In utero cocaine exposure: observations of fetal behavioral state may predict neonatal outcome

Components of fetal behavioral state organization reflect the successful integration of the central nervous system, have a specific developmental timetable, and can be studied with fetal ultrasonographic techniques. To test the hypothesis that evaluation of state organization is a marker of abnormal central nervous system maturation and a predictor of risk, we studied 20 fetuses and newborns exposed to cocaine in utero. Fetal assessments were accomplished by serial ultrasonographic examination, videotaped, and scored by a scheme developed by the authors to assess organization and regulation of behavioral states. Newborn neurobehavioral assessments also emphasized organization and regulation of behavioral state. Abnormal or delayed state behavior was identified in 13 of 20 fetuses. State organization was evaluated as suspect or abnormal for 16 of the 20 exposed newborns. Disorganized behavioral state in the fetus successfully predicted abnormal newborn behavior. These findings support the concepts that cocaine exposure disrupts central nervous system development and that fetal assessment of state is predictive of neonatal outcome.     

Maternal exposure to music and fetal activity

The influence of music on fetal behavior was examined in 20 women to whom two different types of music were played via earphones.A real-time ultrasound scanner was used for direct observation of fetal body movements and breathing movements.A significant decrease in breathing activity was observed in fetuses while their mothers listened to a preferred type of music.     

Effects of acute hypoxemia on fetal movement in the fetal lamb

Chronically instrumented pregnant models were established using 5 Dorset-Rambouillet pregnant ewes with gestational age between 120 and 138 days. Observation of fetal movements were started on the 3rd postoperative day or later when recovery from the surgery to the physiological condition was confirmed by maternal and fetal biophysical parameters. Fetal movements were observed using real-time ultrasound equipment with linear-array transducer placed on the maternal abdomen. Observation encompassed the control period which lasted one hour followed by an experimental period of fetal hypoxemia created by decreasing maternal FIO2. Observation was also continued during the recovery period when the mother was re-exposed to room air. Maternal and fetal samples were periodically obtained during these periods. Frequency of fetal movements was studied in 10 minute periods under the control and hypoxemic conditions. All fetuses exhibited movements during the control period, ranging 1-42 movements/10 minutes, the mean incidence being 16.9 movements/10 minutes. During fetal hypoxemia (average PaO2 decrease: 8.6 mmHg), fetal movements were significantly reduced to 5.5 movements/10 minutes with complete cessation in some cases. In 4 animals which exhibited complete cessation of both fetal movement (FM) and fetal breathing movement (FBM), FBM disappeared before FM, and reappearance of FM was following by FBM during recovery from hypoxemia.     

The effect of methadone on fetal brain function.

The effect of methadone on fetal brain function in terms of the electroencephalogram (EEG) was studied in eight short-term fetal sheep experiments by single injections of 5 to 20 mg. of methadone into the fetal circulation. Plasma methadeone concentrations (determined by radioimmunoassay) greater than 0.065 mg. per cent were associated with an immediate brief decrease in carotid blood flow, a rapid decrease in frequency and amplitude in the EEG that occasionally became isoelectric but recovered, and immediate and relatively prolonged bradycardia. Similar cardiovascular observations were obtained with plasma methadone concentrations less than 0.065 mg. per cent, but the EEG changes were either minimal or not observed. These results indicate that uptake of methadone by the fetal brain is rapid and that electrical activity and heart rate are affected.     

Effects of intra-amniotic meconium exposure on the fetal rat: development of a pathogenic model

OBJECTIVE: To develop an in vivo animal model for the study of the effects of intrauterine meconium exposure on the fetus. METHODS: Timed pregnant Long-Evans rats were purchased on gestational day (GD) 12 and allowed to acclimate for at least 48 h prior to surgery. Laparotomy was performed and both uterine horns were exteriorized through the abdominal incision. A 26-gauge needle was used to inject either 0.1-cm(3) sterile normal saline or a 20% meconium suspension into each individual gestational sac. The uterus was returned to the abdomen and the incision was closed. On GD 21 (term = 21 days) a cesarean section was completed and the number and viability of fetuses in each horn were recorded. RESULTS: A total of 14 animals were involved in this pilot study. One rat underwent sham surgery with only intra-amniotic saline injection and 13/15 fetuses survived to term. Two animals that underwent surgery on day 18 expired < 24 h postinjection. Eleven maternal animals were injected on GD 20 and underwent cesarean delivery at term; survival rates for saline-injected animals were 71.2% compared to 66.2% for meconium-exposed fetuses. CONCLUSION: We have established an in vivo animal model that allows for the examination of the effects of prolonged intrauterine meconium exposure on the fetus.     

