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ARTICLE |
a Slone Epidemiology Center at Boston University, Boston, Massachusetts
b Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts
c Division of Newborn Medicine, Children's Hospital and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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METHODS. Between 1998 and 2003, the Slone Epidemiology Center enrolled 377 mothers of infants with persistent pulmonary hypertension of the newborn and 836 mothers of matched control subjects. Within 6 months of delivery, study nurses interviewed participants regarding demographic, medical, and obstetric characteristics.
RESULTS. Factors that were independently associated with an elevated risk for persistent pulmonary hypertension of the newborn were infant male gender and black or Asian maternal race compared with white race. High prepregnancy BMI (>27 vs <20) was also associated with persistent pulmonary hypertension of the newborn, as were diabetes and asthma. Compared with infants who were delivered vaginally, the risk for persistent pulmonary hypertension of the newborn was higher for those who were born by cesarean section. Compared with infants who were born within 37 to 41 gestational weeks, the risk was higher for those who were born between 34 and 37 completed weeks and for those born beyond 41 weeks. Compared with infants within the 10th and 90th percentiles of birth weight for gestational age distribution, the risk was higher for infants above the 90th percentile.
CONCLUSIONS. Our findings suggest an increased risk for persistent pulmonary hypertension of the newborn associated with cesarean delivery; late preterm or postterm birth; being large for gestational age; and maternal black or Asian race, overweight, diabetes, and asthma. It remains unclear whether some of these factors are direct causes of persistent pulmonary hypertension of the newborn or simply share common causes with it; however, clinicians should be alert to the increased need for monitoring and intervention among pregnancies with these risk factors.
Key Words: pulmonary hypertension • newborn • PPHN • epidemiology • race • BMI • Cesarean section
Abbreviations: PPHN—persistent pulmonary hypertension of the newborn • LMP—last menstrual period • ASD—atrial septal defect • OR—odds ratio • CI—confidence interval
In the pulmonary vessels of the human fetus, regulatory hormones create relatively high vascular resistance, causing the oxygenated blood from the placenta to be diverted away from the lungs through the 2 fetal channels, the ductus arteriosus and the foramen ovale. In the normal fetal-to-neonatal circulatory transition, the lungs expand, vasodilatory factors are released, pulmonary vascular resistance falls, the "right-to-left hemodynamic shunting" ceases, and pulmonary blood flow dramatically increases. However, an abnormal persistence of high pulmonary vascular resistance at birth disrupts the normal transition, causing persistent shunting of the blood away from the lungs through one or both fetal channels. The resulting severely diminished pulmonary blood flow markedly restricts the normal exchange of oxygen and carbon dioxide.1,2 This abnormal condition has been called persistent fetal circulation or persistent pulmonary hypertension of the newborn (PPHN).
PPHN affects between 1 and 2 infants per 1000 live births.3–5 The newborn with PPHN is typically a term or late-preterm infant who does not have associated congenital anomalies and presents within hours of birth with severe respiratory failure that requires intubation and mechanical ventilation.6,7 When untreated, PPHN is frequently fatal. Despite the introduction of treatments such as nitric oxide, extracorporeal membrane oxygenation (ie, heart-lung bypass), and advanced modes of mechanical ventilation, 10% to 20% of affected infants still die.5,8,9 In addition, infants who survive PPHN face increased risks for serious and long-term sequelae (including chronic lung disease, seizures, and neurodevelopmental problems) as a result of both the condition's hypoxemia and the aggressive treatments that PPHN often requires.5,10,11
Although management of PPHN can be improved by prompt identification and vigilant monitoring of neonates who are at high risk for this condition, such efforts are constrained by our limited knowledge of factors that predict which infants are at highest risk for developing PPHN. Established perinatal clinical predictors include postmaturity, nonvertex presentation, fetal distress, cesarean section, meconium staining of the amniotic fluid, neonatal sepsis, and pneumonia.12–14 Data for antenatal factors have been more equivocal. Based on only a few studies, antenatal factors that inconsistently suggested to be associated with a higher risk for developing PPHN include the infant being male and various maternal factors, including low education; black ethnicity; and tobacco use, fever, urinary tract infection, pulmonary disease, vaginal bleeding, and diabetes during pregnancy.6,12,15 To identify additional possible antenatal and perinatal predictors, we performed a multicenter case-control study that was specifically designed to identify risk factors for PPHN.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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The participation rate was 69% for mothers of infants with PPHN and 68% for mothers of control subjects. After exclusion of mothers who could not be located, the rates were 73% and 71% for infants with PPHN and control subjects, respectively.
