The effects of antenatal betamethasone administration on fetal heart rate and behaviour depend on gestational age

OBJECTIVE: We previously reported decreases in fetal heart rate (FHR) variability and body and breathing movements after maternal betamethasone administration. We now test the hypothesis that fetal responsiveness to betamethasone depends on the gestational age at which glucocorticoid therapy is started. DESIGN OF THE STUDY: 1-h recordings of FHR (n=350) and fetal movements (n=310) made during a 5-day period (days 0-4) were available for analysis. The recordings had been obtained from 63 pregnant women at high risk for preterm delivery who received betamethasone (two doses of 12 mg 24 h apart) between 26 and 34 weeks' gestational age (wGA). The response to betamethasone, i.e. the direction and magnitude of change in FHR and movement parameters compared with baseline (day 0), was studied in relation to gestational age at drug administration. RESULTS: Fetuses exposed to betamethasone at 29-34 wGA showed a decrease in FHR on day 1 (indicative of baroreceptor reflex), and reduced breathing activity and prolonged episodes of quiescence with a concomitant decrease in body movements on days 1 and 2. However, these changes were not observed if betamethasone administration occurred at 26-28 wGA. Betamethasone-induced reductions in FHR variability were similar in young and older fetuses. CONCLUSIONS: Age-related differential responsiveness to betamethasone was found for all studied fetal processes (body and breathing movements, FHR, and quiescence), except FHR variability. Our results suggest ontogenic changes in the mechanisms presumed to underlie these processes (glucocorticoid receptor (GR) maturation, cardiovascular and neuro-endocrine development).     

Diurnal rhythms in fetal heart rate baseline and sustained fetal tachycardia in twin pregnancy

OBJECTIVE: To elucidate the synchronization of phases of diurnal rhythms in fetal heart rate (FHR) baseline between twin fetuses and the occurrence of sustained fetal tachycardia. METHODS: FHR was simultaneously recorded in twins for 24 h in 7 monochorionic diamniotic (MD) and 8 dichorionic diamniotic (DD) twin pregnancies at 35 to 38 weeks of gestation. The diurnal rhythms of the hourly mean FHR baseline were tested in each fetus, and the time of occurrence of sustained fetal tachycardia was compared between twins. The correlation coefficients and phase lags of diurnal rhythms between the hourly mean FHR baselines of twins were calculated in each case. RESULTS: There were significant diurnal rhythms in the hourly mean FHR baselines of all twin fetuses (p<0.01). The patterns of diurnal rhythms were similar for each pair of twins, with the exception of the periods of sustained fetal tachycardia. Sustained fetal tachycardia was not coincident between twins. Analysis in which the periods of sustained fetal tachycardia were excluded demonstrated a significant correlation between the hourly mean FHR baselines of twins in all cases (p<0.01). In the case of DD twins, the phase lag between twins was 0; however, phase lags were observed in 4 cases of MD twins. CONCLUSIONS: The results of this study revealed that the diurnal rhythms in the FHR baseline correlated well between twins, and that the occurrences of sustained fetal tachycardia were completely independent.     

地塞米松和倍他米松对大鼠胎肺骨形态发生蛋白信号转导的影响

目的：比较产前地塞米松、倍他米松给药对大鼠胎肺骨形态发生蛋白(BMP)信号转导通路的影响。方法：15只孕鼠随机分成5组：对照组、地塞米松治疗1 d组、3 d组和倍他米松治疗1 d组及3 d组。孕鼠妊娠第19天剖腹取胎鼠肺组织,通过RT-PCR、免疫组化和Western blot技术检测各组胎肺BMP4、BMP受体2（BMPR-II）、Smad1、转录活化因子2（ATF-2）基因转录及蛋白表达水平。结果：(1) BMP4 mRNA、BMPR-II mRNA、Smad1 mRNA的表达在倍他米松3 d组、1 d组及地塞米松3 d组均高于对照组(P＜0.05)。(2)免疫组化结果显示：与对照组相比,BMP4、BMPR-II、pSmad1、ATF-2在地塞米松3 d组、倍他米松1 d组及3 d组表达量显著增加(P＜0.01)。(3) Western blot检测显示与对照组相比,BMP4、BMPR-II蛋白在地塞米松3 d组及倍他米松1 d组、3 d组中表达丰富(P＜0.01)。结论：倍他米松、地塞米松可能参与调控大鼠胎肺BMP信号转导过程。对BMP信号转导分子BMP4、BMPR-II、Smad1表达的上调可能是其促胎肺成熟的重要机制之一。［中国当代儿科杂志,2010,12(11)：891-896］     

