Abstract
Introduction
Prior data suggest that higher nocturnal heart rate may represent a marker of cardiometabolic disease risk in nonpregnant adults. Data on nocturnal heart rate and pregnancy outcomes are limited. We sought to assess the association of maternal nocturnal heart rate with adverse pregnancy outcomes.
Methods
This is a secondary analysis of nulliparas in a prospective cohort at eight US sites undergoing a home sleep study using the Embletta‐Gold device with bipolar electrocardiogram at baseline (60–156 weeks) and follow‐up (220–316 weeks) visits. Exposures were mean, minimum, and maximum nocturnal heart rate at baseline and follow‐up (analyzed separately). Outcomes of interest were gestational diabetes, hypertensive disorders of pregnancy, preterm birth, small‐for‐gestational age, and stillbirth. Multivariable logistic regression models estimated the odds of each outcome, except for stillbirth due to low frequency, per each 5‐beat higher nocturnal heart rate, adjusted for possible confounders.
Results
Among 2952 eligible nulliparas, 30% experienced an adverse pregnancy outcome. We identified higher adjusted odds of gestational diabetes (minimum nocturnal heart rate mean ± standard deviation, gestational diabetes vs. no gestational diabetes: 49 ± 10 vs. 46 ± 11; adjusted odds ratio [aOR] 1.15, 95% confidence interval [CI] 1.03–1.29) and hypertensive disorders of pregnancy (48 ± 11 vs. 46 ± 11; aOR 1.05, 95% CI 1.01–1.10) for each 5‐beat higher minimum nocturnal heart rate at baseline; adjusted odds of gestational diabetes were also higher at baseline and follow‐up for mean and maximum nocturnal heart rate. At follow‐up, we identified lower adjusted odds of small‐for‐gestational age for each 5‐beat higher mean (76 ± 10 vs. 78 ± 9; aOR 0.83, 95% CI 0.78–0.88) and minimum nocturnal heart rate (48 ± 12 vs. 51 ± 13; aOR 0.90, 95% CI 0.86–0.94).
Conclusion
Higher mean, minimum, and/or maximum nocturnal heart rate in pregnancy were associated with higher odds of hypertensive disorders of pregnancy and gestational diabetes. This may reflect higher sympathetic and/or decreased parasympathetic activity in affected gravidas. Conversely, lower mean and minimum nocturnal heart rate in late pregnancy were associated with higher odds of small‐for‐gestational age, which may be reflective of maladaptive hemodynamic changes in affected gravidas.
Keywords: autonomic nervous system, gestational diabetes, hypertensive disorders of pregnancy, nocturnal heart rate, preterm birth, small‐for‐gestational age
Abbreviations
- aOR
adjusted odds ratio
- APO
adverse pregnancy outcome
- CI
confidence interval
- GDM
gestational diabetes
- HDP
hypertensive disorders of pregnancy
- HELLP
hemolysis, elevated liver enzymes, low platelets
- iPTB
indicated preterm birth
- IRLSSG
International Restless Legs Syndrome Study Group
- NHR
nocturnal heart rate
- NuMoM2b
Nulliparous Pregnancy Outcomes Study: Monitoring Mothers‐to‐Be Study
- PTB
preterm birth
- PTSD
post‐traumatic stress disorder
- SD
standard deviation
- SDB
Sleep Disordered Breathing
- sPTB
spontaneous preterm birth
1. INTRODUCTION
Heart rate reflects dynamic changes in the autonomic nervous system, comprised of the combined effects of the sympathetic nervous system and the parasympathetic nervous system [1]. A higher heart rate reflects a sympathetic dominance—either higher sympathetic activity or decreased parasympathetic activity—on the sinus node, and often occurs in response to psychosocial or physiologic stressors [1, 2].
Sleep represents an opportune time to measure resting heart rate, as environmental factors and activities of daily living influence nocturnal heart rate (NHR) less than during the daytime [3]. Chronic psychosocial and/or physiologic stress may incite nocturnal sympathetic activation and suppression of the parasympathetic drive, and is reflected in a higher resting and NHR [2]. Higher NHR may represent a marker of cardiometabolic disease risk, including diabetes, obesity, and hypertension, in nonpregnant adults, among other disease states [3]. NHR responses to respiratory events (i.e., apneas or hypopneas) and sleep stages also vary and predict adverse cardiovascular outcomes in nonpregnant adults [4, 5].
Psychosocial and metabolic stress are risk factors for adverse pregnancy outcomes (APOs), including gestational diabetes (GDM), hypertensive disorders of pregnancy (HDP), preterm birth (PTB), and small‐for‐gestational age (SGA). These APOs cumulatively affect approximately one‐fourth of pregnancies and contribute to significant maternal and neonatal morbidity [6, 7]. Sleep characteristics are also associated with APOs, which may be mediated by autonomic nervous system changes and reflected in NHR responses [8, 9]. NHR is a potential clinical biomarker that reflects increased sleep reactivity as a physiologic response to psychosocial and/or physiologic stress [10]; however, it is unknown whether NHR during pregnancy is associated with APOs. Therefore, we sought to assess this association to evaluate NHR as a potential biomarker to differentiate between individuals who experience, or do not experience, HDP, GDM, PTB, and SGA. We hypothesized that higher mean, minimum, and maximum NHR would be associated with higher risk of these APOs.
2. MATERIALS AND METHODS
This is a secondary analysis of nulliparas enrolled in the prospective observational Sleep Disordered Breathing (SDB) Sub‐study of the Nulliparous Pregnancy Outcomes: Monitoring Mothers‐to‐Be (nuMoM2b) study conducted at eight clinical sites in the United States and managed by an independent data coordinating center. Detailed methods of the nuMoM2b parent study and SDB Sub‐study have been previously published [11, 12]. Each site's local governing Institutional Review Board approved the study. All participants provided informed written consent prior to participation.