The relationship between fetal activity and behavioral states and fetal breathing movements in normal and growth-retarded fetuses

The incidence of fetal breathing was studied during the course of behavioral state observations on 28 low-risk fetuses between 32 and 40 weeks' gestational age and on 12 growth-retarded fetuses between 36 and 40 weeks. Real-time ultrasound scanners were used to detect fetal eye, body, and breathing movements, and the fetal heart rate was recorded continuously. The mean duration of the observation sessions was 110 minutes. The mean incidence of fetal breathing was greater during periods of fetal activity (body and eye movements present, greater heart rate variability) than during quiescence (body and eye movements absent, narrowed heart rate variability) at all gestational ages studied in both low-risk and growth-retarded fetuses. During periods when one of the state variables (body movements, eye movements, heart rate pattern) was in its active condition while the other two were quiet, or the reverse, the incidence of fetal breathing was intermediate between those found when all three state variables were in agreement. After behavioral states had developed, at 38 and 40 weeks, the mean incidence of fetal breathing in the low-risk fetuses was greater during active states than during the quiet state. There was no apparent increase in the degree of linkage between fetal breathing and other expressions of fetal activity after the emergence of behavioral states.     

Computerized assessment of fetal behavioral states

Fetal heart rate and fetal movements provide information on the fetal condition. In the near term human fetus, four behavioural states have been described based upon heart rate patterns and presence or absence of eye and body movements. For our studies concerning fetal physiology as well as the influence of maternal antiepileptic medication and the effects of intrauterine growth retardation on the fetal condition, we developed a computerized system for acquisition and storage of fetal heart rate signals and observed fetal movements. Fetal heart rate is recorded using a commercially available monitor combined with a home-made computer interface. Fetal movements are observed using two real-time ultrasound units. The observers handle keyboards to mark occurrence and duration of various types of fetal movements, and pedals to mark the visibility of the observed part of the fetal body. Keyboards and pedals are scanned by the computer. Special techniques are used to store heart rate and movement signals in an efficient way. Three experts determine fetal heart rate patterns by application of a Delphi group opinion procedure. Fetal behavioral states are identified by the computer using the results of the Delphi procedure, and performing the so-called extended automatic window procedure. This procedure identifies periods of presence and periods of absence of fetal eye and body movements, and incorporates the loss of visibility of the ultrasound images during the recording session. Fetal heart rate variability indices and distributions of fetal movements can be computed in the context of the fetal behavioral state concept.     

Effects of intravenous terbutaline on maternal circulation and fetal heart activity

The effects of terbutaline on maternal circulation and fetal heart activity were studied in 15 healthy pregnant women admitted for external cephalic version. The two-step infusion of terbutaline (5-10 micrograms/min) resulted in increases in maternal heart rate (p less than 0.001), cardiac output (p less than 0.001), systolic arterial pressure (p less than 0.001) and pulse pressure (p less than 0.001), while diastolic arterial pressure (p less than 0.001) and total peripheral vascular resistance (p less than 0.001) were reduced. Mean arterial pressure was unchanged after the infusion. Fetal heart activity assessed by cardiotocography showed a gradual increase in baseline fetal heart rate (p less than 0.01) and an increased percentage acceleration time (p less than 0.05). Fetal movements also increased during the infusion (p less than 0.05). The terbutaline infusion had a positive inotropic effect and produced decreased systemic vascular resistance in the pregnant woman, and placental transfer of the drug resulted in increased fetal heart activity. The potential influence of the drug-induced changes in maternal hemodynamics on utero-placental perfusion require further investigation.     

Testing for fetal exposure to illicit drugs using umbilical cord tissue vs meconium.

