Case Report
Treatment of Early-Onset Preeclampsia With Continuous Positive Airway Pressure Clare Whitehead, MBChB, Stephen Tong, MBBS, PhD, Danielle Wilson, BSc, MSc, Mark Howard, FRACP, PhD, and Susan P. Walker, MBBS, MD BACKGROUND: Preeclampsia is a leading cause of maternal and perinatal morbidity and mortality. There is no treatment for preeclampsia other than delivery. Sleepdisordered breathing is associated with adverse pregnancy outcomes, including preeclampsia, but it is not known whether treatment with continuous positive airway pressure (CPAP) improves perinatal outcomes. CASE: We report a 35-year-old primigravid woman diagnosed with preeclampsia at 30 weeks of gestation. A sleep study confirmed severe sleep-disordered breathing, and CPAP treatment was started. After CPAP treatment, both clinical and biochemical markers of preeclampsia improved. In addition, circulating angiogenic markers of preeclampsia improved. As a result, the pregnancy safely continued for 30 days, allowing the fetus to gain gestation. CONCLUSION: Continuous positive airway pressure may be a novel treatment for women with early-onset preeclampsia associated with sleep-disordered breathing. (Obstet Gynecol 2015;125:1106–9) DOI: 10.1097/AOG.0000000000000508
P
reeclampsia is a leading cause of maternal and perinatal mortality and morbidity. Early-onset preeclampsia (less than 34 weeks of gestation) accounts for 25% of cases and results in a progressive deterioration
From the Translational Obstetrics Group, Department of Obstetrics and Gynaecology, Mercy Hospital for Women, the Department of Respiratory and Sleep Medicine, Austin Hospital, and the Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, Heidelberg, Victoria, Australia. Corresponding author: Susan P. Walker, MBBS, MD, Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, 163 Studley Road, Heidelberg 3084, Victoria, Australia; e-mail: [email protected]. Financial Disclosure The authors did not report any potential conflicts of interest. © 2015 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0029-7844/15
1106
VOL. 125, NO. 5, MAY 2015
Teaching Points 1. Sleep-disordered breathing is associated with a number of adverse outcomes in pregnancy, including preeclampsia. 2. Screening for symptoms of sleep-disordered breathing should be considered in women with early-onset preeclampsia. 3. Continuous positive airway pressure may be a safe and effective treatment for early-onset preeclampsia associated with sleep-disordered breathing.
of both maternal and fetal health. The only treatment is delivery of the placenta. Clinicians are often forced to end the pregnancy for maternal indications, inflicting iatrogenic prematurity on the fetus with an associated high risk of adverse neonatal outcome.1 A treatment that quenches the disease could enable safe prolongation of the pregnancy, allowing women to reach a gestation (eg, greater than 34 weeks of gestation) where fetal outcomes are improved. Sleep-disordered breathing is characterized by pauses in breathing during sleep, leading to oxygen desaturations and altered hemodynamics. There is growing evidence that sleep-disordered breathing is associated with adverse pregnancy outcomes including gestational hypertension (including preeclampsia), gestational diabetes, fetal growth restriction, and stillbirth.2 Sleep-disordered breathing leads to recurrent hypoxia– reoxygenation that activates oxidative stress, endothelial dysfunction, and inflammation. These are pathologic pathways also common to preeclampsia. Continuous positive airway pressure (CPAP) has been shown to improve cardiometabolic function outside pregnancy and we therefore hypothesized that CPAP could be used to treat preeclampsia and prolong pregnancy. We report the case of a woman with early-onset preeclampsia whose pregnancy was successfully prolonged with CPAP treatment.
