Low <scp>FEV<sub>1</sub></scp> is associated with fetal death in pregnant women with sickle cell disease
Authors: Charles F. Hayfron‐Benjamin, Eugenia Vicky Asare, Theodore Boafor, Edeghonghon Olayemi, Yvonne Dei‐Adomakoh, Latif Musah, Enoch Mensah, Titus Beyuo, Adetola A. Kassim, Mark Rodeghier, Michael R. DeBaun, Samuel A. Oppong
Journal: American Journal of Hematology (2021)

Sickle cell disease (SCD), the commonest genetic disease in the world, affects multiple organ systems including the respiratory system.1 Specifically, SCD is associated with lung restriction, airway hyperresponsiveness, pulmonary hypertension, and acute chest syndrome (ACS).1 In pregnancy, a combination of hormonal changes and mechanical effects of the enlarging uterus may result in respiratory dysfunction including rhinitis of pregnancy, sleep-disordered breathing, and small airway closure.2 The combined effects of pulmonary changes in pregnancy and SCD may result in substantial reductions in maternal pulmonary reserves, potentially compromising uteroplacental function and reducing fetal oxygenation. In a systematic review and meta-analysis, we demonstrated that pregnant women living with SCD have an increased risk of maternal and perinatal morbidity and mortality.3 In contrast to poor maternal outcomes, the biological basis of the poor perinatal outcomes is not clear. One potential modifiable risk factor is the role of abnormal pulmonary function in pregnant women with SCD on the outcome of the fetus. In a prospective cohort study of pregnant women with SCD, we tested the hypothesis that impaired pulmonary function during pregnancy, assessed by a reduction in baseline forced expiratory volume in 1 s (FEV1), is associated with an increased risk of adverse perinatal outcomes in pregnant women with SCD. The prospective cohort study included 149 pregnant women with an established diagnosis of SCD managed at Ghana's largest tertiary hospital, the Korle-Bu Teaching Hospital (KBTH), from May, 2015 to December, 2016. This excluded women who were referred with acute pregnancy-related complications, in active labor, or after delivery, and those who were unable to comply with the follow-up requirements for prenatal visits. The KBTH attends to about 11 000 pregnant women annually including ~200 pregnant women with SCD. The primary outcomes of the study were maternal and perinatal mortality rates. To ensure higher quality decision-making and standardized patient care, all study participants received care from a multi-disciplinary team.4 The study received ethical approval from the Institutional Review Boards of the University of Ghana College of Health Sciences (MS-Et/M.12-P4), and Vanderbilt University Medical Center (VUMC IRB #141050). For the current analyses, data from 104 pregnant women (HbSS: 40; HbSC: 64) aged 18–41 years who had spirometry testing within 2 weeks of enrolment, and followed up for at least 12 weeks (at least 6 weeks while pregnant and 6 weeks post-delivery) were included (Figure S1). Acute painful episode was defined as acute pain episodes leading to hospitalization that required oral or intravenous opioid pain management, distinguished from labor pains. Acute chest syndrome was defined based on the presence of at least two of the following criteria, including positive chest signs: temperature > 38°C, increased respiratory rate > 20 breaths per minute, presence of chest pain or pulmonary auscultatory findings, increased oxygen requirement (SpO2 drop >3% from a documented steady-state value on room air), or new radiodensity on chest roentgenogram or pneumonia.4 In the absence of abdominal shielding, a chest roentgenogram was done for only postpartum women. All ACS episodes were adjudicated with the obstetricians and hematologists on the research team to ensure a uniform definition.4 Preeclampsia was defined as (1) systolic blood pressure ≥ 140 mmHg or diastolic blood pressure ≥ 90 mmHg on two separate readings taken at least 4 h apart after 20-week gestation in a study participant with previously normal blood pressure; and (2) proteinuria as ≥300 mg of protein in a 24-h urine sample or a spot urinary protein to creatinine ratio ≥ 0.3 or a urine dipstick reading of 1+ or greater. Malaria infection