A study on cardiac autonomic modulation during pregnancy by non-invasive heart rate variability measurement

Purpose: Remarkable and uncontrollable changes with modifi cation during pregnancy are connected with the autonomic control and consequently with the heart rate variability (HRV). Heart rate variability is a sum of different mechanisms and if pregnancy is a state of change, these modifi cations could be extracted from HRV analysis. Objective: To assess the effect of pregnancy on heart rate variability among pregnant mothers during fi rst trimester of pregnancy and third trimester of pregnancy. Materials and Methods: HRV was measured for 5 minutes of continuous recording of electrocardiogram (ECG) lead II, using windows based HRV analysis system variowin-HR after obtaining permission from the Institutional Review Board of Government Medical College, Bhavnagar and written consent from 30 pregnant subjects and 30 non-pregnant control subjects at autonomic function lab, Dept of Physiology, Bhavnagar. Result: Frequency domain parameters, very low frequency (VLF), low frequency (LF), high frequency (HF) and HF normalized unit (nu) were signifi cantly decreased and LF (nu) and LF/HF signifi cantly increased in pregnant subject in 3rd trimester as compared to their 1st trimester of pregnancy. Time Domain parameters like SDNN, RMSSD, SDSD, NN50 count, pNN50, SD1/SD2, triangular HRV index and average R-R interval were signifi cantly decreased during 3rd trimester of pregnancy. Conclusion: The inhibition of resting parasympathetic activity or vagal blockage and an increment of the sympathetic modulation during the 3rd third trimester of gestation in pregnancy as compared to their 1st trimester and healthy non-pregnant subjects. Sympathovagal imbalance and abnormally low HRV may more pronounce during later stage of normal pregnancy.


INTRODUCTION
The last three decades have witnessed the recognition of a signifi cant relationship between the autonomic nervous system and cardiovascular mortality, including sudden cardiac death. [1]Heart rate variability (HRV) is a non-invasive, easy and economical technique to assess the status of autonomic nervous regulation of cardio vascular system.Heart with a stable and regular heart beat periodically is now considered as the marker for a poor prognostic for longevity. [2]HRV studies enhance understanding of physiological phenomenon of heart activity especially during pregnancy.The changes in the function of every regulatory system during pregnancy are initiated by ovarian and placental hormones in the fi rst trimester, but may also be modifi ed by placental and fetal endocrine factors as gestational age advances.Pregnancy-induced effects on cardiovascular function are increases in heart rate (HR), stroke volume (SV), and cardiac output. [3,4]These changes result from the interactive effects of a primary reduction in peripheral vascular resistance, [5]  indicator). [3,9]Ekholm et al. studies on cardiac autonomic function in human pregnancy have produced conflicting results.Their fi ndings of reduced total power [10,11] and attenuated HR responses to orthostatic tests and the Valsalva maneuver [11] suggest that cardiac parasympathetic modulation is reduced in the resting state during mid pregnancy (22-29 wk of gestation).Studies conducted in early to mid gestation (11-27 wk) [12] were reported reduction in low-frequency HRV during the day and reduction in high-frequency HRV at night.

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To assess the heart rate variability during fi rst trimester of gestation in pregnancy and third trimester of gestation in pregnancy.

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To study the effect of various stages of normal pregnancy on heart rate variability.

MATERIALS AND METHODS
Pregnant subjects were enrolled into the study from Obstetric department after permission was taken from Institutional Review Board (IRB) and Human Ethics Committee of Government Medical College, Bhavnagar.This study was carried out at autonomic nerve function lab, Dept. of Physiology, Govt.Medical College and Sir T Hospital, Bhavnagar.Short HRV was measured for 5 minutes from continuous recording of ECG (heart rate) using windows based HRV analysis system variowin-HR.

Sample size
Due to pregnancy termination or development of pregnancyinduced complication, out of 42 in 1 st visit, 30 pregnant subjects were selected for 2 nd visit.30 normal pregnant subjects and 30 ages matched healthy non-pregnant control subjects were enrolled.

Inclusion criteria of pregnant subjects
Age of 18 yrs-45 yrs and Hb is of >9.0 gm% pregnant subject and giving written consent for HRV recording.

