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Obstetric Anesthesiology: Original Clinical Research Report

Transient Tachypnea of Newborns Is Associated With Maternal Spinal Hypotension During Elective Cesarean Delivery: A Retrospective Cohort Study

Singh, Shubhangi MD*; Lumbreras-Marquez, Mario Isaac MBBS*; Farber, Michaela K. MD, MS*; Xu, Xinling PhD*; Singh, Prashant MD†; Gorman, Terri MD‡; Palanisamy, Arvind MD, FRCA§

Author Information

From the *Department of Anesthesiology and Critical Care, Brigham and Women’s Hospital, Boston, Massachusetts

†Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts

‡Department of Pediatric Newborn Medicine, Brigham and Women’s Hospital, Boston, Massachusetts

§Department of Anesthesiology, Washington University, St Louis, Missouri.

Published ahead of print 12 February 2019.

Accepted for publication December 26, 2018.

Funding: None.

The authors declare no conflicts of interest.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website.

Reprints will not be available from the authors.

Address correspondence to Arvind Palanisamy, MD, FRCA, Department of Anesthesiology, Washington University School of Medicine, St Louis, MO 63110. Address e-mail to [email protected].

doi: 10.1213/ANE.0000000000004064

Abstract

KEY POINTS

  • Question: Is there an association between the severity of predelivery maternal hypotension during spinal anesthesia for elective cesarean delivery and transient tachypnea of newborns?
  • Findings: The composite of degree and duration of maternal systolic blood pressure <90 mm Hg was higher in transient tachypnea of newborn mothers of versus mothers of control neonates with normal respiratory function.
  • Meaning: Prevention of spinal hypotension may be a prudent strategy to decrease the possibility of transient tachypnea of newborns during elective cesarean delivery.

Transient tachypnea of newborns is one of the most common causes of respiratory distress during the newborn period, and occurs in approximately 5.7 per 1000 deliveries at term gestation.1–4 Transient tachypnea of newborns is believed to occur due to a delay in fetal lung fluid clearance5 and needs to be differentiated from other causes of neonatal respiratory distress such as hyaline membrane disease, which occurs due to deficiency of surfactant.6 Transient tachypnea of newborns is self-limited, and the treatment is mainly supportive (eg, oxygen supplementation). However, it often requires admission to the neonatal intensive care unit, which causes separation of babies from mothers and increased health care costs.7 Furthermore, these babies are at higher risk for inpatient admission for respiratory syncytial virus bronchiolitis in infancy5 and reactive airway disease later in life.8

Transient tachypnea of newborns is 2- to 6-fold more common during elective cesarean delivery compared to vaginal birth.9–13 This is attributed to: (1) the absence of catecholamine-mediated fluid resorption in neonate due to the absence of labor and; (2) the absence of “chest squeeze” during vaginal delivery, which facilitates fluid resorption from the fetal lungs.14–16 Although the maternal–fetal risk factors for transient tachypnea of newborns are well understood,13,16 perioperative factors, especially in the setting of elective cesarean delivery, remain poorly investigated. Neuraxial anesthesia is the preferred anesthetic technique for cesarean delivery for several reasons, including avoiding risk of aspiration associated with general anesthetic, maternal ability to witness the birth of the baby, higher neonatal Apgar scores, and lower incidence of transient tachypnea of newborns.17 However, neuraxial technique is still associated with significant maternal hypotension.18–20 To our knowledge, no study has explored the potential role of maternal hemodynamic parameters during neuraxial anesthesia for elective cesarean delivery in the development of transient tachypnea of newborns. This is plausible because: (1) pulmonary fluid resorption is predominantly mediated by catecholamines;21 and (2) maternal hypotension and its treatment can trigger changes in circulating catecholamines with the potential to affect the fetus.22 Therefore, we hypothesized that predelivery maternal hypotension would be associated with transient tachypnea of newborns in women undergoing elective cesarean delivery under neuraxial anesthesia. To test this hypothesis, we performed a retrospective observational cohort study to evaluate the association of degree and duration of systolic blood pressure (SBP) <90 mm Hg (which was summarized by area under the curve) with transient tachypnea of newborns.

METHODS

This retrospective observational cohort study was approved by the institutional review board of our hospital with waiver of informed consent (institutional review board No: 2016P001799). All records of neonates born via elective cesarean delivery between July 2015 and February 2016 were retrospectively reviewed by 2 authors (S.S. and M.I.L.-M.).