CASE A 35-year-old primigravid woman presented at 29 5/7 weeks of gestation with early-onset preeclampsia, as defined by American College of Obstetricians and Gynecologists guidelines.3 She had regular antenatal care, a body mass index (calculated as weight (kg)/[height (m)]2) of 33, and was normotensive with no evidence of renal dysfunction until 29 5/7 weeks of gestation. She presented with pedal edema, headache, and new-onset hypertension with a blood pressure
OBSTETRICS & GYNECOLOGY
Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
of 140/100 mmHg. Urinalysis and biochemical testing confirmed proteinuria (67 mg/dL; normal range less than 10 mg/dL) but a normal platelet count (2683109/L; normal range 150–4003109/L), liver function (alanine aminotransferase 34 international units/L; normal range less than 33 international units/L), and renal function (creatinine 0.76 mg/dL; normal range 0.34–1.1 mg/dL). She was admitted to our tertiary care center, and two doses of betamethasone were administered for fetal lung maturation anticipating preterm delivery. Ultrasound examination confirmed an appropriate-for-gestational-age fetus with an estimated fetal weight on the 90th centile and normal amniotic fluid volume and umbilical artery Doppler studies. Antenatal cardiotocography was normal. The patient reported a history of snoring and daytime somnolence, worse in pregnancy, and a sleep study was performed. This confirmed severe obstructive sleep apnea, with an apnea–hypopnea index of 149 (149 episodes of airway obstruction per hour of sleep). An apnea–hypopnea index greater than 30 is considered severe sleep-disordered breathing. One hundred forty-four events per hour were associated with greater than 4% oxygen desaturation, and 30% of total sleep time was at oxygen saturation less than 90%, with an oxygen saturation nadir of 75%. After an implementation study, CPAP was delivered nightly from 31 weeks of gestation using a Resmed S9 Autoset with pressures set at 14 cm H2O. Compliance was measured using a secure digital memory card installed in the machine. This confirmed nightly use with a mean nocturnal duration of 6 hours 7 minutes (61.48 hours) for the remaining 4 weeks of the pregnancy. There was a marked improvement in the severity of preeclampsia after the start of CPAP (Figs. 1 and 2). Her blood pressure fell from 150/100 mmHg before the start of CPAP, to 130/85 mmHg without antihypertensive medication. Her urinary protein fell from 115 mg/dL to 84 mg/dL (Fig. 1). A trend of decreasing platelets was arrested; rising uric acid levels fell; creatinine levels remained unchanged; and a precipitous rise in alanine aminotransferase stabilized (Fig. 2). After these improvements, she was discharged and monitored as an outpatient in the pregnancy assessment
center twice a week where she had 4 hours of blood pressure monitoring and repeat protein–creatinine ratio and blood testing performed. The improvements in clinical and biochemical parameters reached a nadir at 34 weeks of gestation, after which they deteriorated again, necessitating admission and, subsequently, delivery at 35 weeks 2 days of gestation. Preeclampsia is characterized by an imbalance of proand antiangiogenic factors, which were markedly altered after introduction of CPAP (Fig. 3). Soluble fms-like tyrosine kinase 1 usually rises inexorably with preeclampsia but dropped rapidly after the start of CPAP to near normal pregnancy levels (from 4,796 to 1,948 pg/mL). The ratio of soluble fmslike tyrosine kinase 1 to placental growth factor also fell from 697 to 335. Rising levels of soluble endoglin were also reduced after treatment (from 8,668 to 7,813 pg/mL). Finally, increased levels of endothelin-1, representing endothelial dysfunction, were stabilized with CPAP treatment (from 1.93 to 1.54 pg/mL). The aim of expectant management of preeclampsia is to gain gestation without either maternal or fetal compromise. Regular fetal assessment including measurement of fetal growth and regular fetal Dopplers and cardiotocography were performed. There was no evidence of fetal compromise: the male fetus maintained in utero growth with normal umbilical artery Dopplers, amniotic fluid indices, and fetal heart rate patterns. He was delivered after induction of labor at 35 weeks of gestation as a result of deteriorating maternal health. He weighed 2.8 kg and was briefly admitted to the neonatal unit but discharged home on day 7. The pregnancy was prolonged by 30 days after treatment with CPAP started, allowing a gain in fetal weight of approximately 1 kg.
DISCUSSION Currently the only treatment for early-onset preeclampsia is delivery. The consequences of prematurity for the neonate must be balanced against the risk to the mother of prolonging gestation. Expectant management of early-onset preeclampsia remains controversial with most studies only demonstrating
Fig. 1. The clinical markers of preeclampsia improved after start of continuous positive airway pressure (CPAP). A. Systolic blood pressure normalized with CPAP until rising from 34 5/7 weeks of gestation until delivery. B. Proteinuria remained stable for 3 weeks after initiation of CPAP before precipitously rising after 34 weeks of gestation. The red line represents start of CPAP. Normal range of proteinuria: less than 10 mg/dL. Whitehead. Preeclampsia and Continuous Positive Airway Pressure. Obstet Gynecol 2015.