Exclusion criteria of pregnant subjects
Any illness and pregnancy-induced complication develop at any stage of pregnancy during this study.

Inclusion criteria of non-pregnant subjects
Age of 18 yrs-45 yrs non-pregnant subject having Hb >9.0% and ready for giving written consent for HRV recording.

Exclusion criteria of controls
Any illness.

Procedure
In the presence of relatives and one female staff, all participants were allowed to relax for ten minutes.Case record form containing personal information of subjects, anthropological measurements, last menstrual period, total month of amenorrhea, obstetric history, clinical history and vitals were fi lled up.Subjects were asked to lie down in a supine position and remain quiet, without speaking or making any movements for 5 minutes.
Four electrodes were placed at both infraclavicular and both hypochondrial regions of the subjects.HRV were measured by continuous lead II ECG recording for 5 minutes (short-term HRV) based on R-R interval.The pregnant women were called for two times for HRV measurement, during 1 st trimester of gestation (6-12 weeks of pregnancy) and during 3 rd trimester of gestation (25-36 weeks of pregnancy).Both time domain (SDNN, RMSSD, SDSD, NN50 Count, pNN50%) and frequency domain (VLF, LF, HF, LF/ HF ratio) parameters of HRV analyses were measured.

Statistical analysis
We were using graph Pad InStat statistical software for data analysis.

RESULTS
There is no any signifi cant difference in age and height between cases and controls.This infers that the case subjects and healthy controls were ideally matched for age and height to relatively nullify the effect of confounding variable factor on HRV.The weight and body mass index (BMI) values were statistically signifi cant in both groups.{1 st trimester of gestation and Controls; 3 rd trimester of gestation and Controls} [Table 1a and b].
There were no signifi cant difference in values of HRV parameters among 1 st trimester subject group and control group.This infers that in early normal pregnancy, there may not be any change in the cardiac autonomic regulatory mechanism in spite of hormonal changes.This may be due to other compensatory mechanism [Table 2].
There was signifi cant decrease in both frequency domain parameters and time domain parameters during 3 rd trimester of gestation in pregnancy as compared to healthy control [Table 3].   and healthy non-pregnant control subjects.However, LF, HF and normalized HF were reduced in 1 st trimester of gestation subjects.This may be due to the effect of maternal or placental hormones during the early phase of pregnancy.
Stein et al., reported that in early pregnancy, statistical differences in the spectral indexes tend to be smaller than in late pregnancy with major contradictions in the published data. [13]They were no reported signifi cant differences in early pregnancy (with respect to non-pregnancy) except for LF region and RRsd and mainly, during the sleep-time but no differences were observed at all with respect to late pregnancy. [13]This study among 1 st trimester of gestation shows similar type of result.Greenwood et al. [14] found that the vasomotor sympathetic activity increased in women with normal pregnancy and was even greater in hypertensive pregnant women during the 3 rd trimester of gestation.They concluded that the marked sympathetic hyperactivity during the latter months of normal pregnancy helped to return the arterial pressure to non-pregnant levels, but when the increase in sympathetic nerve activity was excessive, hypertension ensued.Their preliminary data suggest that normal pregnancy may also be associated with an increase in resting vasomotor sympathetic outfl ow, and pregnancy per se can result in sympathetic activation despite a normal blood pressure.That is quite comparable to our study result as LF: HF and LF (nu) increment during the 3 rd trimester of gestation that represents the sympathetic over activity.