Nulliparous pregnant people (i.e., no prior delivery ≥ 20 weeks’ gestation) with a viable singleton pregnancy at the time of screening from 60 to 136 weeks’ gestation were eligible for participation. Participants were then offered enrollment into the SDB Sub‐study, which was designed to evaluate SDB during pregnancy as a risk factor for developing HDP and GDM [9]. Exclusion criteria for the SDB Sub‐study included current SDB treatment with continuous positive airway pressure, severe asthma requiring continuous oral steroid therapy for more than 14 days for treatment of asthma, or a condition requiring oxygen supplementation. After enrollment, participants received routine prenatal care and trained research coordinators obtained longitudinal clinical measurements during study visits [11].
2.1. Sleep study procedures
Level 3 home sleep tests were performed twice during pregnancy for a single night, at baseline between 60 and 156 weeks of pregnancy (within 2 weeks following nuMoM2b study visit 1 from 60 to 136 weeks’ gestation) and at a follow‐up interval between 220 and 316 weeks (within 2 weeks of study visit 3 from 220 to 296 weeks’ gestation) [11]. For each home sleep test, participants self‐applied the Embletta‐Gold device, a six‐channel monitor including a bipolar electrocardiogram. Sleep study data from each study site were transmitted to a central sleep reading center and scored by individuals masked to all other study data [11]. Rather than recording sleep directly with electroencephalogram or electromyography signals, certified polysomnographic technologists estimate sleep and wake times by interpreting movement, heart rate, and respiratory patterns on level 3 sleep monitoring devices and participant self‐report of sleep and wake times on questionnaires [11, 13]. Segments of the home sleep test with heart rate data following sleep initiation were excluded from analysis if significant movement or artifact occurred for a period of ≥20 min [11]. Further details regarding level 3 home sleep tests are provided in the nuMoM2b SDB Sub‐study protocol [11]. At the baseline and follow‐up sleep studies, the Respiratory Event Index was derived as the number of apnea or hypopnea events with ≥3% oxygen desaturation per estimated hour of sleep; a Respiratory Event Index score ≥5 is indicative of at least mild obstructive sleep apnea [14, 15]. The Oxygen Desaturation Index was derived as the number of events with oxygen desaturation ≥3% per estimated hour of sleep [16].
Data regarding exposure to potential disruptors of sleep (systemic steroid use, alcohol or tobacco use, coffee or other caffeine intake, or sleeping pill use) were assessed by participant self‐report in medical interview and/or chart abstraction [11]. All nuMoM2b participants also completed sleep questionnaires at baseline and follow‐up, including the Epworth Sleepiness Scale (a measurement of daytime sleep propensity), assessment of the International Restless Legs Syndrome Study Group diagnostic criteria for restless legs syndrome, and the Women's Health Initiative Insomnia Rating Scale (quantifying insomnia symptom severity) [17, 18, 19].
2.2. Exposures and outcomes
Exposures for this analysis were mean, minimum, and maximum NHR in beats per minute (bpm) at the baseline and follow‐up visits, analyzed separately. Outcomes of interest were the following APOs, assessed individually: GDM, HDP, PTB, SGA, and stillbirth. For this analysis, we excluded individuals who had a diagnosis of pregestational diabetes and chronic hypertension prior to study entry, were under age 18 years, had a pregnancy loss prior to 200 weeks’ gestation or pregnancy termination, or had missing data on all exposure variables or outcomes [9].
APOs were defined, assessed, and adjudicated as extensively outlined in the nuMoM2b parent study, and consistent with methods of assessment and definitions used in prior publications of the nuMoM2b SDB study [8, 9, 12]. GDM and HDP (including cases of gestational hypertension, preeclampsia, eclampsia or HELLP syndrome [hemolysis, elevated liver enzymes, low platelets]) were defined using standard clinical definitions and determined based on chart abstraction, with adjudication when needed [8, 9]. PTB was defined as delivery of a liveborn or stillborn infant prior to 370 week's gestation based on well‐established dating criteria. PTB was further classified as indicated (iPTB; defined as labor induction or cesarean delivery performed in the absence of labor for maternal and/or fetal health reasons) or spontaneous (sPTB; defined as a PTB due to spontaneous onset of preterm labor or prelabor rupture of membranes) [12]. SGA was defined as neonatal birthweight less than the 10th percentile among liveborn infants according to the Alexander growth curve [12]. Stillbirth was defined as fetal death ≥200 week's gestation [12]. We report the incidence of stillbirth, but do not perform additional statistical analysis for this outcome, due to the low frequency.
2.3. Statistical analysis
Descriptive statistics were used to characterize baseline sociodemographic, clinical, and sleep characteristics in the study population overall and stratified by those who did and did not experience any of the APOs. We also report sleep questionnaire scores, estimated average sleep duration (in hours, determined from the sleep study), estimated sleep efficiency percentage (calculated as the proportion of estimated sleep time within the period from sleep onset to sleep offset), and Respiratory Event Index and Oxygen Desaturation Index at baseline and follow‐up [15, 20]. Chi‐squared tests and independent samples t‐tests assessed associations with categorical and continuous variables, respectively. An alpha level of 0.05 was used to determine statistical significance.
Crude and adjusted odds ratios (aOR) and 95% confidence intervals (CI) were calculated from univariate and multivariate logistic regression models to relate NHR exposures with individual APOs. Specifically, multivariate logistic regression models estimated the odds of each outcome per each 5‐beat higher NHR at baseline and follow‐up, with 95% CI based on robust standard errors clustered around study sites, adjusted for possible confounders chosen based on prior literature in conjunction with expert input. The following confounders were assessed at the baseline study visit: age, self‐reported race and ethnicity (as a proxy for discrimination), insurance type, tobacco use, and body mass index. Additional sleep variables (restless legs syndrome symptoms [International Restless Legs Syndrome Study Group score equal to 4], estimated average sleep duration [hours], estimated sleep efficiency percentage, and Oxygen Desaturation Index) were assessed at the baseline and follow‐up study visits and included as covariates in adjusted models as they have been shown to affect cardiovascular responses to autonomic function, and may thus confound the relationship between NHR and the outcomes of interest [21, 22]. We adjusted for Oxygen Desaturation Index in lieu of Respiratory Event Index, as prior analyses of the nuMoM2b cohort suggest that the simpler measure of Oxygen Desaturation Index, which quantifies the frequency of oxygen saturation drops, compared to Respiratory Event Index, which accounts for changes in both airflow and oxygen saturation, may better identity those at increased risk of adverse health outcomes related to pregnancy [15]. Analyses were conducted using Stata version 18.0 MP (College Station, TX) software.