Case Definition

The diagnosis of transient tachypnea of newborns, based on the presence of unexplained tachypnea (respiratory rate >60) with/without nasal flaring, grunting, and chest retractions shortly after birth with resolution within 2–5 days, was determined by a thorough review of the neonate’s chart, including notes from the neonatologist at the time of delivery. Chest x-ray when available was also examined. The selection of cases was independently verified by a neonatologist (T.G.).

Inclusion Criteria

Nonanomalous singleton pregnancies at gestational age ≥37 weeks undergoing elective cesarean delivery under neuraxial anesthesia were included.

Exclusion Criteria

Exclusion criteria included: (1) mothers with gestational or chronic diabetes and gestational or chronic hypertension; (2) induced or spontaneous onset of labor; (3) cesarean delivery at <37 weeks gestation; (4) twin pregnancies; (5) exposure to antenatal steroids; and (6) general anesthesia or combined spinal–epidural anesthetic during which epidural activation was necessary before delivery (failed or suboptimal spinal anesthesia).

Data Extraction

The following data were extracted from maternal anesthetic records: demographics, medications used to initiate spinal anesthesia, sensory dermatomal level before skin incision, baseline SBP and mean arterial pressure (MAP), maternal SBP and MAP at the available time points (every minute being the highest frequency) before umbilical cord clamping, total intravenous fluid administered during the entire case, type of vasopressor administered, and the total vasopressor requirement before umbilical cord clamping. Baseline SBP and MAP were obtained in the preoperative area on the day of cesarean delivery before entry into the operating room. During the study period, prophylactic phenylephrine infusions were not used at our hospital, and the vasopressors were administered as a bolus to treat hypotension. Because this is a retrospective study, the frequency of blood pressure measurement was not standardized and was entirely dependent on the anesthesiologist present in the case. Area under the curves (duration × magnitude) were calculated for SBP ≤90 mm Hg (Supplemental Digital Content 1, Figure 1, https://links.lww.com/AA/C729) and MAP ≤65 mm Hg (Supplemental Digital Content 2, Figure 2, https://links.lww.com/AA/C730) using all available blood pressure values before delivery. Δ-SBP was the difference between the baseline SBP and the intraoperative SBP for each intraoperative blood pressure measurement before the delivery of the baby. Similarly, Δ-MAP was the difference between the baseline MAP and the intraoperative MAP for each intraoperative blood pressure measurement before the delivery of the baby. Area under the curves were also plotted for Δ-SBP (Supplemental Digital Content 3, Figure 3, https://links.lww.com/AA/C731) and Δ-MAP (Supplemental Digital Content 4, Figure 4, https://links.lww.com/AA/C732). Only the positive values (ie, when intraoperative SBP and MAP were less than baseline SBP and MAP, respectively) were used for the calculation of the area under the curve. For the measurements that were missing between minutes, we assumed that the missing SBP/MAP would fall on the straight line between the closest observed 2 points. For example, as shown in Supplemental Digital Content 4, Figure 4, https://links.lww.com/AA/C732, for Δ-MAP, the measurement was missing at minute 18, and we connected the line between minute 17 (the highest point in the figure) and minute 19 (the lowest point in the figure) and assumed that the measurement for minute 18 would fall on this line. Time from achieving adequate spinal anesthesia to delivery was also noted. This article was prepared in adherence to the Strengthening the Reporting of Observational Studies in Epidemiology guidelines.

Statistical Analysis

Primary outcome of the study was to evaluate the association of degree and duration of SBP <90 mm Hg (which was summarized by area under the curve) with transient tachypnea of newborns. Secondary outcomes of the study were to compare the maternal characteristics, neonatal characteristics, hemodynamic parameters, and vasopressor use among the group with transient tachypnea of newborns versus controls.

