Preeclampsia : Early and Late Neonatal Outcomes Ligia Maria Suppo de Souza Rugolo, Maria Regina Bentlin and

Cleide Enoir Petean Trindade Neoreviews 2012;13;e532 DOI: 10.1542/neo.13-9-e532

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Article

developmental outcomes

Preeclampsia: Early and Late Neonatal Outcomes

Ligia Maria Suppo de Souza Rugolo, MD,* Maria Regina Bentlin, MD,* Cleide Enoir Petean Trindade, MD*

Educational Gap
Because preeclampsia can have devastating consequences for both mothers and infants, clinicians need a better understanding of its effects on early and late outcomes in the neonate and how to utilize a multidisciplinary follow-up approach for the most appropriate interventions.

Author Disclosure Drs Rugolo, Bentlin, and Trindade have disclosed no nancial relationships relevant to this article. This commentary does not contain a discussion of an unapproved/ investigative use of a commercial product/ device.

Abstract
Newborn infants exposed to preeclampsia (PE) present increased short-term morbidity, mainly respiratory diseases such as respiratory distress syndrome and bronchopulmonary dysplasia. Gastrointestinal problems are also frequent, although a higher risk of necrotizing enterocolitis has not been conrmed. These problems could be related not just to PE itself but also to prematurity or intrauterine growth restriction, which frequently occur in this maternal disease. Other ndings, however, seem to be due to the direct effect of the maternal disease; these ndings include an increased frequency of neutropenia and thrombocytopenia and a lower incidence of cerebral disorders, such as periventricularintraventricular hemorrhage and cerebral palsy. The evaluation of long-term outcome shows increasing evidence that PE has important implications for the future health of the mother and her child, suggesting that PE is not a simple gestational disorder but a clinical syndrome with an unclear etiology, a genetic component, and a complex pathophysiology. This syndrome involves important maternal and fetal vascular alterations that can persist and cause diseases in later life. The divergence in results on outcomes for children exposed to PE could, in part, be due to methodological differences in the studies, most of which are retrospective case-control studies. Better evidence on prognosis is obtained from cohort studies. Even in the cohort studies, differences in patient characteristics and severity of maternal disease, as well as sample size, follow-up time, and main outcome measures certainly contribute to the variability in results reported in the literature.

Objectives

After completing this article, readers should be able to:

1. Recognize the importance of preeclampsia on early neonatal outcome. 2. List the main effects of preeclampsia on early neonatal outcome. Abbreviations 3. Be concerned about the necessity for monitoring growth and neurodevelopment of children born to BPD: bronchopulmonary dysplasia mothers who had preeclampsia. HELLP: Hemolysis, Elevated Liver enzymes, Low Platelet count 4. Recognize preeclampsia as a risk factor for future IVH: intraventricular hemorrhage diseases. NEC: necrotizing enterocolitis 5. Propose a multidisciplinary follow-up approach for OR: odds ratio infants born to hypertensive mothers. PE: preeclampsia
PVL: periventricular leukomalacia RDS: respiratory distress syndrome VEGFR1: vascular endothelial growth factor receptor-1

Introduction
Hypertensive disorders are the most common obstetric complications in pregnancy, with an incidence of w10%.

*Botucatu School of Medicine University Hospital, Sao Paulo State University (UNESP); Division of Neonatology, Department of Pediatrics, Botucatu, Sao Paulo, Brazil.