Short-term (0-48 h) effects of maternal betamethasone administration on fetal heart rate and its variability

The short-term (0-48 h) effects of maternal betamethasone administration on computerized fetal heart rate (FHR) parameters were studied in 36 pregnancies at increased risk for preterm delivery. FHR was recorded for 90 min immediately before the start of betamethasone treatment and again at 6-h intervals during the next 48 h. Multiple linear regression models were used to assess the possible effects on FHR parameters of gestational age, time of day, clinical indication for treatment, and use of tocolytic drugs. Within 12 h after the start of treatment, significant increases occurred in FHR accelerations, and short- and long-term FHR variability (36%, 28%, and 22%, respectively), whereas basal FHR showed a 5% decrease. FHR variability was decreased by 10% at 42-48 h. The observed changes were more pronounced in older (29-33 wk of gestation) compared with younger fetuses (25-28 wk of gestation). Decelerations occurred only in 4 out of 11 compromised fetuses during betamethasone therapy. We conclude that there are significant changes in FHR parameters during the first 48 h after betamethasone administration. These changes are transient in normal fetuses. However, the compromised fetus may be adversely affected by betamethasone.     

Effects of maternal bilateral adrenalectomy and betamethasone administration on fetal rat encephalic development

The present study examined the effects of maternal bilateral adrenalectomy and betamethasone treatment on fetal encephalic development, in terms of fetal body weight, brain weight, DNA, protein and lipid content and morphological development. Both influenced the developmental time patterns of fetal brain and cerebellum. Fetuses of adrenalectomized rats had decreased body weights, whereas brain weight was not affected. Maternal adrenalectomy produces in fetal brain a decreased number of cells and increased cell size, while betamethasone treatment of adrenalectomized rats increased cell number, which was not different from control values; cell size remained lower than in control fetuses. Lipid content was increased in the fetuses of betamethasone-treated rats. In terms of morphological development, laminated structures (hippocampus and brain and cerebellar cortex) were the ones most affected.     

Maternal anxiety in late pregnancy: effect on fetal movements and fetal heart rate

AIM: To determine whether maternal state and trait anxiety levels affect fetal movements or fetal heart rate (FHR) in the third trimester. SUBJECTS: Forty-one healthy pregnant nulliparous women not on medication and with a singleton pregnancy. STUDY DESIGN: Maternal anxiety was assessed using the Spielberger State- Trait Anxiety Inventory (Form Y) at 36 gestational weeks. The fetuses of the women were examined at 37-40 gestational weeks with ultrasound observation of fetal movements and cardiotocography (CTG). The results of the fetal examinations were compared between women with low and high anxiety scores (low scores being defined as scores below the median and high scores as scores equal to or above the median of the study population), and correlation analyses between anxiety scores and the outcome variables were performed. OUTCOME MEASURES: The presence and duration (expressed as a percentage of the total examination time) of FHR patterns A, B, C, and D, the percentage duration of fetal movements in each FHR pattern, baseline FHR and FHR variability in each FHR pattern. RESULTS: The presence of FHR patterns A, B, C, and D, the duration of FHR patterns A, B, and C, FHR variability in FHR patterns A, B, and C, baseline FHR and the percentage duration of fetal movements in each FHR pattern did not differ between women with low and high state and trait anxiety scores. In fetuses with FHR pattern D, the duration of FHR pattern D increased with increasing maternal trait anxiety scores, (rho=0.88; p=0.008), and FHR variability in FHR pattern D increased with maternal state and trait anxiety scores (r=0.86, p=0.01; r=0.96, p=0.001). CONCLUSION: Maternal anxiety does not seem to affect fetal movements or baseline FHR in late pregnancy, but there is a possible association between maternal anxiety and the duration of FHR pattern D and FHR variability in FHR pattern D.     