Selection of Cases
Diagnostic criteria for PPHN cases were gestational age >34 weeks, presentation shortly after birth with severe respiratory failure, and evidence of pulmonary hypertension. Gestational age as reported in the infant's medical chart at the time of ascertainment was verified by comparing the date of birth with the due date reported by the mother, which was based on her last menstrual period (LMP) or early pregnancy ultrasound estimate. Severe respiratory failure was defined as the need for intubation and mechanical ventilation. Pulmonary hypertension was documented by a 
5% gradient between preductal and postductal oxygen saturation and/or by echocardiographic evidence (>95% of the cases had echocardiographic evidence). Among those who underwent echocardiography, infants were designated as having PPHN when the cardiologist assigned the diagnosis of PPHN or noted marked pulmonary hypertension or the echocardiogram showed right-to-left hemodynamic shunting at the foramen ovale or ductus arteriosus or bidirectional hemodynamic shunting accompanied by leftward bowing of the ventricular septum to a degree consistent with pulmonary arterial pressure more than half of the systemic pressure.
Exclusion criteria were evidence of any congenital cardiothoracic abnormality except for patent ductus arteriosus; patent foramen ovale; atrial septal defect (ASD); or a single, small, muscular ventriculoseptal defect. Infants with an ASD were included because right-to-left atrial hemodynamic shunting commonly occurs among infants with PPHN, and, in describing this finding, neonatal echocardiographic studies sometimes do not distinguish between ASD and patent foramen ovale. Infants who had an isolated small muscular ventriculoseptal defect were included because it is a common and hemodynamically insignificant abnormality.
All infants who were admitted to the NICUs at participating hospitals were screened by study nurses or respiratory therapists who were specially trained to identify infants who might have PPHN. To determine eligibility, one of the authors (Dr Van Marter) reviewed the medical charts of all infants with diagnostic codes for asphyxia, cyanotic congenital heart disease, respiratory distress syndrome, pneumonia, meconium aspiration, transient tachypnea of the newborn, or pulmonary hypertension.
Potential PPHN cases were subsequently classified as (1) "confirmed" when they met every criterion for the case definition of PPHN, (2) "probable" when their clinical courses were highly suggestive of PPHN and their diagnostic criteria for PPHN approximated but did not fall within the specified ranges, (3) "possible" when their clinical courses were consistent with PPHN but diagnostic tests were not performed or were unavailable, or (4) "not a case" when their clinical or diagnostic tests were inconsistent with PPHN. Potential cases were designated "indeterminate" and excluded from consideration when they lacked information that was deemed necessary to classify the infants into 1 of the diagnostic categories. Only confirmed and probable cases were included in the main analyses.
Selection of Control Subjects
Control subjects included infants who were born after 34 weeks' gestation without a birth defect or a respiratory problem and were matched to case patients by birth hospital and calendar date of birth (±30 days). To achieve an intended case:control ratio of 1:2, we initially selected up to 4 potential control subjects for every potential PPHN case. After final classification of PPHN cases and completion of interviews, controls who were matched to confirmed and probable cases and who had completed interviews were selected for the analyses, for a final case:control ratio of 1:2.2.
Assessment of Exposure
Within 6 months of delivery, trained study nurses interviewed the mothers of case and control infants. The telephone interview was detailed and structured, and it included questions on demographic characteristics, the mother's medical history (eg, maternal diabetes, pulmonary disease), pregnancy conditions (eg, fever, vaginal bleeding, urinary tract infections), obstetric history (eg, mode of delivery), smoking habits, and use of all medications (prescription and over-the-counter) during pregnancy. The interviewer entered the mother's responses directly into the computer and had access to computerized dictionaries of drugs and diagnoses. Quality control procedures were conducted both manually and by computer.