Categorical variables (maternal body mass index category, maternal American Society of Anesthesiologists status, baby sex, type of anesthetic, and type of vasopressor used) were summarized using frequencies and percentages, and continuous variables were summarized using mean values and SDs (maternal age, baseline SBP, baby weight, baby length and time from spinal onset to delivery) or median values and interquartile ranges (interquartile ranges; gravidity, parity, bupivacaine dose, fentanyl dose, hydromorphone dose, gestational age, Apgar scores, spinal level, all area under the curves, and vasopressor doses). The normality assumption was evaluated using quantile–quantile plot and tested using Shapiro–Wilk Normality test. Patient characteristics were compared using χ2 test (type of cesarean delivery, sex of the baby, and type of the vasopressor used) or Fisher exact test (maternal body mass index category, maternal American Society of Anesthesiologists status, and type of anesthetic) for categorical variables, and two-sample t-test or Wilcoxon rank-sum test for continuous variables between the transient tachypnea of newborns and control groups. Multivariable logistic regression was used for evaluating the effect of area under the curve for SBP on the outcome variable transient tachypnea of newborns, adjusting for two confounders that were significantly different between the groups (gravidity and type of anesthetic). Collinearity was examined using generalized variance inflation factor with cutoff value 2. All analyses were performed in R version 3.5.0, and SAS version 9.4 (SAS, Cary, NC). Two-sided P < 0.05 was accorded statistical significance. Because of the lack of area under the curve data for hypotension from previous studies, we did not perform an a priori sample size calculation. However, given our sample size, we had 80% power to detect a clinically meaningful difference between the groups (Cohen’s effect size of 0.56).

RESULTS

T1
Table 1.:
Baseline Maternal Characteristics
T2
Table 2.:
Baseline Neonatal Characteristics
T3
Table 3.:
Characteristics of the Type of Anesthesia

Intraoperative hemodynamic changes are compared in Table 4. The median area under the curve for SBP was larger in the transient tachypnea of newborn group compared to the control group (P = .001). Similarly, the median area under the curve for MAP was also larger in the transient tachypnea of newborn group compared to the control group (P = .01). The median area under the curve for Δ-SBP and area under the curve for Δ-MAP were not different between the two groups (Table 4). This severity of hypotension was also reflected in the use of vasopressors for the treatment of intraoperative hypotension (Table 5). Mothers in the transient tachypnea of newborn group received significantly higher amount of phenylephrine and ephedrine compared to the control group (P = .001 and .01, respectively). In addition, the median total intravenous fluid (in milliliters) received during the entire course of cesarean delivery was significantly higher in the transient tachypnea of newborn group (1800; interquartile range, 1500–2000) compared to the control group (1500; interquartile range, 1200–2000).

T4
Table 4.:
Hemodynamic Characteristics
T5
Table 5.:
Vasopressor Requirements

In the multivariable logistic regression, area under the curve for SBP continued to be significantly associated with transient tachypnea of newborns (odds ratio, 1.02; 95% CI, 1.01–1.04, P = .005) after adjusting for type of anesthetic (spinal versus combined spinal epidural) and gravidity (both of which were significantly different between the two groups; Table 6).

T6
Table 6.:
Logistic Regression for Odds of Having Transient Tachypnea of Newborns

Of the 1090 cesarean deliveries at our institution during the study period, 181 (30 transient tachypnea of newborns and 151 controls) met our inclusion criteria (Supplemental Digital Content 5, Figure 5, https://links.lww.com/AA/C733). Maternal baseline demographics did not differ significantly between the 2 groups except for gravidity and parity that were all higher in the transient tachypnea of newborn group (Table 1). The type of cesarean delivery was different between the groups; 26 patients in the transient tachypnea of newborn group (87%) underwent repeat cesarean delivery compared to 101 patients (67%) in the control group (P = .03; Table 1). Baseline characteristics in neonates were not significantly different in the two groups, except that both 1- and 5-minute Apgar scores were significantly lower in transient tachypnea of newborn cases (Table 2). No neonate in either group had an Apgar score <7. Seventeen cases of transient tachypnea of newborns required neonatal intensive care unit care compared to none in the control group. Spinal anesthesia technique in both groups is compared in Table 3. Higher proportion of mothers in the transient tachypnea of newborn group received combined spinal epidural anesthesia compared to the mothers in the control group (P = .04). There were no differences in the dose of medications, height of sensory block, or the time from adequate spinal anesthesia to delivery. One patient in the transient tachypnea of newborn group developed fetal bradycardia in the setting of severe maternal hypotension following spinal anesthesia.

DISCUSSION

Our results suggest that the duration and degree of predelivery maternal SBP <90 mm Hg after neuraxial anesthesia for elective cesarean delivery are associated with transient tachypnea of newborns. Case mothers also received a significantly higher volume of fluids and vasopressors, which probably reflects the underlying severity of hypotension. Our results, therefore, make a case for aggressive prevention and treatment of hypotension during neuraxial anesthesia for elective cesarean delivery.