Changes in fractal features of fetal heart rate during pregnancy

OBJECTIVE: Our objective was to examine whether heart rate time series of healthy normal fetuses possess fractal properties and, if so, to determine whether consistent changes in fractal features according to gestational age exist. DESIGN OF THE STUDY: One hundred nineteen fetal heart rate (FHR) recordings in 55 singleton pregnancies between the 22nd and 41st weeks were analyzed. Fractal analysis developed by Higuchi was performed. Changes of fractal dimension were examined according to gestational age. RESULTS: Two characteristic scaling regions were present in each FHR trace. The fractal dimension defined within 500 ms to 5 s (D(S); median 1.396, range 1.273-1.642) was lower than that defined longer than 30 s (D(L); median 1.933, range 1.492-2.049) in every case. These two values were significantly different (p<0.001). There was a statistically significant difference in the values of D(S) between (22-29 weeks, mean 1.323), (30-33 weeks, mean 1.443) (p=0.004), (34-35 weeks, mean 1.418) (p=0.002), (36 weeks, mean 1.409) (p=0.030), (37-38 weeks, mean 1.394) (p=0.006), and (40-41 weeks, mean 1.452) (p=0.001), respectively. D(S) values between (40-41 weeks), (37-38 weeks) (p=0.012), and (39 weeks, mean 1.369) (p=0.030), respectively, were also significantly different. The values of D(L) decreased from 22-39 weeks (median 1.941) to 40-41 weeks (median 1.891) (p=0.008). CONCLUSIONS: Two distinct fractal structures within the FHR variation were identified. Fractal features of heart rate of healthy normal fetuses change significantly during pregnancy period. Fractal analysis may be useful for evaluating FHR variation.     

Aerobic exercise during pregnancy influences fetal cardiac autonomic control of heart rate and heart rate variability

Background

Previous studies using ultrasound technology showed that fetal heart rate (HR) may be responsive to maternal aerobic exercise. Although it is recognized that cardiac autonomic control may be influenced by the intrauterine environment, little is known about how maternal exercise affects fetal heart development.

Aims

This study tested the hypothesis that regular maternal exercise throughout gestation influences fetal cardiac autonomic control of HR and heart rate variability (HRV) when compared to fetuses of non-exercising women.

Study design

Magnetocardiograms (MCGs) were recorded using a dedicated fetal biomagnetometer at 28, 32 and 36 weeks gestational age (GA) from 26 regularly exercising (> 30 min of aerobic exercise, 3× per week) and 35 healthy, non-exercising pregnant women. Fetal MCG was isolated and normal R-peaks were marked to derive fetal HR and HRV in the time and frequency domains. We applied a mixed-effects model to investigate the effects of exercise, GA and fetal activity state.

Results

At 36 weeks GA, during the active fetal state, fetal HR was significantly lower in the exercise group (p = < 0.0006). Post-hoc comparisons showed significantly increased HRV in the exercise group during the active fetal state at 36 weeks GA for both time and frequency domain measures.

Conclusion

These results indicate that regular maternal exercise throughout gestation results in significantly lower fetal HR and increased HRV.     

The effect of antenatal steroid treatment on fetal autonomic heart rate regulation revealed by fetal magnetocardiography (fMCG)

Background

Steroid administration to accelerate fetal lung maturation reduces neonatal morbidity and mortality in the case of preterm delivery. Behavioral observations suggest effects on fetal cardiovascular regulation.

Aim

We hypothesize that beat to beat heart rate variability (fHRV) derived from fetal magnetocardiography (fMCG) will reveal a direct, acute steroidal effect on fetal autonomic heart rate regulation.

Subjects

Eight patients between 29 and 34 weeks of gestation at risk for preterm birth who were treated with betamethasone (2 × 12 mg within 24 h).

Study design

Subjects were studied prior to the first and within 6 h after the second administration. Continuous fMCG was recorded with a 31-channel-SQUID biomagnetometer. Each dataset was processed by subtracting maternal cardiac artefacts and determining the time instants of the fetal heart beats. fHRV analysis was applied to periods of fetal quiescence of 4 min length.

Outcome measures

We compared fHRV prior versus post steroid administration.

Results

Steroid exposure reduced all parameters of overall fHRV significantly. The fHRV parameters representing short term variability remained unaffected. Mean fetal heart rate significantly decreased. The complexity of the heart rate patterns increased.

Conclusion

Our results suggest an acute shift in the symptaho-vagal balance of fetuses exposed to betamethasone in utero toward sympathetic suppression.     

Total leukocyte and neutrophil count changes associated with antenatal betamethasone administration in premature infants

The white blood cell counts of 84 premature infants were included in a retrospective study of 45 infants treated antenatally with betamethasone and 39 non-treated infants. A significant increase in neutrophil and immature neutrophil forms was found in the treated group when the drug was administered to the mother close to delivery. This effect lasted for three days. Afterwards, although the counts were not significantly high compared to the control group, their physiological decrease was delayed. This study indicates that the known stimulating effect of steroids on total leukocyte and neutrophil counts in adult humans and fetal lambs, also occurs in premature infants. This fact supports recent reports which propose the antenatal maternal administration of betamethasone as a cause of leukemoid reaction or leukocytosis after birth.     