VOL. 125, NO. 5, MAY 2015
Whitehead et al
Preeclampsia and Continuous Positive Airway Pressure
Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
1107
Fig. 2. The biochemical markers of preeclampsia also improved after continuous positive airway pressure (CPAP) start. A. The falling platelet count was reversed. B. Serum uric acid gradually fell until 34 weeks of gestation. C. The initial deterioration in liver function as evidenced by a rising alanine transaminase level was stabilized by CPAP. D. Serum creatinine continued to rise despite CPAP. The red line represents start of CPAP. Normal ranges: platelet count 150–4003109/L; uric acid 0.14–0.34 mmol/L; alanine transaminase less than 33 international units/L; creatinine 0.34–1.1 mg/dL. Whitehead. Preeclampsia and Continuous Positive Airway Pressure. Obstet Gynecol 2015.
a gain of 7–10 days of gestation.1,4 As such, few studies have shown improvement in neonatal outcome with any gains achieved at the potential expense of maternal health. In this case, we demonstrate an improvement in the clinical, biochemical, and angiogenic markers of preeclampsia but importantly a prolongation of the pregnancy by 30 days after initiation of CPAP. This increase in gestation vastly improved neonatal outcome without jeopardizing maternal health.
Preeclampsia shares common risk factors with cardiovascular disease and sleep-disordered breathing including obesity, essential hypertension, and diabetes. The link between sleep-disordered breathing and preeclampsia has recently been described. Women with sleep-disordered breathing have an odds ratio for preeclampsia of 3.1.5 In addition, sleep-disordered breathing has an estimated causal role in 20–40% of hypertensive disorders of pregnancy. Continuous positive airway pressure may provide a novel treatment
Fig. 3. Angiogenic biomarkers of preeclampsia improved with continuous positive airway pressure (CPAP) treatment. Soluble fms-like tyrosine kinase 1 (sFlt-1) (A), soluble endoglin (B), and the sFlt-1/ placental growth factor (PIGF) ratio (C) fell with CPAP. Endothelin-1, a marker of endothelial dysfunction, fell with CPAP treatment (D). The red line represents start of CPAP. Whitehead. Preeclampsia and Continuous Positive Airway Pressure. Obstet Gynecol 2015.
1108
Whitehead et al
Preeclampsia and Continuous Positive Airway Pressure
OBSTETRICS & GYNECOLOGY
Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
opportunity for this subset of women but its efficacy is unknown. Reid et al6 randomized women with gestational hypertension to CPAP but showed no improvement in blood pressure after a single night of CPAP. In contrast in our study, daily CPAP reduced blood pressure, allowing safe prolongation of the pregnancy. Preeclampsia is a multisystem disorder manifested by widespread endothelial dysfunction, perpetrated by placental factors secreted into the maternal circulation when the placenta has been exposed to hypoxia, inflammation, or both. As a result, there is an imbalance of circulating angiogenic factors leading to vasoconstriction and end-organ damage. Soluble fms-like tyrosine kinase 1, soluble endoglin, and placental growth factor have been well characterized in preeclampsia and show a demonstrable change weeks before the clinical manifestation of preeclampsia.7 Removal of these circulating toxins has been proposed as a treatment for preeclampsia. To date, only extracorporeal apheresis has been shown to reduce the levels of soluble fms-like tyrosine kinase 1 in established preeclampsia but apheresis only reduced circulating soluble fms-like tyrosine kinase 1 levels by between 17% and 34%.8 Soluble fms-like tyrosine kinase 1 levels rebounded within 4 days to pretreatment levels, necessitating multiple treatments with apheresis. In contrast in our case, soluble fms-like tyrosine kinase 1 levels were reduced by more than 50% after initiation of CPAP, and soluble fms-like tyrosine kinase 1 levels remained low for 23 days, perhaps as a result of the continued nocturnal exposure to treatment. Furthermore, CPAP is favorable in comparison with apheresis because it less invasive, has known safety profiles, is readily tolerated by patients, and is relatively inexpensive. In both our case and those presented by Thadhani et al, alterations in sFlt-1 levels reflected changes in the clinical and biochemical markers of preeclampsia. However, we also demonstrate changes in additional
VOL. 125, NO. 5, MAY 2015
Whitehead et al
