytokines are reported to be associated with various pregnancy complications and health outcomes of the offspring. However, reference values during pregnancy have not been established, effects of clinical and obstetric factors have not been examined, and interactions between different cytokines have not yet been reported. METHODS: In this cross-sectional study, we recruited 120 mother-newborn pairs. Maternal venous blood samples (6 mL) were taken on admission to the labor ward; newborn venous blood samples (6 mL) were drawn from the placental part of the umbilical cord (UC). Adiponectin, TNF-α, and IL-6 serum concentrations were measured by commercial immunoassays. Clinical and obstetric variables were analyzed for their association with maternal and UC cytokine concentrations. RESULTS: Forty-six adiponectin pairs, 55 TNF-α pairs, and 14 IL-6 pairs were available for analysis. Correlation between UC and maternal adiponectin-, IL-6-, and TNF-α levels was low. We found a significant correlation of UC adiponectin with maternal brain-derived neurotrophic factor (BDNF) and maternal adiponectin, and between maternal leptin and maternal TNF-α. CONCLUSIONS: Clinical and obstetric variables as well as interactions between cytokines may have an impact on serum concentrations of the respective cytokines in maternal and UC blood. Further studies are required to confirm our findings.

Actin filaments in sensory hairs of inner ear receptor cells.

Receptor cells in the ear are excited through the bending of sensory hairs which project in a bundle from their surface. The individual stereocilia of a bundle contain filaments about 5 nm in diameter. The identity of these filaments has been investigated in the crista ampullaris of the frog and guinea pig by a technique of decoration with subfragment-1 of myosin (S-1). After demembranation with Triton X-100 and incubation with S-1, "arrowhead" formation was observed along the filaments of the stereocilia and their rootlets and also along filaments in the cuticular plate inside the receptor cell. The distance between attached S-1 was 35 nm and arrowheads pointed in towards the cell soma. It is concluded that the filaments of stereocilia are composed of actin.

The ultrastructure of the sensory hairs and associated organelles of the cochlear inner hair cell, with reference to directional sensitivity.

From the apical end of the inner hair cell of the organ of Corti in the guinea pig cochlea protrude four to five rows of stereocilia shaped in a pattern not unlike the wings of a bird. In the area devoid of cuticular substance facing toward the tunnel of Corti lies a consistently present centriole. The ultrastructure of this centriole is similar to that of the basal body of the kinocilium located in the periphery of the sensory hair bundles in the vestibular and lateral line organ sensory cells and to that of the centrioles of other cells. The physiological implications of the anatomical orientation of this centriole are discussed in terms of directional sensitivity.

Receptor potentials from hair cells of the lateral line.

Intracellular recordings from hair cells in the tail lateral line of mudpuppy Necturus maculosus show receptor potentials less than 800 microvolts, peak to peak, from stimuli that are considered large compared to natural stimuli. The hair cells are in neuromasts that are sensitive at the time of recording and are identified by both in vivo and in vitro examination of intracellular staining.

Intracellular recordings from cochlear outer hair cells.

Intracellular recordings were made from outer hair cells in the third turn of the guinea pig cochlea, and the electrical characteristics of the cells were compared to those of inner hair cells, supporting cells, and extracellular spaces from the same recording region. Outer hair cells have higher membrane potentials than do inner hair cells, but they produce smaller a-c receptor potentials. The frequency response characteristics of both types of hair cells are probably not significantly different. In the frequency region where tuning is optimal, both cell types produce depolarizing d-c receptor potentials, but outer hair cells also generate hyperpolarizing responses at low frequencies.

In vitro studies of cochlear excitation.

Although initially met with scepticism, the in vitro temporal bone preparation of the cochlea has proved to be a very important tool for investigating the function of the mammalian auditory system. As present techniques are able to maintain sufficient cellular viability, the in vitro preparation offers a valuable bridge between investigations using isolated outer hair cells and the intact system in vivo.

Determinants of brain-derived neurotrophic factor (BDNF) in umbilical cord and maternal serum.

OBJECTIVE: Brain-derived neurotrophic factor (BDNF) plays a fundamental role in brain development; additionally, it is involved in various aspects of cerebral function, including neurodegenerative and psychiatric diseases. Involvement of BDNF in parturition has not been investigated. The aim of our study was to analyze determinants of umbilical cord BDNF (UC-BDNF) concentrations of healthy, term newborns and their respective mothers. METHODS: This cross-sectional prospective study was performed at a tertiary referral center. Maternal venous blood samples were taken on admission to labor ward; newborn venous blood samples were drawn from the umbilical cord (UC), before delivery of the placenta. Analysis was performed with a commercially available immunoassay. Univariate analyses and stepwise multivariate regression models were applied. RESULTS: 120 patients were recruited. UC-BDNF levels were lower than maternal serum concentrations (median 641 ng/mL, IQR 506 vs. median 780 ng/mL, IQR 602). Correlation between UC- and maternal BDNF was low (R=0.251, p=0.01). In univariate analysis, mode of delivery (MoD), gestational age (GA), body mass index at delivery, and gestational diabetes were determinants of UC-BDNF (MoD and smoking for maternal BDNF, respectively). Stepwise multivariate regression analysis revealed a model with MoD and GA as determinants for UC-BDNF (MoD for maternal BDNF). CONCLUSIONS: MoD and GA at delivery are determinants of circulating BDNF in the mother and newborn. We hypothesize that BDNF, like other neuroendocrine factors, is involved in the neuroendocrine cascade of delivery. Timing and mode of delivery may exert BDNF-induced effects on the cerebral function of newborns and their mothers.