We specifically asked women whether a health care provider had diagnosed "high blood pressure" or "toxemia or preeclampsia" during their pregnancy and the dates when the condition started and ended. We defined gestational hypertension as hypertension (with or without preeclampsia) starting after the 20th week of pregnancy, because hypertension diagnosed earlier in gestation may be unrelated to pregnancy. For transient characteristics such as infections, we also focused on the period between 20 completed weeks after the first LMP day and the date of delivery. Maternal recall of timing was enhanced by using a calendar that highlighted key dates, including the woman's LMP and delivery dates.
We asked women specific questions about the presence, timing, and severity of respiratory symptoms. With the assistance of Dr Michael Schatz, an expert on asthma during pregnancy, we asked questions that enabled us to classify asthma as (1) definite when a health care provider had diagnosed asthma or reactive airways disease and the condition was present during the past 5 years; (2) probable when women reported bronchitis, wheezing, chest tightness, or cough with at least 1 positive response on the timing of asthma symptoms (ie, symptoms occur seasonally; at night; during or after colds; after exercise; or after exposure to animals, cut grass, or dust); and (3) possible when women reported only shortness of breath in the past 5 years with at least 1 positive response on the timing of asthma symptoms, or bronchitis, wheezing, chest tightness, or cough with no positive response on the timing of asthma symptoms. Dyspnea of pregnancy (ie, only shortness of breath and only during pregnancy) was not considered asthma.
Data Analysis
Matched odds ratios (ORs) and 95% confidence intervals (CIs) were estimated for PPHN in relation to a number of risk factors using multivariate conditional logistic regression. Analyses were performed using SAS 8.2 (SAS Institute, Cary, NC).
To separate the potential impact of fetal growth restriction from prematurity, we considered birth weight relative to gestational age. We defined as small for gestational age those infants who were <10th percentile of birth weight relative to other infants of the same gestational age (in weeks) according to US references.17 In addition, we defined as large for gestational age those infants who were >90th percentile of these reference curves.
Risk factor analyses were repeated for cases who were born preterm (between 34 and 37 completed weeks since LMP) and term (38 or more weeks). We also classified cases according to their clinical presentation and explored whether specific subgroups of PPHN were preferentially associated with certain risk factors. For these subanalyses, we broke the individual matching and instead used frequency matching for region and calendar year by considering them as stratifying factors in the multivariate conditional logistic regression models.
Because information on fetal distress had been collected for PPHN cases but not for controls, a variable for fetal distress could not be included in the statistical model. To explore indirectly whether fetal distress confounded the association between mode of delivery and PPHN, we compared how often fetal distress was the indication for cesarean section among 2 groups of infants who were delivered by cesarean section: PPHN cases and a recent sample of 61 nonmalformed newborns who were delivered in the same hospitals as the cases and for whom delivery information was available.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Of the 231 patients who had PPHN and were delivered by cesarean section, 46 (19.9%) were elective cesarean sections because of a previous section or because of multiple pregnancy, placenta previa, or breech presentation, whereas 111 (48.1%) were emergency cesarean sections, because of either fetal distress or presence of meconium, cord prolapse, nuchal cord, maternal preeclampsia, or abruptio placentae. For 74 (32%) patients, it was unclear whether the cesarean section was elective or emergent. In the control group of 61 nonmalformed newborns, 49.2% had elective cesarean sections and 18% had emergency cesarean sections because of either fetal distress or other factors; 32.8% had insufficient information regarding the proximal indication. Among those with cesarean section, fetal distress was identified in 38.5% of the cases and 11.5% of the control subjects.