markers of preeclampsia: placental growth factor, soluble endoglin, and ET-1. This adds weight to the assumption that CPAP stabilizes the endothelial dysfunction of preeclampsia, although caution is necessary when interpreting this single case of improvement in preeclampsia with successful prolongation of pregnancy. Further studies are required to confirm these findings in a larger cohort of patients. In conclusion, we present an improvement in the clinical, biochemical, and angiogenic markers of preeclampsia with CPAP. Most importantly, CPAP sufficiently quenched disease progression to enable pregnancy prolongation and improved neonatal outcome. REFERENCES 1. Haddad B, Sibai BM. Expectant management in pregnancies with severe pre-eclampsia. Semin Perinatol 2009;33:143–51. 2. Romero R, Badr MS. A role for sleep disorders in pregnancy complications: challenges and opportunities. Am J Obstet Gynecol 2014;210:3–11. 3. Diagnosis and management of pre-eclampsia and eclampsia. ACOG Practice Bulletin No. 33. American College of Obstetricians and Gynecologists. Obstet Gynecol 2002;99:159–67. 4. Vigil-De Gracia P, Reyes Tejada O, Calle Miñaca A, Tellez G, Chon VY, Herrarte E, et al. Expectant management of severe preeclampsia remote from term: the MEXPRE Latin Study, a randomized, multicenter clinical trial. Am J Obstet Gynecol 2013;209:425.e1–8. 5. Pamidi S, Pinto LM, Marc I, Benedetti A, Schwartzman K, Kimoff RJ. Maternal sleep-disordered breathing and adverse pregnancy outcomes: a systematic review and meta analysis. Am J Obstet Gynecol 2014;210:52.e1–14. 6. Reid J, Taylor-Gjevre R, Gjevre J, Skomro R, Fenton M, Olatunbosun F, et al. Can gestational hypertension be modified by treating nocturnal airflow limitation? J Clin Sleep Med 2013;9:311–7. 7. Levine RJ, Maynard SE, Qian C, Lim KH, England LJ, Yu KF, et al. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med 2004;350:672–83. 8. Thadhani R, Kisner T, Hagmann H, Bossung V, Noack S, Schaarschmidt W, et al. Pilot study of extracorporeal removal of soluble fms-like tyrosine kinase 1 in preeclampsia. Circulation 2011;124:940–50.
Preeclampsia and Continuous Positive Airway Pressure
Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
1109
Treatment of Early-Onset Preeclampsia With Continuous Positive Airway Pressure Clare Whitehead, MBChB, Stephen Tong, MBBS, PhD, Danielle Wilson, BSc, MSc, Mark Howard, FRACP, PhD, and Susan P. Walker, MBBS, MD BACKGROUND: Preeclampsia is a leading cause of maternal and perinatal morbidity and mortality. There is no treatment for preeclampsia other than delivery. Sleepdisordered breathing is associated with adverse pregnancy outcomes, including preeclampsia, but it is not known whether treatment with continuous positive airway pressure (CPAP) improves perinatal outcomes. CASE: We report a 35-year-old primigravid woman diagnosed with preeclampsia at 30 weeks of gestation. A sleep study confirmed severe sleep-disordered breathing, and CPAP treatment was started. After CPAP treatment, both clinical and biochemical markers of preeclampsia improved. In addition, circulating angiogenic markers of preeclampsia improved. As a result, the pregnancy safely continued for 30 days, allowing the fetus to gain gestation. CONCLUSION: Continuous positive airway pressure may be a novel treatment for women with early-onset preeclampsia associated with sleep-disordered breathing. (Obstet Gynecol 2015;125:1106–9) DOI: 10.1097/AOG.0000000000000508
P
reeclampsia is a leading cause of maternal and perinatal mortality and morbidity. Early-onset preeclampsia (less than 34 weeks of gestation) accounts for 25% of cases and results in a progressive deterioration
From the Translational Obstetrics Group, Department of Obstetrics and Gynaecology, Mercy Hospital for Women, the Department of Respiratory and Sleep Medicine, Austin Hospital, and the Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, Heidelberg, Victoria, Australia. Corresponding author: Susan P. Walker, MBBS, MD, Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, 163 Studley Road, Heidelberg 3084, Victoria, Australia; e-mail: [email protected]. Financial Disclosure The authors did not report any potential conflicts of interest. © 2015 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0029-7844/15
1106
VOL. 125, NO. 5, MAY 2015
Teaching Points 1. Sleep-disordered breathing is associated with a number of adverse outcomes in pregnancy, including preeclampsia. 2. Screening for symptoms of sleep-disordered breathing should be considered in women with early-onset preeclampsia. 3. Continuous positive airway pressure may be a safe and effective treatment for early-onset preeclampsia associated with sleep-disordered breathing.