was defined using the World Health Organization definition of examining stained thick smears under the light microscope. Gestational age was estimated based on the first-trimester ultrasound scan. Serial obstetric ultrasounds were performed bi-weekly in the third trimester to monitor fetal growth. Umbilical artery Doppler studies were performed in those with suspected intrauterine growth restriction (IUGR). Premature birth was defined as births that occurred before 37 weeks of gestation. Low birth weight (LBW) and very low birth weight (VLBW) were defined as birth weights below 2500 and 1500 grams respectively. Fetal death was defined as a fetus weighing greater than 500 g with no signs of life at birth and meeting all the following criteria; no fetal heartbeat; no respiratory effort; absence of pulsation in the umbilical cord; and no definitive movement of voluntary muscles. Spirometry was performed at the baseline visit (<28 weeks of pregnancy) using the Morgan FVL spirometer according to the American Thoracic Society/European Respiratory Society guidelines. The predicted values of the FEV1, forced vital capacity (FVC), and the FEV1/FVC ratio were determined for each participant using the Global Lung Initiative 2012 equations. Before the start of our study, we defined poor lung function as FEV1 percent predicted<65 based on the BODE index in COPD guidelines.5 Compared with FEV1 percent predicted >65, the 5-year hazard ratios (95% CI) of death in people with FEV1 percent predicted of 50–64 was 1.95(1.61–2.35).5 Differences in clinical characteristics and pregnancy outcome measures between the FEV1% predicted ≥65 (n = 94) and FEV1% predicted <65 (n = 10) groups were assessed by the chi-square test or Fisher's exact test for categorical variables, and t test for continuous covariates or the Mann–Whitney U test for covariates not normally distributed. Given the small number of fetal deaths, a multivariable penalized logistic regression was used to estimate adjusted odds ratios with 95% confidence intervals. For the same reason, only a small number of covariates were used in the model. A p value of less than 0.05 was considered statistically significant. The IBM SPSS version 25 for Windows was used for statistical analysis. The proportions of HbSS and HbSC phenotypes were similar in the group with FEV1 percent predicted ≥65 and the group with FEV1 percent predicted <65 (Table 1). Additionally, maternal parity was similar in the two groups. Moreover, the two groups were similar with respect to the mean maternal ages, gestational ages, maternal BMI, and hemoglobin concentrations. The mean FVC percent predicted and FEV1/FVC% predicted were higher in the FEV1 percent predicted ≥65 group compared with the FEV1 percent predicted <65 group. The rate of fetal death was higher in participants with FEV1 percent predicted <65 compared to those with FEV1 percent predicted ≥65 (30.0% vs. 4.3%, p = 0.01) with an overall prevalence of 6.8% (seven of 103). Two fetal deaths occurred in women who experienced maternal death; one each in the FEV1 percent predicted<65 and FEV1 percent predicted ≥65% groups. In a multivariable penalized regression model, FEV1 percent predicted <65 was associated with a nearly eight-fold increased risk of fetal death (OR 7.81, 95% CI[1.59–38.38], p = 0.01) (Table S1). Phenotype (HbSS) (3.41[0.68–17.19], p = 0.13) and low maternal BMI (1.00[0.84–1.20], p = 0.95) were not associated with fetal death. The preterm delivery rate of 30.1% in pregnant women with SCD was high, as compared with the rates expected in the general population (10%). Preterm delivery rate was almost doubled in pregnant women with FEV1 percent predicted <65, compared with those with FEV1 percent predicted ≥65 (50.0% vs. 28.0%, p = 0.16), although the difference was not statistically significant. Similarly, the difference in the rate of VLBW between the FEV1 percent predicted ≥65 group and the FEV1 percent predicted <65 group (12.5% vs. 4.3%, p = 0.35) was not statistically significant. The mean events/patient-year for acute pain episodes and ACS were higher by 33% and 150% respectively, in pregnant women with FEV1 percent predicted <65, compared with those with FEV1 percent predicted ≥65. Compared with pregnant