Effect of PPHN Definition
Restriction of analyses to infants who were born after 37 completed weeks of gestation did not materially change the estimates for the risk factors noted. Among preterm infants, the sample size (60 cases and 42 control subjects) was insufficient to adequately estimate ORs for all risk factors. However, male gender and high BMI were associated with an increased risk, whereas black or Asian race and maternal asthma were not associated with the risk for PPHN.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Cesarean Section
Numerous publications have reported cesarean section delivery, including elective cesarean delivery, to be associated with a high incidence of respiratory distress syndrome13,18–20 and PPHN.12,21,22 A particularly high risk for respiratory distress has been observed when elective cesarean sections were performed before 39 weeks of gestation (presumably by miscalculation of gestational age),18–20,23 leading some to suggest that cesarean section may cause PPHN through delivery of infants who have significant pulmonary immaturity, which sets the stage for a maladaptive perinatal circulatory transition.24 However, miscalculation of gestational age in elective cesarean deliveries is less likely in the current medical era given more accurate pregnancy dating. Further and more directly, in our study, cesarean section remained a predictor of high PPHN risk even among term infants, diminishing support for the iatrogenic pulmonary immaturity hypothesis.
Alternatively, cesarean section itself might cause PPHN. For example, without labor, the normal perinatal increases of endogenous prostaglandin and catecholamine levels, which promote clearance of lung fluid, might not be achieved. Moreover, the physical compression that results from normal vaginal delivery, which expels fetal lung and airway liquid, is lacking in infants who are born by cesarean section.24,25 In fact, elective cesarean section has been associated with neonatal respiratory morbidity particularly, although not exclusively, in the absence of preceding labor.18–20,23 However, we found a similarly increased risk for PPHN for cesarean section with and without labor, which suggests that absence of labor and its associated humoral factors does not fully account for the increased risk for PPHN among cesarean deliveries. The potential beneficial effect of compression in the birth canal remains a plausible but herein untestable explanation.
Interpreting the association between cesarean section and PPHN is made challenging by the fact that certain antecedents (eg, fetal distress) might serve both as indications for cesarean section and as underlying causes, consequences, or markers for PPHN. We found that factors such as maternal race, weight, diabetes, or preeclampsia did not account for the increased risk for PPHN among cesarean section deliveries. Conversely, at least 48% of the cesarean sections in the patients with PPHN were emergently conducted because of fetal or maternal complications, compared with 18% in the source population. Therefore, the increased incidence of PPHN after cesarean section might be largely attributable to underlying fetal conditions that triggered the intervention and ultimately result in PPHN, rather than to a direct causal effect of the cesarean section (or lack of vaginal delivery) per se.
Race
This study confirms the previously reported elevated risk for PPHN among black infants.6,12 In addition, we found an elevated risk for Asian infants. The differences do not seem to be explained by socioeconomic factors (eg, maternal education, family income) or mediated through a higher incidence of preterm deliveries (ie, the increased risk for black and Asian infants remained among term infants). Indeed, black and Asian patients with PPHN were more often term infants than were white patients.
Maternal BMI and Diabetes
Maternal overweight and diabetes were associated with PPHN in our population. Both obesity and insulin resistance are known to induce endothelial dysfunction and inflammation26 and might therefore have a direct impact on fetal lung development. However, they are also widely known independent risk factors for a number of adverse pregnancy outcomes, including preeclampsia, macrosomia, and cesarean deliveries,27,28 conditions that themselves might be in the causal pathway between overweight or diabetes and PPHN. Our findings suggest that the association between maternal overweight and PPHN is not explained by the higher incidence of preeclampsia or larger fetuses among overweight women. However, the OR for diabetes became null when birth weight for gestational age and, particularly, mode of delivery were included in the model. On the basis of these findings, one might speculate that maternal diabetes increases the risk for PPHN by increasing the prevalence of macrosomia as well as other conditions that often result in cesarean deliveries. Alternatively, adjustment for intermediate variables (birth weight and mode of delivery) might introduce selection bias.29 For example, within cesarean deliveries, the risk for PPHN might actually be lower among women with diabetes than among women without diabetes, not because of a protective effect of diabetes but because women without diabetes might have indications for cesarean section, such as fetal distress, which are more strongly associated with PPHN than diabetes itself.