On multivariable logistic regression, maternal area under the curve for SBP was significantly associated with transient tachypnea of newborns after adjusting for gravidity and the type of anesthesia (spinal versus combined spinal epidural). The exact mechanisms underlying the association between maternal hypotension after spinal anesthesia and transient tachypnea of newborns are not clear. Fetal lung fluid clearance depends on absorption of sodium through the amiloride-sensitive epithelial Na+ channels,23–25 and its subsequent release into the lung interstitium via Na+/K+ ATPase.2,3,24,26–28 Based on the current understanding of the etiology of transient tachypnea of newborns, this process may be impaired because of either disruption of catecholamine balance, or a decrease in ATP production from severely impaired uteroplacental perfusion from maternal hypotension.1,29 In addition, lower fetal systemic blood pressure associated with severe maternal hypotension29 may decrease the rate of decline in pulmonary pressure in newborns and serve as a contributory factor.

On univariable analysis, vasopressor doses received were significantly higher in the transient tachypnea of newborn group compared with the control group. During the study period, vasopressors were administered only to treat hypotension and not prophylactically. Therefore, this finding also suggests higher severity of predelivery maternal hypotension in the transient tachypnea of newborn group. The total amount of intravenous fluids administered during the case to mothers in the transient tachypnea of newborn group was also significantly higher compared with that in the control group. However, the exact amount of fluid administered before the delivery could not be ascertained due to the retrospective nature of the study design. Nevertheless, the use of more vasopressors and fluids in the transient tachypnea of newborn group appears consistent with the severity of intraoperative hypotension.

Given the study design and the lack of a standard approach to treat hypotension at our institution during the study period, it was not possible to evaluate the specific role of vasopressors in the development of transient tachypnea of newborns. Prophylactic phenylephrine infusion is now popular because of its ability to ameliorate both spinal and supine maternal hypotension, with minimal effects on fetal metabolism.30 By contrast, ephedrine use is associated with decreased fetal umbilical cord pH due to increased fetal metabolic activity.22,31 To our knowledge, no studies have examined the association between the choice of vasopressor and transient tachypnea of newborns. Evaluating the incidence of transient tachypnea of newborns during distinct standard-of-care epochs (prophylaxis versus treatment of hypotension, ephedrine versus phenylephrine) should provide a better understanding of the association among maternal hypotension, vasopressor use, and development of transient tachypnea of newborns.

Our study has a few limitations. First, limitations inherent to a retrospective study apply. The frequency of blood pressure measurement was not standardized and was entirely dependent on the anesthesiologist. Similarly, the threshold for treatment of hypotension was subjective and dependent on the anesthesiologist as well. It was not possible to control for artefacts induced by patient movement and shivering. The effects of these limitations are minimized to a certain extent with calculated assumptions for missing blood pressure values and considering both degree and duration of hypotension. Therefore, area under the curve for SBP and area under the curve for MAP used in this study are better markers of the magnitude of hypotension. Second, the diagnosis of transient tachypnea of newborns was subjective because it was based on the available data in the neonate’s chart, including the notes and clinical impression of the neonatologist. However, chest x-rays were reviewed when available, neonates with respiratory distress and tachypnea from other etiologies were excluded, and the diagnosis was independently verified upon chart review by a neonatologist. Third, our findings should be interpreted in the context of our exclusion criteria. Because we excluded patients with complicated medical history, our study is more likely applicable to otherwise healthy patients undergoing elective cesarean delivery. Fourth, given the small number of transient tachypnea of newborn cases, we were limited in our ability to adjust for more variables in our multivariable model leading to possibility of bias by residual confounding.

In summary, our study suggests that the degree and duration of maternal SBP <90 mm Hg (area under the curve for SBP) during elective cesarean delivery are significantly associated with transient tachypnea of newborns. Our findings lay the groundwork for future prospective studies to assess the neonatal respiratory effects of maternal hypotension, its treatment, and prevention.

DISCLOSURES

Name: Shubhangi Singh, MD.

Contribution: This author helped frame the methodology, collect the data, analyze the data, and prepare the manuscript.

Name: Mario Isaac Lumbreras-Marquez, MBBS.

Contribution: This author helped collect the data and prepare the manuscript.

Name: Michaela K. Farber, MD, MS.

Contribution: This author helped frame the methodology and prepare the manuscript.

Name: Xinling Xu, PhD.

Contribution: This author helped analyze the data.

Name: Prashant Singh, MD.

Contribution: This author helped frame the methodology and analyze the data.

Name: Terri Gorman, MD.

Contribution: This author helped collect the data and prepare the manuscript.

Name: Arvind Palanisamy, MD, FRCA.

Contribution: This author helped construct the study, frame the methodology, and prepare the manuscript.

This manuscript was handled by: Jill M. Mhyre, MD.

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