3. RESULTS
3.1. Baseline demographic, clinical, and sleep characteristics
Of 10,038 nulliparas enrolled in the nuMoM2b parent study, 2952 had SDB Sub‐study data available and met all other eligibility criteria for analytic cohort inclusion (Figure 1). Individuals enrolled in the nuMoM2b parent study who participated in the SDB Sub‐study had similar baseline characteristics as those who did not [9]. The mean (±standard deviation) gestational ages of the baseline and follow‐up sleep studies were 11.9 (±1.6) and 27.5 (±1.9) weeks, respectively. A higher proportion of participants who experienced an APO (vs. those who did not) were Black, had public insurance, had higher body mass index at study entry, and were more likely to give birth by cesarean (Table 1). Regarding potential sleep disruptors, more participants affected by any APO reported systemic steroid use during pregnancy and former alcohol use in the last three months preceding study entry. No differences in sleeping pill use were observed. Participants who had an APO were more likely to have restless legs syndrome symptoms at baseline, a higher Women's Health Initiative Insomnia Rating Scale score at follow‐up, lower sleep efficiency percentage at baseline and follow‐up, and higher Respiratory Event Index and Oxygen Desaturation Index scores at baseline and follow‐up (Table 2). Mean sleep duration was similar at both baseline (8.0 h) and follow‐up (7.8 h) regardless of APO occurrence. The average (±standard deviation) for the mean, minimum, and maximum NHR for the overall cohort was 71.1 (±8.4), 46.0 (±10.9), and 101.9 (±14.1) bpm at baseline, and 77.6 (±9.3), 50.7 (±12.5), and 108.2 (±15.3) bpm at follow‐up.
FIGURE 1.
Participant flow diagram. Participant flow diagram illustrates selection of the analytic cohort. APO, adverse pregnancy outcome; SDB, Sleep Disordered Breathing.
TABLE 1.
Baseline demographic and clinical characteristics.
|
Total N = 2952 mean ± SD or n (%) |
No APO N = 2067 mean ± SD or n (%) |
Any APO N = 885 mean ± SD or n (%) |
p‐value | |
|---|---|---|---|---|
| Maternal age at V1 (years) | 27.0 ± 5.4 | 26.9 ± 5.3 | 27.1 ± 5.8 | 0.55 |
| Self‐reported maternal race and ethnicity | <0.001 | |||
| Non‐Hispanic White | 1808 (61.2) | 1299 (62.8) | 509 (57.5) | |
| Non‐Hispanic Black | 355 (12.0) | 211 (10.2) | 144 (16.3) | |
| Hispanic | 539 (18.3) | 382 (18.5) | 157 (17.7) | |
| Asian | 113 (3.8) | 81 (3.9) | 32 (3.6) | |
| Other | 137 (4.6) | 94 (4.5) | 43 (4.9) | |
| Insurance | 0.01 | |||
| Public insurance | 743 (25.3) | 487 (23.7) | 256 (29.1) | |
| Private insurance | 1625 (55.3) | 1170 (56.9) | 455 (51.6) | |
| Self‐pay or other sources | 571 (19.4) | 401 (19.5) | 170 (19.3) | |
| Maternal body mass index, baseline visit (kg/m2) | 26.1 (6.1) | 25.7 (5.8) | 27.0 (6.7) | <0.001 |
| Underweight (<18.5) | 65 (2.2) | 46 (2.3) | 19 (2.2) | <0.001 |
| Normal weight (18.5–24.9) | 1492 (51.1) | 1090 (53.5) | 402 (45.6) | |
| Overweight (25–29.9) | 750 (25.7) | 528 (25.9) | 222 (25.2) | |
| Obese (30–34.9) | 319 (10.9) | 202 (9.9) | 117 (13.3) | |
| Morbidly obese (≥35) | 292 (10.0) | 170 (8.3) | 122 (13.8) | |
| Gestational weight gain (kg) | 15.6 ± 7.5 | 15.8 ± 6.9 | 15.1 ± 8.7 | 0.02 |
| Mode of conception | 0.38 | |||
| Spontaneous conception | 2837 (96.1) | 1993 (96.4) | 844 (95.4) | |
| In vitro fertilization | 58 (2.0) | 35 (1.7) | 23 (2.6) | |
| Intrauterine insemination | 55 (1.9) | 38 (1.8) | 17 (1.9) | |
| Other | 2 (0.1) | 1 (0.0) | 1 (0.1) | |
| History of mood disorder | 0.16 | |||
| No mood disorder | 2381 (82.4) | 1700 (83.4) | 681 (79.9) | |
| Depression | 186 (6.4) | 121 (5.9) | 65 (7.6) | |
| Anxiety | 216 (7.5) | 145 (7.1) | 71 (8.3) | |
| Bipolar/PTSD/schizophrenia/others | 108 (3.7) | 73 (3.6) | 35 (4.1) | |
| Asthma | 401 (13.9) | 273 (13.5) | 128 (14.7) | 0.39 |
| Systemic steroid use during pregnancy a | 12 (0.4) | 5 (0.2) | 7 (0.8) | 0.03 |
| Alcohol use, baseline visit | 0.01 | |||
| Never | 499 (16.9) | 368 (17.8) | 131 (14.8) | |
| Former use in last three months prior to baseline visit | 623 (21.1) | 410(19.8) | 213 (24.1) | |
| Current use in the last three months | 1829 (61.9) | 1288 (62.3) | 541 (61.1) | |
| Tobacco use, baseline visit | 0.29 | |||
| Never smoker | 1790 (60.7) | 1261 (61.0) | 529 (59.8) | |
| Former smoker in last three months prior to baseline visit | 672 (22.8) | 477 (23.1) | 195 (22.0) | |
| Current smoker in the last three months | 489 (16.6) | 328 (15.9) | 161 (18.2) | |
| Coffee/caffeine intake, baseline visit | 0.41 | |||
| Never | 1070 (43.1) | 758 (43.5) | 312 (42.3) | |
| Occasionally | 260 (10.5) | 174 (10.0) | 86 (11.7) | |
| 1–4 times per week | 368 (14.8) | 251 (14.4) | 117 (15.9) | |
| 5–7 times per week | 782 (31.5) | 559 (32.1) | 223 (30.2) | |
| Sleeping pill use, baseline visit b (nights/week) | 0.1 (0.6) | 0.1 (0.6) | 0.2 (0.7) | 0.28 |
| Sleeping pill use, follow‐up visit b (nights/week) | 0.1 (0.6) | 0.1 (0.6) | 0.1 (0.6) | 0.80 |
| Cesarean birth | 772 (26.7) | 511 (25.1) | 261 (30.6) | 0.002 |
| Male fetal sex | 1475 (51.3) | 1046 (51.5) | 429 (51.0) | 0.79 |
Abbreviations: APO, adverse pregnancy outcome; PTSD, post‐traumatic stress disorder; SD, standard deviation.