Smoking and Asthma
Smoking and maternal pulmonary disease had been proposed as risk factors for PPHN because they impair placental function and contribute to fetal hypoxemia, which has been shown to induce pulmonary hypertension.1,30 In previous epidemiologic studies, the effect of smoking on PPHN could not be adequately assessed because of lack of information on dosage and timing and insufficient sample size to determine the independent effect of smoking.6,12 Our findings do not confirm the hypothesized effects of smoking on the risk for PPHN and are sufficiently robust to exclude ORs of 1.6. However, our definition of smoking exposure was based on maternal report and no biomarker for exposure to maternal or environmental tobacco smoke was available, so our estimates of in utero smoking exposure lack precision. Conversely, we found a higher risk for PPHN among mothers with asthma, and it is of note that this increased risk was not explained by the medications that were used to treat the condition. Maternal asthma might increase the risk for developing PPHN through fetal hypoxemia or through other pathophysiologic processes; however, genetic predisposition to lung disorders or unknown environmental exposures could increase the risk for both asthma in the mother and PPHN in the fetus.
Other Factors
We confirmed the previously suggested higher risk for developing PPHN for boys and postmature infants and a modest increased risk for fewer years of maternal education. However, we did not find an increased risk associated with maternal fever, urinary tract infection, vaginal infections, respiratory infections, or use of antibiotics late in pregnancy (ORs were close to 1, and the CIs excluded a two-fold increased risk).6,12–15,31 Although indirect evidence may suggest a role for cocaine in the etiology of PPHN, we were not able to test this hypothesis because maternal report of illicit drug use is unreliable and other options for identifying cocaine exposure were infeasible.
Possible Etiologic Heterogeneity
Although PPHN has a common clinical presentation, its etiology is thought to fall into 3 different groups2: (1) hypoplasia of pulmonary vasculature, as is seen in congenital diaphragmatic hernia or oligohydramnios; (2) congenital pulmonary vascular remodeling involving increased muscularization of pulmonary arterioles,7 often considered as idiopathic PPHN; and (3) normal arteriolar number and muscularization but maladaptation to circulatory transition (eg, decreased production of or responsiveness to vasodilators such as nitric oxide and prostacyclin and/or increased release of or responsiveness to vasoconstrictors); such maladaptation results in abnormally constricted pulmonary vasculature,31 as occurs in developmental immaturity, meconium aspiration syndrome, or sepsis.3
Because we excluded from the study PPHN patients with major malformations and none of the patients had oligohydramnios, study cases likely occurred via vascular remodeling or maladaptation. In an attempt to identify subsets of the disease with potentially different risk factors, we conducted secondary analyses by stratifying PPHN cases according to various clinical characteristics. Findings were consistent with the existence of 2 distinct subgroups of PPHN: preterm and term. Preterm patients with PPHN most often presented with presumed surfactant deficiency and probably represent the maladaptation type. The term population most often presented with fetal distress and might represent the congenital type.
Strengths and Limitations
Strengths of this study include the broad screening by specialists who were experienced in caring for infants with PPHN, the careful selection of patients who met the strict case definition for PPHN, use of an individually matched control group, and the collection of detailed information on a wide variety of factors. A potential limitation of this study is the retrospective design, which introduces the possibility of inaccurate recall of previous events and recall bias. For minimization of inaccurate recall, all interviews were conducted within 6 months after delivery and used a carefully designed and structured questionnaire.32 Moreover, most of the predictors that were identified by this study are accurately recalled (eg, race, mode of delivery, fetal gender). Concern regarding recall bias is minimized by the fact that the study interviewers specifically and similarly probed both case and control participants and that neither interviewers nor participants were aware of the study hypotheses at the time of the interview. Another limitation is the incomplete information on surfactant deficiency, sepsis, and other clinical characteristics for the case patients, which was abstracted from medical charts, as well as information on indications for cesarean section for the matched control subjects. Also, despite surveillance at community hospitals, we might have underascertained fatal PPHN cases because infants with severe PPHN may die before transfer to a tertiary hospital, where the diagnosis would be made with precision. If predictors for fatal cases were distinctive, then risk factors that we identified may not apply to them.
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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1 per 100 births). Therefore, clinicians should be alert to the increased need for monitoring and intervention for such higher risk newborn infants. Additional research will be needed to clarify why and how predictors that were identified in this and other studies are associated with the risk for PPHN.