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These disorders provide great challenges for obstetricians and neonatologists because they are associated with a number of adverse maternal outcomes and short- and long-term neonatal complications. (1) Despite their high incidence and potential severity, there are few studies on neonatal outcome in hypertensive disorders of pregnancy, and results are variable. Some aspects should be considered in more detail to better understand the conicting results. Hypertension in pregnancy is a broad spectrum of disorders and is classied by the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy into four categories: chronic hypertension (manifesting before or during the rst 20 weeks of pregnancy); gestational hypertension (manifesting after 20 weeks gestation, without proteinuria); preeclampsia (PE) (hypertension developing after 20 weeks gestation and associated with proteinuria in previously normotensive women); and PE superimposed on chronic hypertension (PE diagnosed in previously hypertensive women). (2) The gestational and neonatal outcomes for each of these types of hypertension differ, with the worst outcome generally found in severe PE, whereas in chronic hypertension, the fetal and neonatal repercussions are less severe. (1)(3) A recent study, however, comparing neonatal outcome in the four hypertension categories and normotensive pregnancy found higher prematurity rates, lower birthweight and weight for gestational age, worse birth conditions, and longer hospital stay in neonates born after any kind of maternal hypertensive disorder compared to the control group. (4) Researchers attention has focused mainly on PE, the main manifestation of the disease, with a complex multifactorial etiology involving inammatory mediators, oxidative stress, and immunologic and genetic factors that can be transmitted to descendants and associated with future diseases. (1)(5) In addition to concern about fetal intrauterine growth restriction and premature births, which are frequent in pregnancies complicated by PE, there are questions about which of these characteristics inuence neonatal prognosis, and what are the direct repercussions of maternal disease on prognosis of the offspring. The clinical PE spectrum includes placental disease, represented by abnormal placentation in healthy women, and maternal disease, in which the pregnant woman is affected by some pre-existent pathology such as cardiovascular disease, hypertension, or diabetes. Both of these types are generally present at different intensity levels in most cases of PE, which may explain the variability in its

manifestations and in maternal-fetal repercussions. There is also an important genetic component to this disease, which shows a familial predisposition, and geographical and racial variability, because various PE-related genes and polymorphisms have been identied, suggesting multifactorial polygenic inheritance. (5) PE manifested before 32 to 34 weeks gestation is considered more severe; however, in most cases manifestation is late and mild or moderate, with neonatal outcome similar or better than in early gestational hypertension. (3)(4) Preterm delivery owing to maternal or fetal indications is a common pregnancy outcome in women who develop PE; however, in late-onset PE, w25% of preterm deliveries are considered iatrogenic. This fact is a reason for concern, because prematurity is a determinant factor in neonatal prognosis, and late prematurity is responsible for increased neonatal morbidity and mortality. (6)(7)

Outcome
The relationship between PE and short- and long-term neonatal outcome is controversial in the literature. Some authors have suggested that exposure to a stressful intrauterine environment in PE could accelerate organ maturation and improve the outcome of preterm infants. (8) Others have not found differences between neonatal morbidity and mortality in preterm infants of mothers who did or did not have PE, (9) although a higher morbidity has been reported in some of these patients. (10) Obstetric management and postnatal events are considered determinant in these results. The short- and long-term outcomes for newborn infants born to mothers who have PE are addressed in the following sections, with emphasis on results from cohort studies and case control studies.