Fetal behavior in normal dichorionic twin pregnancy

Objectives

A prospective study was performed to compare fetal behavioral development in healthy dichorionic twins and singletons, and identify twin intra-pair associations (synchrony) of fetal movements and rest–activity cycles using different criteria to define synchrony.

Subjects and methods

Twenty pregnant women carrying dichorionic twins participated. Serial simultaneous 1-hr recordings of fetal movements were made on twins between 11 and 40 weeks' gestation (wGA) using two ultrasound machines. All twins were born healthy after 36 wGA and of appropriate weight for gestation. The incidences of fetal generalized body movements (GM) and breathing movements in twins were compared with institutional reference values for singletons. A comprehensive smoothing procedure on the raw movement data was performed to evaluate previously reported variation in twin intra-pair synchrony.

Results

Twin fetuses were less active (GM) than singletons throughout pregnancy, but their breathing activity was higher in the third trimester. The incidences of fetal GM, quiescence, and breathing were fairly correlated within twin pairs. However, the temporal association or simultaneous occurrence of these activities was poor, especially after 30 weeks' gestation, coinciding with emerging rest–activity cycles. There was no evidence of a consistently more active (‘dominant’) twin half. Potential confounders had no effect on behavioral development in fetal twins.

Conclusions

The results show differential behavioral development between normal dichorionic fetal twins and singletons. Within fetal twin-pairs, we found poor synchrony of movements and independent occurrence of rest–activity cycles. Previous research on fetal twin behavior appears to have overestimated the degree of intra-pair movement synchrony.     

Effect of antenatal betamethasone therapy on maternal-fetal Doppler velocimetry

Background: The effect of antenatal betamethasone on fetal parameters includes a transient reduction of FHR variation and of fetal body movements. An effect on maternal–fetal blood flow has also been shown, with non-univocal results. Aims: To evaluate the effect of antenatal betamethasone in third trimester singleton high-risk pregnancies by Doppler technology. Subjects and methods: Thirty-six pregnant women who received a full course of betamethasone (12 mg i.m. two times, 24 h apart) were studied. The Doppler examination included the assessment of the pulsatility index (PI) of the umbilical artery (UA PI), the middle cerebral artery (MCA PI) and of resistance index of uterine arteries (Ut RI) before treatment, and 48 and 96 h after second dose of betamethasone. Results: No significant variation was noted in UA PI through betamethasone therapy. MCA PI decreased significantly 48 h from the last injection of betamethasone (P=0.002), and returned to basal values at 96 h. No difference was found for the other Doppler parameters examined. When serial Doppler studies were analyzed according to the gestational age, in the group <32 weeks’ gestation, MCA PI decreased significantly after 48 h (P<0.006) and returned to pre-treatment values after 96 h from the last betamethasone dose. Conversely, no difference was found in Doppler serial measurements in any of the analyzed districts in the subgroup ≥32 weeks. Conclusion: Betamethasone treatment is associated with a significant, although transient, reduction of MCA PI, especially at gestational ages <32 weeks’.     

Effects of women's stress-elicited physiological activity and chronic anxiety on fetal heart rate

This study examined the effects of pregnant women's acute stress reactivity and chronic anxiety on fetal heart rate (HR). Thirty-two healthy third trimester pregnant women were instrumented to monitor continuous electrocardiography, blood pressure, respiration, and fetal HR. Subjects completed the trait anxiety subscale of the State Trait Anxiety Index, then rested quietly for a 5-minute baseline period, followed by a 5-minute Stroop color-word matching task and a 5-minute recovery period. Fetal HR changes during women's recovery from a stressful task were associated with the women's concurrently collected HR and blood pressure changes (r =.63, p <.05). Fetal HR changes during recovery, as well as during women's exposure to the Stroop task, were correlated with their mothers' trait anxiety scores (r =.39, p <.05 and r = -.52, p <.01, respectively). Finally, a combination of measures of women's cardiovascular activity during recovery and trait anxiety scores accounted for two thirds of the variance in fetal HR changes during the same recovery period (r =.69, p <.001). The results from this study link changes in fetal behavior with acute changes in women's cardiovascular activity after psychological stress and women's anxiety status. This indicates that variations in women's emotion-based physiological activity can affect the fetus and may be centrally important to fetal development.     

Does fetal heart rate predict subsequent heart rate in childhood?