Systemic steroid use, assessed from the baseline study visit through delivery via chart abstraction and/or medical interview, was defined as receipt of any steroid compound to reduce inflammation or immune response (i.e., for management of autoimmune disease) and/or receipt of semi‐synthetic corticosteroids for acceleration of fetal lung maturity. Individuals on continuous oral steroid therapy for 14 days or more to treat asthma were excluded from the NuMoM2b Sleep Disordered Breathing Sub‐study.
Sleeping pill use was assessed by self‐report in medical interview and/or chart abstraction.
TABLE 2.
Sleep characteristics.
|
Total N = 2952 mean ± SD or n (%) |
No APO N = 2067 mean ± SD or n (%) |
Any APO N = 885 mean ± SD or n (%) |
p‐value | |
|---|---|---|---|---|
| Baseline | ||||
| Gestational age of sleep study (weeks’ gestation) | 11.9 ± 1.6 | 11.9 ± 1.6 | 11.9 ± 1.6 | 0.99 |
| Epworth Sleepiness Scale (score 0–27) | 8.1 ± 4.1 | 8.1 ± 4.2 | 8.0 ± 4.1 | 0.72 |
| Restless Legs Syndrome Symptoms (IRLSSG score = 4) a | 418 (16.6) | 272 (15.3) | 146 (19.6) | 0.01 |
| Women's Health Initiative Insomnia Rating Scale (score 0–20) | 8.0 ± 4.3 | 7.9 ± 4.3 | 8.3 ± 4.4 | 0.08 |
| Clinically significant insomnia symptoms (score ≥9) [19] | 1132 (42.7) | 783 (41.7) | 349 (44.9) | 0.14 |
| Estimated sleep duration (hours) | 8.0 ± 1.3 | 8.0 ± 1.2 | 8.0 ± 1.3 | 0.42 |
| Estimated sleep efficiency (%) | 92.5 ± 8.6 | 92.7 ± 8.7 | 91.9 ± 8.5 | 0.02 |
| Respiratory Event Index ≥5% b | 0.1 ± 0.7 | 0.1 ± 0.3 | 0.2 ± 1.3 | <0.001 |
| At least 1 apnea or hypopnea event per estimated sleep hour | 647 (21.9) | 414 (20.0) | 233 (26.3) | <0.001 |
| Respiratory Event Index score ≥5 | 6 (0.2) | 1 (0.0) | 5 (0.6) | 0.004 |
| Oxygen Desaturation Index ≥3% c | 2.0 ± 3.0 | 1.8 ± 2.5 | 2.4 ± 3.9 | <0.001 |
| Follow‐up | ||||
| Gestational age of sleep study (weeks’ gestation) | 27.5 ± 1.9 | 27.5 ± 1.9 | 27.6 ± 1.9 | 0.36 |
| Epworth Sleepiness Scale (score 0–27) | 6.7 ± 4.1 | 6.7 ± 4.1 | 6.7 ± 4.2 | 0.99 |
| Restless Legs Syndrome Symptoms (IRLSSG score = 4) a | 710 (27.4) | 501 (27.2) | 209 (27.8) | 0.73 |
| Women's Health Initiative Insomnia Rating Scale (score 0–20) | 8.5 ± 4.4 | 8.3 ± 4.3 | 8.9 ± 4.6 | 0.003 |
| Clinically significant insomnia symptoms (score ≥9) [19] | 1263 (47.0) | 879 (45.9) | 384 (49.8) | 0.07 |
| Estimated sleep duration (hours) | 7.8 ± 1.3 | 7.8 ± 1.3 | 7.8 ± 1.4 | 0.87 |
| Estimated sleep efficiency (%) | 92.2 ± 9.2 | 92.6 ± 8.7 | 91.1 ± 10.4 | <0.001 |
| Respiratory Event Index ≥5% b | 0.3 ± 1.3 | 0.3 ± 0.9 | 0.6 ± 1.9 | <0.001 |
| At least 1 apnea or hypopnea event per estimated sleep hour | 738 (36.1) | 486 (33.1) | 252 (43.5) | <0.001 |
| Respiratory Event Index score ≥5 | 30 (1.5) | 12 (0.8) | 18 (3.1) | <0.001 |
| Oxygen Desaturation Index ≥3% c | 3.5 ± 4.8 | 3.2 ± 4.2 | 4.3 ± 5.9 | <0.001 |
Abbreviations: APO, adverse pregnancy outcome; SD, standard deviation.
Restless Legs Syndrome symptoms were determined to be present if the International Restless Legs Syndrome Study Group (IRLSSG) diagnostic criteria score was equal to 4.