of both maternal and fetal health. The only treatment is delivery of the placenta. Clinicians are often forced to end the pregnancy for maternal indications, inflicting iatrogenic prematurity on the fetus with an associated high risk of adverse neonatal outcome.1 A treatment that quenches the disease could enable safe prolongation of the pregnancy, allowing women to reach a gestation (eg, greater than 34 weeks of gestation) where fetal outcomes are improved. Sleep-disordered breathing is characterized by pauses in breathing during sleep, leading to oxygen desaturations and altered hemodynamics. There is growing evidence that sleep-disordered breathing is associated with adverse pregnancy outcomes including gestational hypertension (including preeclampsia), gestational diabetes, fetal growth restriction, and stillbirth.2 Sleep-disordered breathing leads to recurrent hypoxia– reoxygenation that activates oxidative stress, endothelial dysfunction, and inflammation. These are pathologic pathways also common to preeclampsia. Continuous positive airway pressure (CPAP) has been shown to improve cardiometabolic function outside pregnancy and we therefore hypothesized that CPAP could be used to treat preeclampsia and prolong pregnancy. We report the case of a woman with early-onset preeclampsia whose pregnancy was successfully prolonged with CPAP treatment.
CASE A 35-year-old primigravid woman presented at 29 5/7 weeks of gestation with early-onset preeclampsia, as defined by American College of Obstetricians and Gynecologists guidelines.3 She had regular antenatal care, a body mass index (calculated as weight (kg)/[height (m)]2) of 33, and was normotensive with no evidence of renal dysfunction until 29 5/7 weeks of gestation. She presented with pedal edema, headache, and new-onset hypertension with a blood pressure
OBSTETRICS & GYNECOLOGY
Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
of 140/100 mmHg. Urinalysis and biochemical testing confirmed proteinuria (67 mg/dL; normal range less than 10 mg/dL) but a normal platelet count (2683109/L; normal range 150–4003109/L), liver function (alanine aminotransferase 34 international units/L; normal range less than 33 international units/L), and renal function (creatinine 0.76 mg/dL; normal range 0.34–1.1 mg/dL). She was admitted to our tertiary care center, and two doses of betamethasone were administered for fetal lung maturation anticipating preterm delivery. Ultrasound examination confirmed an appropriate-for-gestational-age fetus with an estimated fetal weight on the 90th centile and normal amniotic fluid volume and umbilical artery Doppler studies. Antenatal cardiotocography was normal. The patient reported a history of snoring and daytime somnolence, worse in pregnancy, and a sleep study was performed. This confirmed severe obstructive sleep apnea, with an apnea–hypopnea index of 149 (149 episodes of airway obstruction per hour of sleep). An apnea–hypopnea index greater than 30 is considered severe sleep-disordered breathing. One hundred forty-four events per hour were associated with greater than 4% oxygen desaturation, and 30% of total sleep time was at oxygen saturation less than 90%, with an oxygen saturation nadir of 75%. After an implementation study, CPAP was delivered nightly from 31 weeks of gestation using a Resmed S9 Autoset with pressures set at 14 cm H2O. Compliance was measured using a secure digital memory card installed in the machine. This confirmed nightly use with a mean nocturnal duration of 6 hours 7 minutes (61.48 hours) for the remaining 4 weeks of the pregnancy. There was a marked improvement in the severity of preeclampsia after the start of CPAP (Figs. 1 and 2). Her blood pressure fell from 150/100 mmHg before the start of CPAP, to 130/85 mmHg without antihypertensive medication. Her urinary protein fell from 115 mg/dL to 84 mg/dL (Fig. 1). A trend of decreasing platelets was arrested; rising uric acid levels fell; creatinine levels remained unchanged; and a precipitous rise in alanine aminotransferase stabilized (Fig. 2). After these improvements, she was discharged and monitored as an outpatient in the pregnancy assessment