OBJECTIVE: We assessed the agreement of testing for fetal exposure to illicit drugs contrasting paired specimens of meconium vs umbilical cord tissue. METHODS: We obtained paired samples of meconium and umbilical cord tissue from 118 pregnancies with high suspicion of illicit drug use by the mothers. Each specimen was tested for amphetamines, opiates, cocaine, cannabinoids, and phencyclidine using drug class-specific immunoassays. RESULTS: The agreement of drug screening results between cord and meconium was above 90% for all drugs tested. Meconium identified 21 cases as positive for amphetamines. The paired cord identified 20 of these, and in addition identified three other positives that the meconium labeled as negative. Gas chromatography-mass spectrometry confirmed these three cord samples as methamphetamine positive. Meconium identified 97 samples that were negative for amphetamines, while the cord identified 94 of these as negative but three as positive. Agreement of cord with meconium for amphetamines was 96.6%. The concordance for opiates was 94.9%, for cocaine was 99.2%, and for cannabinoids was 90.7%. CONCLUSIONS: Umbilical cord tissue performs as well as meconium in assessing fetal drug exposure to amphetamines, opiates, cocaine, and cannabinoids. Results of studies using the cord may have a more rapid return to the clinician, because waiting for meconium to be passed sometimes requires several days. Moreover, in some cases the meconium is passed in utero making collection impossible, whereas cord should always be available for drug testing.     

The effect of maternal methadone use on the fetal heart pattern: a computerised CTG analysis

Using a computerised analysis, the cardiotocograph (CTG) from women who use methadone (n= 25) when compared with women who do not use methadone (n= 25) showed a significant reduction in the fetal heart baseline rate, with a significant reduction in number of accelerations and episodes of high variation. The short-term variation, number of decelerations and episodes of low variation were not different between the two groups. The time taken to meet the standardised criteria was not different, and it is possible that a computer-assisted CTG analysis could be more accurate than a naked eye interpretation.     

Effects of chronic hyperglycemia on electrocortical activity states in unanesthetized fetal lambs

Electrocortical activity (ECoG), tracheal pressure and nuchal muscle activity were recorded in utero in 8 chronically hyperglycemic and 10 control unanesthetized fetal lambs to investigate the effects of chronic hyperglycemia on fetal electrocortical activity states. The chronically hyperglycemic state, induced by alloxan administered to the ewes, existed for at least 40 days prior to the experiments. The mean duration of episodes of high voltage (HV) ECoG was significantly increased in the hyperglycemic group (mean +/- SD: 21.8 +/- 9.2 min) compared with the control group (14.8 +/- 3.3 min), but the incidence of low voltage (LV) ECoG was not different between the groups. ECoG power spectra were not different between the groups. During LV ECoG, the proportions of time with neck movements were significantly less in the hyperglycemic than in the control group. No difference in percentages of time with long neck muscle activity was seen during the HV state in both groups. The incidence of breathing movements was equal in both groups, during HV as well as LV ECoG. No differences in breathing interval were observed.     

Effects of clonidine on breathing movements and electrocortical activity in the fetal lamb

Clonidine is a recommended antihypertensive for use during pregnancy, although little is known of its fetal effects. This study examines the effects of clonidine on breathing and sleep-state cycling in fetal lambs. Clonidine was infused into a fetal lateral ventricle for up to 24 hours at 128 to 135 days' gestation. Control infusions of artificial cerebrospinal fluid had no effect. Clonidine infusion significantly reduced the incidence and episode duration of fetal breathing for the duration of the infusion period. Cycling of electrocortical activity became irregular and rapid, and the incidence of high-voltage electrocortical activity (equivalent to quiet sleep) was reduced. Fetal heart rate decreased but arterial pressure was unaffected. After infusion the breathing incidence and episode duration both increased significantly compared with control, with continuous high-amplitude breathing for several hours, whereas the incidence of high-voltage electrocortical activity remained low. Because lung development is promoted by fetal breathing, long-term use of clonidine during pregnancy could slow lung development by reducing fetal breathing activity.     