Respiratory Event Index was derived as the number of apnea or hypopnea events with ≥3% oxygen desaturation per estimated sleep hour. A Respiratory Event Index score ≥5 (i.e., at least 5 apnea or hypopnea events per estimated sleep hour) is indicative of at least mild obstructive sleep apnea. A Respiratory Event Index score < 5 is considered normal (i.e., no sleep apnea) [14, 15].
Oxygen Desaturation index was derived as the number of events with oxygen desaturation ≥3% per estimated sleep hour.
3.2. Analysis of NHR and APOs
Individual APOs occurred with the following frequency: GDM: 4.1% (118/2911), HDP: 13.6% (392/2890), PTB: 8.7% (256/2938; sPTB: 4.7% [n = 138], iPTB: 3.0% [n = 88], PTB classification unknown: 1.0% [n = 30]), SGA: 10.7% (309/2880), and stillbirth: 1.4% (41/2942). Participants with GDM had higher mean, minimum, and maximum NHR at baseline and follow‐up than those without GDM (Table 3). For each 5‐beat higher NHR metric at baseline and follow‐up, the adjusted odds of GDM were higher in affected, compared to unaffected, participants by 6%–34% (Table 3).
TABLE 3.
Association between maternal nocturnal heart rate and adverse pregnancy outcomes.
| APO absent | APO present | ||||
|---|---|---|---|---|---|
|
Adverse pregnancy outcome (APO) Gestational diabetes |
No GDM mean ± SD N = 2793 |
GDM mean ± SD N = 118 |
p‐value |
Crude OR for each 5‐beat higher NHR a (95% CI) b |
Adjusted OR for each 5‐beat higher NHR a , c (95% CI) b |
| Baseline | |||||
| Mean NHR | 70.9 ± 8.4 | 74.9 ± 7.9 | <0.001 | 1.33 (1.24, 1.42) | 1.34 (1.22, 1.48) |
| Minimum NHR | 45.9 ± 10.9 | 49.0 ± 10.0 | 0.002 | 1.15 (1.05, 1.25) | 1.15 (1.03, 1.29) |
| Maximum NHR | 101.7 ± 14.0 | 106.0 ± 13.3 | 0.001 | 1.10 (1.07, 1.12) | 1.06 (1.02, 1.10) |
| Follow‐up | |||||
| Mean NHR | 77.4 ± 9.3 | 81.8 ± 9.5 | <0.001 | 1.28 (1.15, 1.43) | 1.23 (1.06, 1.42) |
| Minimum NHR | 50.5 ± 12.5 | 54.0 ± 13.2 | 0.01 | 1.12 (1.03, 1.22) | 1.09 (1.03, 1.15) |
| Maximum NHR | 108.0 ± 15.4 | 113.7 ± 14.1 | 0.001 | 1.09 (1.06, 1.11) | 1.11 (1.04, 1.18) |
| Hypertensive disorders of pregnancy |
No HDP mean ± SD N = 2498 |
HDP mean ± SD N = 392 |
p‐value | ||
|---|---|---|---|---|---|
| Baseline | |||||
| Mean NHR | 70.9 ± 8.3 | 72.6 ± 8.4 | <0.001 | 1.13 (1.08, 1.19) | 1.05 (0.99, 1.13) |
| Minimum NHR | 45.7 ± 10.9 | 47.6 ± 10.7 | 0.002 | 1.08 (1.03, 1.14) | 1.05 (1.01, 1.10) |
| Maximum NHR | 101.7 ± 14.0 | 102.7 ± 14.4 | 0.18 | 1.03 (1.00, 1.05) | 0.99 (0.95, 1.04) |
| Follow‐up | |||||
| Mean NHR | 77.3 ± 9.3 | 79.5 ± 9.2 | <0.001 | 1.13 (1.08, 1.19) | 1.08 (0.97, 1.19) |
| Minimum NHR | 50.5 ± 12.6 | 51.8 ± 12.0 | 0.12 | 1.04 (0.99, 1.10) | 1.00 (0.94, 1.06) |
| Maximum NHR | 107.8 ± 15.5 | 110.4 ± 14.4 | 0.01 | 1.05 (0.98, 1.05) | 1.04 (0.98, 1.11) |
| Preterm birth (<370 weeks’ gestation) |
No PTB mean ± SD N = 2682 |
PTB mean ± SD N = 256 |
p‐value | ||
|---|---|---|---|---|---|
| Baseline | |||||
| Mean NHR | 71.0 ± 8.4 | 71.6 ± 8.6 | 0.29 | 1.04 (1.00, 1.09) | 1.00 (0.92, 1.09) |
| Minimum NHR | 46.0 ± 10.8 | 45.4 ± 11.8 | 0.35 | 0.97 (0.91, 1.04) | 0.93 (0.84, 1.02) |
| Maximum NHR | 101.7 ± 13.8 | 104.0 ± 16.8 | 0.01 | 1.06 (1.01, 1.10) | 1.08 (1.02, 1.14) |
| Follow‐up | |||||
| Mean NHR | 77.6 ± 9.3 | 77.6 ± 10.0 | 0.97 | 1.00 (0.92, 1.08) | 0.95 (0.89, 1.02) |
| Minimum NHR | 50.8 ± 12.5 | 48.3 ± 13.4 | 0.02 | 0.93 (0.87, 0.98) | 0.90 (0.86, 0.94) |
| Maximum NHR | 108.1 ± 15.3 | 110.3 ± 16.2 | 0.10 | 1.04 (1.01, 1.08) | 1.05 (1.00, 1.10) |
| Small‐for‐gestational age (birthweight <10th percentile) |
No SGA mean ± SD N = 2571 |
SGA mean ± SD N = 309 |
p‐value | ||
|---|---|---|---|---|---|
| Baseline | |||||
| Mean NHR | 71.0 ± 8.3 | 71.6 ± 9.2 | 0.29 | 1.04 (0.94, 1.15) | 0.99 (0.87, 1.13) |
| Minimum NHR | 46.0 ± 10.8 | 46.1 ± 11.6 | 0.83 | 1.01 (0.94, 1.07) | 1.00 (0.93, 1.08) |
| Maximum NHR | 101.7 ± 13.9 | 102.9 ± 15.4 | 0.18 | 1.03 (1.00, 1.06) | 1.00 (0.95, 1.05) |
| Follow‐up | |||||
| Mean NHR | 77.8 ± 9.2 | 75.8 ± 9.6 | 0.002 | 0.89 (0.83, 0.95) | 0.83 (0.78, 0.88) |
| Minimum NHR | 51.0 ± 12.5 | 48.0 ± 12.3 | <0.001 | 0.91 (0.87, 0.96) | 0.90 (0.86, 0.94) |
| Maximum NHR | 108.1 ± 15.3 | 108.5 ± 15.3 | 0.72 | 1.01 (0.97, 1.05) | 0.99 (0.95, 1.03) |
Abbreviations: CI, confidence interval; GDM, gestational diabetes; HDP, hypertensive disorders of pregnancy; NHR, nocturnal heart rate; OR, odds ratio; PTB, preterm birth; SD, standard deviation; SGA, small‐for‐gestational age.