As per
As per Table 4, in frequency domain parameters, mean values of VLF, LF, HF, HF normalized were signifi cantly reduced in 3 rd trimester of gestation in pregnancy and mean values of LF: HF and LF normalized were signifi cantly increased during the 3 rd trimester of pregnancy as compared to the 1 st trimester of gestation in pregnancy.This shows the sympathetic dominance is more during 3 rd trimester of pregnancy as compared to 1 st trimester of gestation.Reduction in HF and LF during 3 rd trimester of gestation in pregnancy shows the decreased activity of parasympathetic system or its turn to developing vagal blockage as pregnancy advance.
In normalized units, an increased LF (0.7273 ± 0.12) and a diminished HF (0.2663 ± 0.1030) were observed during 3 rd trimester of gestation in pregnancy.These indicate a shift of sympathovagal balance towards a sympathetic predominance and a reduced vagal tone during 3 rd trimester of gestation.Similar conclusions were obtained by considering the changes in LF/HF ratio.Signifi cant reduction in RMSSD, NN50 count, pNN50% and HF (ms 2 ) during Heiskanen et al's., [15] study showed that in normal pregnancy, the increment of the heart rate could be partially associated with the inhibition of resting parasympathetic activity connected with an increment of the sympathetic modulation but during the 3 rd third trimester of pregnancy there could be a parasympathetic deactivation instead of an increment of the sympathetic activity (under unstimulated conditions) even when the head-up tilt test induce changes in the parasympathetic activity and the sympathovagal balance.
The presence of a high vagal tone seems to be a marker of physiological, biological and psychological flexibility.So, decreased vagal tone in 3 rd trimester of gestation group in our study may cause loss of fl exibility in physiological systems in general, and in the cardiovascular system in particular, which has been linked with a number of diseases and dysfunctions.So, abnormally low heart rate variability in our study indicates that even normal pregnancy without any complication can impact dramatically on dynamic autonomic control of heart.This is an issue that requires inter-disciplinary approaches across multiple levels of analysis, ranging from the psychological to the biochemical investigation.

CONCLUSION
As normal pregnancy advances in its stage, the inhibition of resting parasympathetic activity connected with an increment of the sympathetic modulation is noted.The effect of sympathetic dominance may be controlled by other mechanism of the body during the 3 rd trimester of gestation in pregnancy such as regulation of blood pressure, heart rate and cardiac output in normal pregnancy.
HRV can be applied as early diagnosis of pregnancy induced cardiac abnormalities with correlate it with other investigation.
cardiac autonomic modulation and barorefl ex function that lead to a higher resting heart rate.International Journal of Medicine and Public Health | Oct-Dec 2014 | Vol 4 | Issue 4 VLF = Very low frequency, LF = Low frequency, HF = High frequency, LF = HF-LF and HF ratio, LF(nu) = Normalized LF, HF(nu) = Normalized HF, SDNN = Standard deviation of all NN interval, RMSSD = The square root of the mean of the sum of the squares of diff erences between adjacent NN intervals, SDSD = Standard deviation of diff erences between adjacent NN intervals, NN50 = Number of pairs of adjacent NN intervals diff ering by more than 50 ms in the entire recording, pNN50% = NN50 count divided by the total number of all NN intervals, HR = Heart rate

Table 1 : (a) Mean ± SD values of anthropological measurement among 1 st trimester of gestation in pregnant subject and 3 rd trimester of pregnancy and healthy non pregnant control subjects Parameters 1 st trimester of gestation (n = 30) Control non pregnant (n = 30) P-value
Frequency domain parameters like VLF, LF, HF and HF (nu) were signifi cantly decreased and LF (nu) and LF/HF were signifi cantly increased during 3 rd trimester of gestation as compared with their 1 st trimester of pregnancy.In time domain (power spectral) parameters, there are decreased mean values of SDNN, RMSSD, SDSD, NN50 count, pNN50, SD1/SD2.Triangular HRV index and average R-R interval are more decreased during 3 rd trimester of pregnancy.Heart Rate and Mode values are increased in 3 rd trimester as compare with 1 st trimester [Table4].DISCUSSIONAs per Table2, there were no statistical signifi cant difference in the mean values of frequency domain parameters and time domain parameters among the 1 st trimester of gestation in pregnancy subjects SD = Standard deviation, n = Number of participants, NS = No signifi cance, S = Signifi cance, P-value <0.05 indicates signifi cance

Table 3 : Comparative values of frequency domain parameters and time domain parameters between 3 rd trimester pregnant subjects and healthy non pregnant controls
International Journal of Medicine and Public Health | Oct-Dec 2014 | Vol 4 | Issue 4

Table 4 : Comparison of frequency domain parameters and time domain parameters among same subjects between their 1 st trimester of gestation and 3 rd trimester of gestation in pregnancy Parameters 1 st trimester of gestation (Mean ± SD) (n = 30) 3 rd trimester of (Mean ± SD) (n = 30)
International Journal of Medicine and Public Health | Oct-Dec 2014 | Vol 4 | Issue 4