women with FEV1 percent predicted ≥65, pregnant women with FEV1 percent predicted <65 had over twice the rate of hospitalization for malaria and nearly five times the rate of maternal deaths. However, these differences were not statistically significant. Similarly, FEV1 percent predicted <65 was not associated with preeclampsia and medically assisted delivery including cesarean section. A significant limitation of this study is the lack of a pre-gestational pulmonary function test. Another limitation is the relatively smaller sample size in the FEV1 percent predicted <65 group. This could have accounted for the lack of statistically significant difference in some pregnancy outcome measures between the two groups. Our study is also limited by phenotype distribution (HbSS vs. HbSC). However, disease severity/outcomes do not differ between pregnant women with HbSC and HbSS. Finally, we did not assess maternal pulmonary hypertension; compared to low FEV1 percent predicted with low tricuspid regurgitant jet velocity, low FEV1 percent predicted with elevated tricuspid regurgitant jet velocity is a stronger predictor of earlier mortality in SCD.6 Our study contributes unique data, as no prior study has evaluated the impact of maternal pulmonary function on perinatal outcomes in SCD. These observations which warrant further investigation, show that in pregnant women with SCD, poor baseline gestational pulmonary function is a significant predictor of fetal death. Stratification based on FEV1 percent predicted may add valuable information on perinatal risk assessment in pregnant women with SCD. Further, interventions aimed at optimizing pulmonary function in pregnant women with SCD with low FEV1 percent predicted may be valuable in reducing the rates of fetal deaths. Additionally, a study focusing on understanding the mechanisms linking poor gestational pulmonary function and adverse perinatal outcomes in SCD may be valuable in developing targeted interventions for decreasing fetal deaths. The authors acknowledge the late Professor Samuel Amenyi Obed and the leadership of the Department of Obstetrics and Gynecology, KBTH for administrative support, funds from University of Ghana, Office of Research, Innovation and Development (ORID); Doris Duke Charitable Foundation; Burroughs Wellcome Foundation, Phillips Family Donation; Aaron Ardoin Foundation for Sickle Cell Anemia; and J.C. Peterson, M.D. endowed chair funds from Vanderbilt University School of Medicine. We also acknowledge the donation of pulse oximetry machines by the team from Vanderbilt University Medical Center. This work was supported by the Office of Research Innovation and Development (ORID), University of Ghana, Doris Duke Charitable Foundation, Burroughs Wellcome Foundation, Phillips Family Donation, Aaron Ardoin Foundation for Sickle Cell Anemia; Vanderbilt University School of Medicine (J.C. Peterson, M.D.); Office of Research and Innovation and Development (ORID) Research Fund/8/LMG-008, University of Ghana (awarded to EO and SAO) and Vanderbilt University Medical Center Gift Funds; the National Center for Research Resources, Grant/Award Number: Grant UL1 RR024975-01; the National Center for Advancing Translational Sciences, Grant/Award Number: Grant 2 UL1 TR000445-06. The authors declare no conflict of interest. S.A.O., C.F.H-B., E.O., A.A.K., and M.R.D. conceived the idea; S.A.O., C.F.H-B., E.V.A., E.O., T.K.B., L.M., and Y.D-A. performed the experiment; M.R., C.F.H-B., E.V.A., S.A.O. and M.R.D. analyzed and interpreted the data; C.F.H-B., E.V.A., T.K.B., E.O., Y.D-A., L.M., E.M., T.B., A.A.K, R.D., M.R.D., and S.A.O. authors participated in writing the article, reviewed and approved the final version before submission. The data that support the findings of this study are available from the corresponding author upon reasonable request. Figure S1. Flowchart showing selection of study participants Definition of abbreviations: ATS/ERS, American Thoracic Society/European Respiratory Society; FEV1, forced expiratory volume in 1 s; SCD, sickle cell disease. Table S1. Multivariable penalized logistic regression models for fetal death among pregnant women with SCD (n = 103). 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