Supporting cells contribute to control of hearing sensitivity.

The mammalian hearing organ, the organ of Corti, was studied in an in vitro preparation of the guinea pig temporal bone. As in vivo, the hearing organ responded with an electrical potential, the cochlear microphonic potential, when stimulated with a test tone. After exposure to intense sound, the response to the test tone was reduced. The electrical response either recovered within 10-20 min or remained permanently reduced, thus corresponding to a temporary or sustained loss of sensitivity. Using laser scanning confocal microscopy, stimulus-induced changes of the cellular structure of the hearing organ were simultaneously studied. The cells in the organ were labeled with two fluorescent probes, a membrane dye and a cytoplasm dye, showing enzymatic activity in living cells. Confocal microscopy images were collected and compared before and after intense sound exposure. The results were as follows. (1) The organ of Corti could be divided into two different structural entities in terms of their susceptibility to damage: an inner, structurally stable region comprised of the inner hair cell with its supporting cells and the inner and outer pillar cells; and an outer region that exhibited dynamic structural changes and consisted of the outer hair cells and the third Deiters' cell with its attached Hensen's cells. (2) Exposure to intense sound caused the Deiters' cells and Hensen's cells to move in toward the center of the cochlear turn. (3) This event coincided with a reduced sensitivity to the test tone (i.e., reduced cochlear microphonic potential). (4) The displacement and sensitivity loss could be reversible. It is concluded that these observations have relevance for understanding the mechanisms behind hearing loss after noise exposure and that the supporting cells take an active part in protection against trauma during high-intensity sound exposure.

Clinical spectrum of fetal long QT syndrome: a single-center experience.

OBJECTIVE: A considerable proportion of unexplained intrauterine fetal deaths are attributed to long QT syndrome (LQTS) susceptibility. Additionally, the estimated prevalence of LQTS in newborns is 1 in 2000. Still, prenatal diagnosis of LQTS is very rare. The aim of this study was to assess the frequency of prenatal diagnosis of LQTS at our institution, present the cases, compare our findings with the existing literature and propose a possible screening approach. METHODS: We searched our fetal database between 2006 and 2013 for cases with suspected diagnosis of LQTS. RESULTS: During the investigation period around 26 000 fetuses were evaluated and three cases of suspected fetal LQTS identified. Two cases of familial LQTS had no or mild intrauterine manifestation of the condition, the third fetus had a de-novo mutation with severe, early-onset disease. CONCLUSIONS: LQTS continues to be a challenging prenatal diagnosis. In fetuses who present with complex arrhythmias, a high degree of suspicion is required, and close surveillance and timely delivery in the presence of a multidisciplinary team are necessary. For asymptomatic cases or screening purposes, routine fetal heart rate registration and detailed assessment of cases with a low for gestational age baseline may be an option.

Vital staining of the hearing organ: visualization of cellular structure with confocal microscopy.

Cells inside the intact organ of Corti were labelled with fluorescent probes reflecting various aspects of structure and function. The dyes were introduced into the perilymphatic space by perfusion of the scala tympani of the temporal bone from the guinea-pig maintained in isolation. The dyes were able to diffuse through the basilar membrane and into the organ of Corti where they were spontaneously absorbed by the sensory and supporting cells. Confocal microscopic observation was made through an opening in the apex of the cochlea. A number of different dyes were used; a carbocyanine dye which stains mitochondria; two styryl dyes which are absorbed by the cell membranes and calcein, a cytoplasmic marker that fluoresces in vital cells. Extracellular space was stained by a cell-impermeant Dextran fluorescein. The most striking finding was that the membrane dyes preferentially stained the sensory cells and neural elements whereas the staining of the supporting cells was faint. The cytoplasmic dye in general stained sensory and supporting cells to the same extent. By tilting the organ, a view could be obtained from the side like a radial section through the organ. Outer and inner hair cells with their sensory hairs, nerve fibres and nerve endings, especially under the inner hair cells, could be seen in profile. Introduction of a high molecular weight Dextran into the endolymphatic space outlined the tectorial membrane which was seen in negative contrast. The simultaneous perfusion with a membrane dye stained the hair cells and their sensory hairs. Merging of the two images gave the possibility to examine, in the living tissue, the cilia to tectorial membrane relationship. Of general interest is the finding that the membrane dyes preferentially stained the sensory and neural elements of the nervous system, represented here by the hair cells and nerve fibres of the inner ear.