Odds ratios are reported for the association between each 5‐beat higher nocturnal heart rate and individual APOs.
95% confidence intervals are based on robust standard errors clustered around study sites.
Adjusted odds ratios are reported for the association between each 5‐beat higher nocturnal heart rate and individual APOs. Models include the following confounders: maternal age, self‐reported race/ethnicity (as a proxy for discrimination), insurance type, tobacco use, and maternal body mass index (assessed at the baseline study visit), as well as restless legs syndrome, average sleep duration (hours), sleep efficiency %, and Oxygen Desaturation Index (assessed at baseline and follow‐up, as appropriate based on the corresponding study visit at which each outcome was assessed).
Participants with HDP had higher mean (baseline and follow‐up), minimum (baseline), and maximum (follow‐up) NHR than those without HDP (Table 3). The association of higher minimum NHR at baseline in participants with HDP persisted in adjusted analysis, with 5% (95% CI 1%–10%) higher odds of HDP for each 5‐beat higher minimum NHR at baseline; the association of all other NHR metrics with HDP were no longer significant.
At baseline, participants with PTB had higher maximum NHR, with 8% (95% CI 2%–14%) higher adjusted odds of PTB for each 5‐beat higher maximum NHR (Table 3). Conversely, at follow‐up, participants with PTB had lower minimum NHR, with a 10% (95% CI 6%–14%) lower adjusted odds of PTB associated with each 5‐beat higher minimum NHR. Subgroup analyses by PTB subtype revealed the observed association of higher maximum NHR at baseline may be attributed to participants with iPTB, with 10% (95% CI 1%–19%) higher adjusted odds of iPTB for each 5‐beat increase in maximum NHR (Table S1). The observed association of lower minimum NHR at baseline may be attributed to participants with sPTB, with a 14% (95% CI 8%–20%) lower adjusted odds of sPTB for each 5‐beat higher sPTB.
Finally, participants with a SGA neonate had similar NHR metrics at baseline, but lower mean and minimum NHR at follow‐up, with 17% (95% CI 12%–22%) and 10% (95% CI 6%–14%) lower adjusted odds of SGA for each 5‐beat higher mean and minimum NHR at follow‐up, respectively (Table 3).
4. DISCUSSION
4.1. Principal findings
In this cohort of nulliparous individuals, higher minimum NHR in early pregnancy was associated with higher odds of HDP or GDM. A consistent association of higher mean, maximum, and minimum NHR with GDM was present both in early and mid‐pregnancy. Potential associations of NHR with PTB overall, and by subtypes of PTB (indicated or spontaneous), were inconsistent in early and mid‐pregnancy. Finally, lower mean and minimum NHR was associated with higher odds of SGA, although these associations were only seen in mid‐pregnancy.
4.2. Results in context of what is known
During pregnancy, significant hemodynamic adaptations occur, including increased heart rate and cardiac output, and decreased systemic vascular resistance [23, 24]. The autonomic nervous system regulates these adaptations via increased sympathetic tone and parasympathetic withdrawal in order to augment the uterine and transplacental blood flow required for fetal growth [23, 25]. Autonomic nervous system dysfunction is considered to be a contributor to APOs, but limited literature exists regarding the association of NHR across gestation with pregnancy outcomes [23]. NHR progressively increases from early pregnancy through 34 weeks, after which a slight downtrend begins to occur [26]. Although NHR may be a truer reflection of underlying maladaptive physiologic changes in pregnancy compared to daytime heart rate, prior studies evaluating autonomic modulation of heart rate in association with APOs have mainly assessed daytime heart rate, for only short periods (i.e., <60 min), and/or have been limited by small sample sizes [23, 25]. Enhanced understanding of NHR patterns may elucidate pathophysiologic mechanisms underlying APOs.
In contrast to the present study, few studies have evaluated NHR in association with GDM or HDP among a large, racially and ethnically diverse population and at different time points across gestation, especially in early pregnancy. For example, in a case‐control study of 63 White pregnant people from New Zealand predominately in the third trimester, Pöyhönen‐Alho et al. evaluated noradrenaline levels in association with heart rate variability on an overnight Holter recording and identified attenuated autonomic nervous system modulation with lower parasympathetic cardiac resting tone in pregnant people with GDM compared to controls [27]. In 120 Chinese pregnant people, Guo et al. assessed noradrenaline concentration in conjunction with NHR variability on a 24‐h Holter monitor at >32 weeks’ gestation, and identified higher autonomic nervous system imbalance in pregnant people with preeclampsia compared to those without [28]. Despite differences in the study population (i.e., participant demographics, sample size) and study design (i.e., time points and methods of heart rate assessment) of these studies compared to that of the nuMom2b SDB cohort, our findings support the conclusions of these prior studies that suggest a similar relationship between NHR as a biomarker autonomic nervous system dysfunction and GDM or HDP.