Early Outcomes
RESPIRATORY MORBIDITY. RESPIRATORY DISTRESS SYNDROME. Conditions that cause chronic stress may be associated with accelerated fetal pulmonary maturity due to increased cortisol production by the fetus. In this sense, PE may reduce the risk of respiratory distress syndrome (RDS), but results from the literature are conicting. A lower incidence of RDS has been shown in preterm infants less than 34 weeks gestation born to preeclamptic mothers compared with a control group (8) and also in late preterm infants, as recently reported in a large population study in the Netherlands. (7) On the other hand, large cohort studies have shown a higher risk of RDS in preterm infants of mothers who had PE, mainly in those less than 32 weeks gestation, suggesting
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that lung maturity is not accelerated by PE. (11) Even in elective deliveries of late preterm infants born to mothers who have PE, in whom lung maturity has been documented by lecithin/sphingomyelin ratios, infants are not without risk, because w10% develop RDS. (12) Compared with normotensive pregnancies, late preterm infants born to preeclamptic women have greater rates of admission to the NICU, longer neonatal hospitalization, higher respiratory morbidity, greater rates of RDS, and increased needs for respiratory assistance. (3) (6)(13) In our service, we investigated neonatal respiratory morbidity in a cohort of 421 preterm infants who have a mean gestational age of 34 weeks. Of these infants, 144 were born to hypertensive mothers. RDS incidence was 30%, and multivariate analysis showed that gestational age (odds ratio [OR] 2.1) and PE (OR 2.8) were signicant risk factors for RDS. These aspects lead to an important obstetric dilemma: to determine the optimal timing of delivery in stable PE between 34 and 36 weeks gestation. It is necessary to balance the maternal and fetal risks of prolonging the pregnancy versus the potential benets of further fetal maturation. (6) It is a matter of concern that increased neonatal respiratory morbidity not only occurs in PE but is also seen in gestational hypertension, and it affects infants less than 34 weeks gestational age, late preterm infants, and even early term newborns. (3)(13) Perinatal outcome can be worse and RDS can be more frequent in severe gestational hypertension than in mild PE. (14) Currently, available data suggest that PE may be a risk factor for RDS, although data do not allow clarifying the role of PE in fetal lung maturation. BRONCHOPULMONARY DYSPLASIA. Pulmonary alveolarization depends on adequate intrauterine vascular growth, and fetal angiogenesis can be impaired in PE. Pregnant women who have PE have been shown to have increased levels of the soluble vascular endothelial growth factor receptor-1 (soluble VEGFR1, also known as sFlt1), an antagonist of VEGF. The impaired VEGF signaling in utero can disrupt lung development and increase the risk of bronchopulmonary dysplasia (BPD). This mechanism was demonstrated in an experimental study in which intra-amniotic infusion of sFlt-1 caused a reduction in the number of pulmonary alveoli and vessels and increased apoptosis in fetal pulmonary endothelial and mesenchymal cells. (15) Although some studies have shown an increased risk of BPD in PE, especially in severe cases associated with intrauterine growth restriction, (6) (16) results are not uniform, and other authors have not found an association between PE and BPD. (17)
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HEMATOLOGIC ABNORMALITIES. Thrombocytopenia and neutropenia are common hematologic disorders, especially in small-for-gestational-age infants born to mothers who had PE. Although the mechanism of action and clinical consequences have not been studied adequately, these abnormalities can be severe depending on the intensity of intrauterine growth restriction and placental dysfunction. Hematologic abnormalities related to chronic fetal hypoxia, such as increased levels of erythropoietin, increased numbers of nucleated red blood cells, and polycythemia have been described. (18) THROMBOCYTOPENIA. Thrombocytopenia is a transitory alteration, more commonly found in the rst 72 hours after birth, with resolution by 10 days, and in most cases it is not severe. The potential mechanisms of thrombocytopenia include decreased platelet production associated with fetal hypoxia, microangiopathic sequestration, and destruction in the placental thrombi. (6)(19) Newborns with intrauterine growth restriction are at higher risk of thrombocytopenia. (20) NEUTROPENIA. Neutropenia can occur in up to 50% of infants born to mothers who have PE, mainly in those with intrauterine growth restriction. It is a transient hematologic alteration, lasting days to weeks, related to the severity of pregnancy-induced hypertension. Although the mechanism of PE resulting in neutropenia has not been fully established, it has been suggested that neutropenia could result from decreased neutrophil production owing to the presence of some placental inhibitor factor. Neutropenia mainly affects the smaller and younger neonates and may be associated with an increased risk of nosocomial infection. (6)(21) In a case-control study of 543 pregnancies complicated by hypertensive syndrome, neutropenia was found in 5.9% of newborns, with a clear predominance in multiple pregnancies and a higher risk of sepsis in multiple pregnancies with neutropenia. (22) A multicenter study by the Brazilian Network on Neonatal Research with a cohort of 911 very low birthweight preterm infants (308 born to preeclamptic women) showed a higher incidence of neutropenia in the PE group compared to the control group (16.9% vs 10.8%, P .008), but the incidence of sepsis was similar in both groups. Neutropenia was associated with death independently of maternal PE and sepsis. (23) SEPSIS. There is concern about the possible relationship between PE and sepsis, and a higher incidence of sepsis was reported in preterm infants of mothers who