center twice a week where she had 4 hours of blood pressure monitoring and repeat protein–creatinine ratio and blood testing performed. The improvements in clinical and biochemical parameters reached a nadir at 34 weeks of gestation, after which they deteriorated again, necessitating admission and, subsequently, delivery at 35 weeks 2 days of gestation. Preeclampsia is characterized by an imbalance of proand antiangiogenic factors, which were markedly altered after introduction of CPAP (Fig. 3). Soluble fms-like tyrosine kinase 1 usually rises inexorably with preeclampsia but dropped rapidly after the start of CPAP to near normal pregnancy levels (from 4,796 to 1,948 pg/mL). The ratio of soluble fmslike tyrosine kinase 1 to placental growth factor also fell from 697 to 335. Rising levels of soluble endoglin were also reduced after treatment (from 8,668 to 7,813 pg/mL). Finally, increased levels of endothelin-1, representing endothelial dysfunction, were stabilized with CPAP treatment (from 1.93 to 1.54 pg/mL). The aim of expectant management of preeclampsia is to gain gestation without either maternal or fetal compromise. Regular fetal assessment including measurement of fetal growth and regular fetal Dopplers and cardiotocography were performed. There was no evidence of fetal compromise: the male fetus maintained in utero growth with normal umbilical artery Dopplers, amniotic fluid indices, and fetal heart rate patterns. He was delivered after induction of labor at 35 weeks of gestation as a result of deteriorating maternal health. He weighed 2.8 kg and was briefly admitted to the neonatal unit but discharged home on day 7. The pregnancy was prolonged by 30 days after treatment with CPAP started, allowing a gain in fetal weight of approximately 1 kg.
DISCUSSION Currently the only treatment for early-onset preeclampsia is delivery. The consequences of prematurity for the neonate must be balanced against the risk to the mother of prolonging gestation. Expectant management of early-onset preeclampsia remains controversial with most studies only demonstrating
Fig. 1. The clinical markers of preeclampsia improved after start of continuous positive airway pressure (CPAP). A. Systolic blood pressure normalized with CPAP until rising from 34 5/7 weeks of gestation until delivery. B. Proteinuria remained stable for 3 weeks after initiation of CPAP before precipitously rising after 34 weeks of gestation. The red line represents start of CPAP. Normal range of proteinuria: less than 10 mg/dL. Whitehead. Preeclampsia and Continuous Positive Airway Pressure. Obstet Gynecol 2015.
VOL. 125, NO. 5, MAY 2015
Whitehead et al
Preeclampsia and Continuous Positive Airway Pressure
Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
1107
Fig. 2. The biochemical markers of preeclampsia also improved after continuous positive airway pressure (CPAP) start. A. The falling platelet count was reversed. B. Serum uric acid gradually fell until 34 weeks of gestation. C. The initial deterioration in liver function as evidenced by a rising alanine transaminase level was stabilized by CPAP. D. Serum creatinine continued to rise despite CPAP. The red line represents start of CPAP. Normal ranges: platelet count 150–4003109/L; uric acid 0.14–0.34 mmol/L; alanine transaminase less than 33 international units/L; creatinine 0.34–1.1 mg/dL. Whitehead. Preeclampsia and Continuous Positive Airway Pressure. Obstet Gynecol 2015.
a gain of 7–10 days of gestation.1,4 As such, few studies have shown improvement in neonatal outcome with any gains achieved at the potential expense of maternal health. In this case, we demonstrate an improvement in the clinical, biochemical, and angiogenic markers of preeclampsia but importantly a prolongation of the pregnancy by 30 days after initiation of CPAP. This increase in gestation vastly improved neonatal outcome without jeopardizing maternal health.
Preeclampsia shares common risk factors with cardiovascular disease and sleep-disordered breathing including obesity, essential hypertension, and diabetes. The link between sleep-disordered breathing and preeclampsia has recently been described. Women with sleep-disordered breathing have an odds ratio for preeclampsia of 3.1.5 In addition, sleep-disordered breathing has an estimated causal role in 20–40% of hypertensive disorders of pregnancy. Continuous positive airway pressure may provide a novel treatment
Fig. 3. Angiogenic biomarkers of preeclampsia improved with continuous positive airway pressure (CPAP) treatment. Soluble fms-like tyrosine kinase 1 (sFlt-1) (A), soluble endoglin (B), and the sFlt-1/ placental growth factor (PIGF) ratio (C) fell with CPAP. Endothelin-1, a marker of endothelial dysfunction, fell with CPAP treatment (D). The red line represents start of CPAP. Whitehead. Preeclampsia and Continuous Positive Airway Pressure. Obstet Gynecol 2015.