Prior literature is also limited in evaluating associations between NHR and PTB and/or SGA. With respect to PTB, a recent US study evaluated a wearable, ambulatory device to monitor NHR changes longitudinally in 241 pregnant individuals at ≥24 weeks’ gestation and identified the presence of an inflection point in NHR variability may be an indicator of time to delivery; however, this study was underpowered to explore the predictive odds of NHR and/or NHR variability inflection as an indicator of an individual's PTB risk [29]. In our study, we were unable to identify a consistent association between NHR patterns and PTB. Regarding fetal growth, prior studies demonstrate lower daytime maternal resting heart rate is associated with lower neonatal birthweight and/or SGA, but these studies did not evaluate NHR [30, 31, 32]. However, we similarly identified an association with lower mean and minimum NHR—which can be considered to reflect resting heart rate—with SGA in mid‐pregnancy.
4.3. Clinical implications
Our findings highlight the potential pathophysiologic link between the autonomic nervous system with GDM and HDP. Hyperinsulinemia in response to hyperglycemia in gravidas with GDM contributes to higher neurovascular transduction, sympathoexcitation, and ultimately NHR compared to that in individuals without GDM [33, 34]. With respect to HDP, lower activity of the parasympathetic nervous system and heightened activity of the sympathetic nervous system leads to: (1) an increase in peripheral vascular resistance with resultant blood pressure elevations and (2) placental ischemia with subsequent reperfusion injury and release of abnormal prohypertensive, antiangiogenic, pro‐inflammatory soluble placental factors in maternal circulation [25, 35]. This relative overactivation of sympathetic over parasympathetic tone may underlie the association of NHR with APOs. However, beyond autonomic nervous system imbalances, other potential mechanisms may underlie our findings. In nonpregnant adults, lower resting heart rate is associated with lower risk of hypertension or diabetes and higher levels of physical activity [36, 37, 38, 39, 40]. It is possible that baseline cardiovascular health in pregnancy may similarly influence the association of NHR with HDP and GDM.
The potential association of NHR with SGA is complex, considering the potential etiologies for impaired fetal growth and overlap in some cases with HDP and/or indicated PTB. It is important to note that etiologies of SGA are multifactorial; while pathologic cases of fetal growth restriction and SGA are related to placental vascular malperfusion, nonpathologic cases are constitutional in nature or related to other maternal factors [41]. The differences in NHR patterns we observed specific to SGA, when compared to that with HDP, may be related to these heterogeneous causes of SGA. However, even in SGA cases due to placental dysfunction, prior investigators have suggested that lower NHR may reflect inadequate maternal hemodynamic and cardiovascular adaptations to placentation and pregnancy that are associated with impaired fetal growth and SGA [30, 42–44]. Other confounders could include that higher antenatal resting heart rate has been linked to obesity, a risk factor for macrosomia and birth of a large‐for‐gestational age neonate, independent of GDM [30, 45, 46].
4.4. Research implications
Additional research is warranted to evaluate the interaction of sleep‐related contributors to APOs (i.e., Respiratory Event Index and/or Oxygen Desaturation Index) with NHR during pregnancy to determine if SDB is an independent risk factor for alterations in both NHR and APOs [47]. Although we adjusted for ODI in this analysis, we did not evaluate APOs within the context of apnea‐specific NHR changes. Alterations in NHR may reflect sleep quality and SDB‐related autonomic responses given that autonomic function varies with sleep stage and recurrent apneas, hypopneas, and/or desaturations [21, 22]. Additional research to elucidate how these sleep indices may moderate the association of NHR and APOs is warranted to determine their utility as targets for intervention, given the independent association of SDB observed with APOs, particularly HDP and GDM [9]. Conversely, if a significant interaction of SDB with NHR and the risk of APOs is not identified, this would suggest autonomic nervous system changes may influence the relationship between NHR and APOs to a greater extent than SDB.
Beyond sleep‐specific factors, future evaluation of other clinical risk factors (e.g., anemia or other chronic conditions) for aberrant NHR in pregnancy that may influence the observed associations with APOs is warranted. Finally, given limited accessibility to home sleep studies to capture NHR for clinical use at present, future studies should validate ambulatory remote monitoring devices (e.g., wearable sensors such as smart watches) for monitoring NHR during pregnancy.
4.5. Strengths and limitations
Our study findings are derived from a large, geographically and demographically diverse study population and prospective, longitudinal ascertainment of NHR. NHR was evaluated over one night of sleep in both early and mid‐pregnancy using a validated home sleep monitor device, with periods of sustained movement and/or artifact excluded from analysis. Overall, our findings are hypothesis‐generating and an important addition to emerging literature on NHR as a novel biomarker for the most common APOs that has the potential to be used in conjunction with other routine clinical markers.
However, our study is limited by the ability to only evaluate static metrics of NHR at two discrete time points in pregnancy. Future evaluation of NHR variability that captures duration and patterns of NHR fluctuations, at additional time points longitudinally across gestation, may provide greater insight into how autonomic dysfunction modulates the relationship between NHR and APOs. In addition, NHR assessed in this study is not necessarily synonymous with heart rate during sleep. While we adjusted for a crude measure of sleep efficiency from the home sleep study, the Embletta‐Gold device does not provide electroencephalogram‐based sleep metrics validated for sleep staging (e.g., rapid eye movement sleep, slow wave sleep, etc.) in pregnancy; therefore, these data do not address whether sleep stage may interact with the NHR findings and associated APOs. The Embletta‐Gold device is also unable to identify respiratory effort‐related sleep arousal nor provide a rapid eye movement–specific respiratory disturbance index; thus, this analysis accounts for changes in NHR related to desaturation‐based respiratory events, but we are unable to evaluate changes in NHR that account for arousal‐based respiratory events as recommended, per the American Academy of Sleep Medicine, when evaluating SDB [48]. Finally, even though we accounted for several important clinical variables that may influence autonomic dysfunction, as in any observational study, unmeasured confounding likely exists (e.g., insomnia symptom severity, gestational weight gain, cardiovascular fitness and physical activity in pregnancy, endocrine conditions, hyperemesis gravidarum, medication exposures with secondary chronotropic effects, additional social determinants of health, etc.). Considering this risk of residual confounding, we cannot conclude that the associations identified between NHR and APOs are entirely independent. Finally, due to the exploratory nature of this analysis, we did not account for multiple comparisons.