Effects of maternal ethanol infusion on fetal cardiovascular and brain activity in lambs

Ethanol (1 gm/kg of maternal body weight administered over 1 hour) was infused intravenously into 11 chronically prepared pregnant ewes between 128 to 137 days' gestation. Fetal breathing movements were suppressed for 9 hours following ethanol administration, and both high- and low-voltage fetal electrocortical activity were suppressed for 3 hours and replaced by intermediate-voltage electrocortical activity. Fetal blood gases and pH were not altered. These data support the hypothesis that ethanol suppresses fetal breathing movements by a direct central mechanism rather than indirectly by alteration of electrocortical activity.     

Effects of central angiotensin II receptor antagonism on fetal swallowing and cardiovascular activity

OBJECTIVE: Fetal plasma angiotensin II levels are 10 times the levels found in adults. Despite these high levels, central injection of angiotensin II may stimulate fetal swallowing and increase fetal arterial blood pressure. We postulated that the high rate of spontaneous fetal swallowing and normal fetal pressor regulation may be dependent, in part, on central angiotensin II. In view of the potential dipsogenic role of both type 1 and type 2 angiotensin II receptors, we examined the central effect of the nonselective angiotensin II receptor antagonist saralasin on fetal swallowing and cardiovascular responses. STUDY DESIGN: Six time-dated pregnant ewes and fetuses were chronically prepared with fetal vascular and intracerebroventricular catheters, electrocorticograms, and esophageal electromyogram electrodes and studied at 130 +/- 1 days' gestation. After an initial 2-hour baseline period (0 to 2 hours), saralasin (1 mL, 64 microg) was injected intracerebroventricularly (2 to 4 hours). After 4 hours the dose of saralasin was repeated together with angiotensin II (1 mL, 6.4 microg), and the fetuses were monitored for a final 2 hours. Four fetuses also underwent an identical control study (on an alternate day) in which saralasin was replaced with artificial cerebrospinal fluid. RESULTS: Blockade of central angiotensin II receptors by intracerebroventricular saralasin significantly reduced mean (+/- SEM) spontaneous fetal swallowing (1.3 +/- 0.1 to 0.4 +/- 0.1 swallows per minute; P <.001) but did not alter fetal mean blood pressure (50 +/- 5 versus 56 +/- 5 mm Hg). Intracerebroventricular angiotensin II, in the presence of saralasin, did not affect swallowing (0.6 +/- 0.1 swallows per minute) or fetal blood pressure. In the control study, intracerebroventricular artificial cerebrospinal fluid did not change fetal swallowing (0.9 +/- 0.1 versus 1.0 +/- 0.1 swallows per minute), whereas intracerebroventricular angiotensin II significantly increased swallowing activity (1.0 +/- 0.1 versus 2.0 +/- 0.1 swallows per minute; P <.001) and fetal blood pressure (51 +/- 2 to 59 +/- 3 mm Hg; P =.003). CONCLUSIONS: Tonic activity of central angiotensin II receptor stimulation contributed to the high rate of basal ovine fetal swallowing but not fetal basal blood pressure. Angiotensin II-mediated fetal dipsogenic and pressor responses are a result of specific angiotensin II receptor binding in central brain regions. These results indicate that fetal exposure to angiotensin II antagonists or angiotensin-converting enzyme inhibitors may have adverse effects on fetal and amniotic fluid homeostasis.     

Effect of tocolytic drugs on fetal heart rate variability: a systematic review

Introduction: Tocolytics may cause changes in fetal heart rate (HR) pattern, while fetal heart rate variability (HRV) is an important marker of fetal well-being. We aim to systematically review the literature on how tocolytic drugs affect fetal HRV.

Materials and methods: We searched CENTRAL, PubMed and EMBASE up to June 2016. Studies published in English, using computerized or visual analysis to describe the effect of tocolytics on HRV in human fetuses were included. Studies describing tocolytics during labor, external cephalic version, pre-eclampsia and infection were excluded. Eventually, we included six studies, describing 169 pregnant women.

Results: Nifedipine, atosiban and indomethacin administration show no clinically important effect on fetal HRV. Following administration of magnesium sulfate decreased variability and cases of bradycardia are described. Fenoterol administration results in a slight increase in fetal HR with no changes in variability. After ritodrine administration increased fetal HR and decreased variability is seen. The effect of co-administration of corticosteroids should be taken into account.

Conclusion: In order to prevent iatrogenic preterm labor, the effects of tocolytic drugs on fetal HRV should be taken into account when monitoring these fetuses.