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ACKNOWLEDGMENTS |
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We thank Dawn Jacobs, RN, MPH, Fiona Rice, MPH, Rita Krolak, RN, Kathleen Sheehan, RN, Karen Bennett Mark, RN, Clare Coughlin, RN, Nastia Dynkin, Nancy Rodriquez-Sheridan, Meghan Malone-Moses, Michelle Hose, RN, Beth Smith, RN, Patricia Maloney, RN, and Merianne Mitchell, RT, for assistance in data collection and computer programming and Dr Michael Schatz for assistance in the ascertainment and classification of asthma. We also thank the mothers who participated in the study, as well as the medical and nursing staff at each participating hospital: Baystate Medical Center, Beth Israel Deaconess Medical Center, Boston Medical Center, Brigham & Women's Hospital, Brockton Hospital, Cambridge Hospital, Caritas Good Samaritan Medical Center, Charlton Memorial Hospital, Children's Hospital, Emerson Hospital, Falmouth Hospital, Haverhill-Hale Hospital, Jordan Hospital, Kent Hospital, Lawrence General Hospital, Lowell General Hospital, Melrose-Wakefield Hospital, Metro West Medical Center-Framingham, Mt Auburn Hospital, New England Medical Center, Newton-Wellesley Hospital, North Shore Medical Center, Rhode Island Hospital, Saints Memorial Medical Center, South Shore Hospital, Southern New Hampshire Medical Center, St Elizabeth's Medical Center, St Luke's Hospital, St Vincent Hospital, UMASS Memorial Health Care, Women & Infants' Hospital, Abington Memorial Hospital, Albert Einstein Medical Center, Alfred I. duPont Hospital for Children, Bryn Mawr Hospital, Chester County Hospital, Children's Hospital of Philadelphia, Christiana Care Health Services, Community Hospital, Crozer-Chester Medical Center, Doylestown Hospital, Frankford Hospital, Hahnemann University Hospital, Hospital of the University of Pennsylvania, Lankenau Hospital, Lancaster General Hospital, Lehigh Valley Hospital, Nanticoke Memorial Hospital, Pennsylvania Hospital, Sacred Heart Hospital, St Christopher's Hospital for Children, St Mary Medical Center, Temple University Health Sciences Center, Reading Hospital & Medical Center, Thomas Jefferson University Hospital, Grand River Hospital, Guelph General Hospital, Hamilton Health Sciences Corp, Hospital for Sick Children, Humber River Regional Hospital-Church Site, Humber River Regional Hospital-Finch Site, Joseph Brant Memorial Hospital, Lakeridge Health Corp, London Health Sciences Center, Mt Sinai Hospital, North York General Hospital, Oakville Trafalgar Memorial Hospital, Scarborough Hospital–General Division, Scarborough Hospital–Grace Division, St Joseph's Health Centre-London, St Joseph's Health Centre-Toronto, St Joseph's Healthcare-Hamilton, St Michael's Hospital, Sunnybrook & Women's College Health Sciences Center, Toronto East General Hospital, Toronto General Hospital, Trillium Health Center, William Osler Heath Centre, York Central Hospital, York County Hospital, Alvarado Hospital, Balboa Naval Medical Center, Camp Pendleton Naval Hospital, Children's Hospital and Health Center, Kaiser Zion Medical Center, Palomar Medical Center, Pomerado Hospital, Scripps Mercy Hospital, Scripps Memorial Hospital-Chula Vista, Scripps Memorial Hospital-Encinitas, Scripps Memorial Hospital-La Jolla, Sharp Chula Vista Hospital, Sharp Coronado Hospital, Sharp Grossmont Hospital, Sharp Mary Birch Hospital, Tri-City Medical Center, and UCSD Medical Center.
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FOOTNOTES |
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Address correspondence to Allen A. Mitchell, MD, Slone Epidemiology Center at Boston University, 1010 Commonwealth Ave, Boston, MA 02215. E-mail: amitchell{at}slone.bu.edu
The authors have indicated they have no financial relationships relevant to this article to disclose.
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