5. CONCLUSION
NHR in early and mid‐pregnancy was positively associated with GDM. Minimum NHR was positively associated with HDP in early pregnancy, and negatively associated with SGA in mid‐pregnancy. We identified potential, but inconsistent, associations between NHR and PTB; if an independent association between NHR and PTB exists requires further evaluation. Future studies should account for a broader array of potential confounders to verify the independent association of NHR with these APOs. Additional studies evaluating the association of NHR variability with APOs are also warranted to better elucidate pathophysiologic processes that underlie the link between NHR and APOs, and to evaluate whether NHR could be used as a clinical biomarker to help risk stratify individuals at higher versus lower risk of APOs.
AUTHOR CONTRIBUTIONS
All authors have fulfilled criteria for authorship and have read and approve the submitted manuscript.
CONFLICT OF INTEREST STATEMENT
The authors report no conflicts of interest.
ETHICS STATEMENT
Each site's local governing Institutional Review Board approved the study prior to study initiation. All participants provided informed written consent prior to participation.
Supporting information
Supporting Information
ACKNOWLEDGMENTS
The following institutions and researchers compose the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers‐to‐be (nuMoM2b) Network: Eunice Kennedy Shriver National Institute of Child Health and Human Development—Uma M. Reddy, MD, MPH, Marian Willinger, PhD, Maurice Davis, DHA, MPA, MHSA; National Heart Lung and Blood Institute—Aaron Laposky, PhD; Case Western Reserve University / Ohio State University—Brian M. Mercer, MD, Jay Iams, MD, Wendy Dalton, RN, Cheryl Latimer, RN, LuAnn Polito, RN, JD, Judette M. Louis, MD; Columbia University / Christiana Care—Ronald Wapner, MD, Matthew K. Hoffman, MD, MPH, Karin Fuchs, MD, Caroline Torres, MD, Stephanie Lynch, RN, BSN, CCRC, Ameneh Onativia, MD, Michelle DiVito, MSN, CCRC, Chia‐Ling, Nhan‐Chang, MD, Robert C. Basner, MD; Indiana University—David M. Haas, MD, MS, Tatiana Foroud, PhD, Emily Perkins, BS, MA, CCRP, Shannon Barnes, RN, MSN, Alicia Winters, BS, Catherine L. McCormick, RN, Frank P. Schubert, MD, MS; University of Pittsburgh—Hyagriv N. Simhan, MD, MSCR, Steve N. Caritis, MD, Melissa Bickus, RN, BS, Paul D. Speer, MD, Stephen P. Emery, MD, Ashi R. Daftary, MD, Francesca L. Facco, MD; Northwestern University—William A. Grobman, MD, MBA, Alan M. Peaceman, MD, Phyllis C. Zee, MD, PhD, Peggy Campbell, RN, BSN, CCRC, Jessica S. Shepard, MPH, Crystal N. Williams, BA; University of California at Irvine—Deborah A. Wing, MD, Pathik D. Wadhwa, MD, PhD, Michael P. Nageotte, MD, Judith H. Chung, MD, PhD, Pamela J. Rumney, RNC, CCRC, Manuel Porto, MD, Valerie Pham, RDMS; University of Pennsylvania—Samuel Parry, MD, Jack Ludmir, MD, Michal Elovitz, MD, Mary Peters, BA, MPH, Brittany Araujo, BS, Grace Pien, MD, MSCE; University of Utah—Robert M. Silver, MD, M. Sean Esplin, MD, Kelly Vorwaller, RN, Julie Postma, RN, Valerie Morby, RN, Melanie Williams, RN, Linda Meadows, RN; RTI International—Corette B. Parker, DrPH, Matthew A. Koch, MD, PhD, Deborah W. McFadden, MBA, Barbara V. Alexander, MSPH, Venkat Yetukuri, MS, Shannon Hunter, MS, Tommy E. Holder, Jr, BS, Holly L. Franklin, MPH, Martha J. DeCain, BS, Christopher Griggs, BS; Harvard University, Brigham and Women's Hospital—Susan Redline, MD, MPH, Daniel Mobley, RPSGT, Susan Surovec, BA, Julianne Ulanski, BS; University of Texas Medical Branch at Galveston—George R. Saade, MD. The identifier for nuMoM2b in ClinicalTrials.Gov is NCT01322529. The manuscript reports on the prospective observational Sleep Disordered Breathing (SDB) Sub‐study of the Nulliparous Pregnancy Outcomes: Monitoring Mothers‐to‐Be (nuMoM2b) study. Study activities were conducted at 8 clinical sites for the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) nuMoM2b network (Case Western Reserve University, Columbia University, Indiana University, University of Pittsburgh, Northwestern University, University of California at Irvine, University of Pennsylvania, and the University of Utah). This study was supported by grant funding from the Eunice Kennedy Shriver NICHD and the National Heart, Lung, and Blood Institute (NHLBI): U10 HD063036; U10 HD063072; U10 HD063047; U10 HD063037; U10 HD063041; U10 HD063020; U10 HD063046; U10 HD063048; and U10 HD063053. In addition, support was provided by Clinical and Translational Science Institutes: UL1TR001108 and UL1TR000153.
This manuscript was presented as a poster at the Society for Maternal Fetal Medicine 44th Annual Pregnancy Meeting from February 10–14, 2024 in National Harbor, MD (Abstract #441).
DATA AVAILABILITY STATEMENT
Data described in the manuscript are publicly available in the NICHD Data and Specimen Hub (DASH).
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Data Availability Statement
Data described in the manuscript are publicly available in the NICHD Data and Specimen Hub (DASH).