The vibration pattern of the hearing organ in the waltzing guinea-pig measured using laser heterodyne interferometry.

The mechanical tuning characteristics of the hearing organ were measured in response to sound stimulation using laser heterodyne interferometry in in vitro preparations of temporal bones from waltzing guinea-pigs expressing different degrees of hearing organ and sensory cell degeneration. Measurements were made at various stages of structural changes allowing us to correlate structure and mechanical function. It was found that the characteristic frequency of the response at a given location in the cochlea occurred at lower frequencies than what is normally seen and that the sharpness of the mechanical tuning was considerably reduced when sensory hair cells were absent and the hearing organ structurally altered. However, even when extensive hair cell degeneration was evident a residual mechanical tuning was present. These results further support the concept that the sensory hair cells plays a key role in determining normal auditory tuning characteristics. It is suggested that the basilar membrane mechanics gives rise to a broadly tuned mechanical response on which a sharper tuning mechanism, originating from the hair cells, is superimposed.

The tuned displacement response of the hearing organ is generated by the outer hair cells.

The motile responses of the guinea-pig hearing organ in response to a tone applied to the ear were measured by laser interferometry. Two types of responses can be recorded: (i) a vibration at the frequency of the applied tone; and (ii) a displacement response consisting of a shift in the position of the organ surface. The purpose of this study is to characterize the displacement response. The results are as follows. There is a relationship between the frequency of highest sensitivity (best-frequency) of the displacement response and the site from which it is recorded. High best-frequencies are noticed at more basal locations, low best-frequencies towards the apex. The displacement response is more frequency-selective than the vibration response. The displacement response is observed within physiological sound pressure levels. Its sharpness is dependent on the stimulus intensity, it shows biological variability and can be manipulated by drugs that are known to modify the receptor potential of the sensory cells, or to interfere with outer hair cell motility. These results suggest that the displacement response is an important step in the transduction process in the mammalian hearing organ and that it is generated by the motile action of the outer hair cells.

Cupular movement and nerve impulse response in the isolated semicircular canal.

The aim of the study was to record nerve impulse responses to controlled displacements of the cupula and relate these to observations of cupular motion. The preparation was the skate semicircular canal, isolated and maintained in a chamber. The canal was cut and tied tightly to an oil-filled tube driven by a 1 microliter syringe. In some experiments dye was used to make the face of the cupula visible. Small volume displacements (0.02 microliter) caused a billowing of the central portion of the cupula, whereas for repeated large displacements (0.1 microliter) the top of the cupula moved along the roof of the ampulla. Displacements of the latter amount were close to saturation in the characteristic functions (spike rate versus volume displacement) of nerve firing. It seems that the discharge rate of tonically responding units in the skate crista ampullaris rather faithfully record the force acting on the cupula. The motion of the base of the cupula rather than its tip appears to be the relevant parameter in setting the level of excitation in the sensory cells within the physiological range of stimulation. Such a mode of operation would ensure the highest sensitivity of the sense organ.

Quinine causes isolated outer hair cells to change length.

The outer hair cells have been shown to exhibit motile properties which are likely to participate in the cochlear performance. Quinine is known to induce hearing loss as well as contraction of skeletal muscle. Isolated outer hair cells were exposed to quinine and tetracaine. This resulted in a biphasic elongation-shortening response, quantitatively as well as qualitatively altered by tetracaine. These findings are in good agreement with similar studies on muscle.

Frequency-specific position shift in the guinea pig organ of Corti.

The organ of hearing is tuned as expressed both in the vibratory response of the cochlear partition and in the resulting receptor potentials of the sensory cells. We now demonstrate a sharply tuned response, consisting of a position shift of the surface of the organ of Corti, occurring during the presentation of a tone. The magnitude of the position shift exceeds that of the vibratory response to the stimulus. The shift is most pronounced in the region of the outer hair cells, and its affected by an inhibitor of outer hair cell motility. We conclude that the response is induced by the action of the outer hair cells.

Hydrops in the cochlea can be induced by sound as well as by static pressure.

The Reissner's membrane (RM) was visualised by confocal microscopy in the isolated temporal bone of the guinea pig. The function of the organ was followed by measuring its physiological response. Static pressure applied in the basal coil caused a distention of the RM in the apical coil into the scala vestibuli. The sensitivity to a test tone was reduced. When the pressure was relieved, the RM returned to its original position and the response recovered. If the increased pressure was maintained, the RM would bulge further. The RM could then be reversibly stretched and return gradually, with a delay, to its original position. Alternatively, it could be over-stretched and return with an over-shoot past its original position toward the organ of Corti. In response to repetitive tone pulses of above 80 dB, hydrops of the RM also developed. This was accompanied by a reduced sensitivity. A slow recovery to the original position, or over-shoot, and return of responsiveness could be seen. Above 106 dB sustained loss was generally seen. It is concluded that the RM can accommodate increased scala media pressure by distention. This will relieve the organ of Corti from part of the pressure and may protect the organ from trauma.