An investigation to determine whether there is any relationship between extremes of fetal heart rate during labour and subsequent heart rate at the age of 10 was carried out using data from the 1970 cohort of British Births. In 11,000 nationally representative children it was found that low fetal heart rate (below 120 beats/min) was associated with a heart rate at age 10 which was significantly lower than in those children whose fetal heart rate had remained between 120 and 160 beats/min (P less than 0.01). This relationship could not be explained by fetal asphyxiation, maternal antenatal hypotension or the method of pain relief during labour. There was no equivalent relationship with high fetal heart rate during labour. This could imply that some fetuses with low heart rates are not exhibiting fetal distress but have an inherent tendency to relatively slow heart rates.     

Effect of antenatal administration of thyrotrophin releasing hormone on fetal flow velocity waveforms

AIM—To determine whether antenatal administration of thyrotrophin releasing hormone (TRH), to promote lung maturation, alters blood flow through the fetal middle cerebral, umbilical artery, or ductus arteriosus and through the maternal uterine arteries.METHODS—The effect of transplacentally administered TRH on the fetal circulation was prospectively evaluated in 30 patients between 24 and 34 weeks'' gestation. TRH (400 µg) was given to the mother intravenously either as a bolus or an infusion. Fetal effects were determined by measuring the maximum velocity and pulsatility index (PI) in middle cerebral artery, ductus arteriosus, uterine artery and umbilical artery Doppler waveforms. Measurements were made immediately before, and 10 and 60 minutes after maternal TRH administration.RESULTS—Intravenous injection of TRH had no significant effect on PI in the uterine, umbilical, or middle cerebral artery and the ductus arteriosus within 60 minutes of administration in either group.CONCLUSION—The antenatal use of TRH in conjunction with steroids for fetal lung maturity does not affect utero-placental or fetal haemodynamic variables, as measured by Doppler. These findings, therefore, do not support the suggestion that antenatal intravenous administration of TRH either as bolus or infusion may have immediate adverse vascular effects in the fetus.     

Alcohol in pregnancy and fetal heart damage]

Alcohol abuse and addiction during pregnancy can induce damage of the heart muscle and heart defects in the offspring. Between 1973 and 1991 216 children with fetal alcohol syndrome were diagnosed and examined for congenital heart defects. In 63 children (= 29,1%) heart defects were present, established mainly by heart catheterization and/or echocardiography. Most frequently ventricular septal defects (24/63) and atrial septal defects (23/63) occurred, less frequent were AV-defects (3), PDA (3), Fallots teralogy (5), and other malformations (5). Biopsy during heart surgery in 3 children revealed histological and electron microscopic changes of alcohol-cardiomyopathy. Heart defects are predominantly found in children with higher degree of severity concerning the clinical syndrome, less frequently in alcohol effects (4/38 = 11%). Alcohol in pregnancy, even in the course of so called social drinking, usual drinking and binge drinking has to be considered as an essential and preventable co-factor within the multifactorial etiology of congenital heart defects.     

Fetal heart rate in early pregnancy

Heart rates were measured by transvaginal sonography twice weekly in ten first trimester fetuses in women who conceived after in-vitro fertilization (IVF) or zygote intra-fallopian transfer (ZIFT). From week 6 to week 9 of menstrual age a rapid increase of the mean heart rate was observed from 113 to 167 beats per min, followed by a slow decrease to 156 beats per min. A close correlation between crown-rump length and heart rate was established.     

Increased constriction of the ductus arteriosus with combined administration of indomethacin and betamethasone in fetal rats

To find a better treatment for patient ductus arteriosus of preterm infants, we studied the combined effect of indomethacin and betamethasone on the fetal ductus in rats. We used a rapid whole-body freezing technique, and the ratio of the inner diameter of the ductus to the main pulmonary artery, which was 1.0 in controls, was used as an index of constriction. Indices of ductal constriction 4 h after administration of indomethacin (1 mg/kg) alone, betamethasone (1 mg/kg) alone or in combination in near-term rats were 0.56 +/- 0.05 (mean +/- SEM), 0.76 +/- 0.06, and 0.17 +/- 0.03, respectively. In preterm rats too, a marked increase in fetal ductus constriction was observed with the combined administration of these two drugs. Study of the dose effect of betamethasone revealed that maximal effects were obtained with 1 mg/kg of betamethasone combined with indomethacin in both preterm and near-term fetal rats. Increased constriction of the fetal ductus with combination treatment persisted from 1 to 8 h after administration. Administration of betamethasone 24 h before the rat was killed did not augment constriction of the fetal ductus by indomethacin administered 4 h before they were killed. Fetal ductus constriction by sulindac, another nonsteroidal antiinflammatory drug with little inhibitory effect on renal function, also was augmented by combined use with betamethasone (1 mg/kg). In conclusion, ductal constriction was markedly increased by combined administration of indomethacin and betamethasone in near-term and preterm fetal rats.