1108
Whitehead et al
Preeclampsia and Continuous Positive Airway Pressure
OBSTETRICS & GYNECOLOGY
Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
opportunity for this subset of women but its efficacy is unknown. Reid et al6 randomized women with gestational hypertension to CPAP but showed no improvement in blood pressure after a single night of CPAP. In contrast in our study, daily CPAP reduced blood pressure, allowing safe prolongation of the pregnancy. Preeclampsia is a multisystem disorder manifested by widespread endothelial dysfunction, perpetrated by placental factors secreted into the maternal circulation when the placenta has been exposed to hypoxia, inflammation, or both. As a result, there is an imbalance of circulating angiogenic factors leading to vasoconstriction and end-organ damage. Soluble fms-like tyrosine kinase 1, soluble endoglin, and placental growth factor have been well characterized in preeclampsia and show a demonstrable change weeks before the clinical manifestation of preeclampsia.7 Removal of these circulating toxins has been proposed as a treatment for preeclampsia. To date, only extracorporeal apheresis has been shown to reduce the levels of soluble fms-like tyrosine kinase 1 in established preeclampsia but apheresis only reduced circulating soluble fms-like tyrosine kinase 1 levels by between 17% and 34%.8 Soluble fms-like tyrosine kinase 1 levels rebounded within 4 days to pretreatment levels, necessitating multiple treatments with apheresis. In contrast in our case, soluble fms-like tyrosine kinase 1 levels were reduced by more than 50% after initiation of CPAP, and soluble fms-like tyrosine kinase 1 levels remained low for 23 days, perhaps as a result of the continued nocturnal exposure to treatment. Furthermore, CPAP is favorable in comparison with apheresis because it less invasive, has known safety profiles, is readily tolerated by patients, and is relatively inexpensive. In both our case and those presented by Thadhani et al, alterations in sFlt-1 levels reflected changes in the clinical and biochemical markers of preeclampsia. However, we also demonstrate changes in additional
VOL. 125, NO. 5, MAY 2015
Whitehead et al
markers of preeclampsia: placental growth factor, soluble endoglin, and ET-1. This adds weight to the assumption that CPAP stabilizes the endothelial dysfunction of preeclampsia, although caution is necessary when interpreting this single case of improvement in preeclampsia with successful prolongation of pregnancy. Further studies are required to confirm these findings in a larger cohort of patients. In conclusion, we present an improvement in the clinical, biochemical, and angiogenic markers of preeclampsia with CPAP. Most importantly, CPAP sufficiently quenched disease progression to enable pregnancy prolongation and improved neonatal outcome. REFERENCES 1. Haddad B, Sibai BM. Expectant management in pregnancies with severe pre-eclampsia. Semin Perinatol 2009;33:143–51. 2. Romero R, Badr MS. A role for sleep disorders in pregnancy complications: challenges and opportunities. Am J Obstet Gynecol 2014;210:3–11. 3. Diagnosis and management of pre-eclampsia and eclampsia. ACOG Practice Bulletin No. 33. American College of Obstetricians and Gynecologists. Obstet Gynecol 2002;99:159–67. 4. Vigil-De Gracia P, Reyes Tejada O, Calle Miñaca A, Tellez G, Chon VY, Herrarte E, et al. Expectant management of severe preeclampsia remote from term: the MEXPRE Latin Study, a randomized, multicenter clinical trial. Am J Obstet Gynecol 2013;209:425.e1–8. 5. Pamidi S, Pinto LM, Marc I, Benedetti A, Schwartzman K, Kimoff RJ. Maternal sleep-disordered breathing and adverse pregnancy outcomes: a systematic review and meta analysis. Am J Obstet Gynecol 2014;210:52.e1–14. 6. Reid J, Taylor-Gjevre R, Gjevre J, Skomro R, Fenton M, Olatunbosun F, et al. Can gestational hypertension be modified by treating nocturnal airflow limitation? J Clin Sleep Med 2013;9:311–7. 7. Levine RJ, Maynard SE, Qian C, Lim KH, England LJ, Yu KF, et al. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med 2004;350:672–83. 8. Thadhani R, Kisner T, Hagmann H, Bossung V, Noack S, Schaarschmidt W, et al. Pilot study of extracorporeal removal of soluble fms-like tyrosine kinase 1 in preeclampsia. Circulation 2011;124:940–50.
Preeclampsia and Continuous Positive Airway Pressure
Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
1109