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have HELLP syndrome (Hemolysis, Elevated Liver enzymes, Low Platelet count) and severe PE compared to normotensive mothers. (24) Some studies have not shown an increased incidence of sepsis in the newborn infants of mothers who have PE, however. (9)(23) In the Brazilian Network on Neonatal Research cohort study, a similar incidence of early-onset sepsis (4.6% vs 4.2%) and late-onset sepsis (24% vs 22%) was found in very low birthweight infants born to preeclamptic and normotensive mothers respectively, regardless of the presence of neutropenia. (23) From the available data, the risk of sepsis in infants born to preeclamptic mothers is still controversial, but those with prolonged neutropenia could be at higher risk of infection because of impaired host immunity after birth. NECROTIZING ENTEROCOLITIS. Necrotizing enterocolitis (NEC) occurs especially in preterm infants who have intrauterine distress and abnormal antenatal umbilical Doppler ow (absent or reversed end-diastolic ow), a common condition in PE. (18)(25) Consequently, PE should be considered a risk factor for NEC. Small-for-gestational-age infants who have absent end-diastolic umbilical artery Doppler ow are thought to have an increased risk for feeding intolerance and NEC. (26) A high prevalence of NEC (18%) was found in 242 infants born to women who had severe PE before 34 weeks gestation, and almost half of infants who had suspected NEC had absent end-diastolic umbilical artery Doppler ow. The authors suggest that enteral feeding should be introduced cautiously in preterm infants of preeclamptic mothers who have absent end-diastolic umbilical artery Doppler ow. (27) In a cross-sectional study, the prevalence of NEC in very low birthweight preterm infants was 8%, and maternal hypertensive disorders were independent risk factors for NEC (OR 5.21; 95% condence interval: 1.6416.58). (28) Although some studies did not show a difference in NEC incidence in preterm infants of preeclamptic mothers, (9)(29) a higher frequency of feeding problems, including gastric residues, regurgitation, and gastroesophageal reux, was demonstrated in these infants compared with controls or those exposed to intra-amniotic infection (46% vs 13% vs 11%, respectively). (29) INTRAVENTRICULAR HEMORRHAGE AND CYSTIC PERIVENTRICULAR LEUKOMALACIA. Periventricular leukomalacia (PVL) and grades 3 to 4 intraventricular hemorrhage (IVH) account for most cases of cerebral palsy in preterm infants. Overall, 60% to 100% of patients with PVL or severe IVH develop cerebral palsy. (30)(31) The pathogenesis of cerebral lesions is complex and multifactorial.

Cytokines can play a central role in the apoptosis of neural cells and affect oligodendrocyte progenitor cells, especially between 24 and 34 weeks gestation. (31) Animal studies have shown that exposure to chronic hypoxia can induce adaptive mechanisms that protect against subsequent hypoxic-ischemic lesions. (32) Although chronic hypoxia can confer cerebral protection, there is not sufcient evidence to conrm the hypothesis that small-for-gestational-age newborns of mothers who had PE have neuroprotection. Most studies about risk factors for PVL are retrospective and show good concordance for the association of PVL with inammatory or infectious events, such as premature rupture of membranes and chorioamnionitis. (31) The association between PE and PVL is inconsistent, however, with a low occurrence of PVL (<2%) reported in preterm infants (2432 weeks gestation) exposed to chronic fetal distress in PE associated with intrauterine growth restriction. (33) The EPIPAGE cohort examined the relationship between different causes of preterm delivery, including maternal hypertension and cerebral injury (PVL and severe IVH). Infants born to hypertensive mothers had lower risk of cerebral injury, whereas those born after preterm rupture of membranes with short latency or idiopathic preterm labor showed a higher risk of PVL or severe IVH. (30) A case-control study to determine the effect of magnesium sulfate in PVL development showed that preterm infants exposed to magnesium sulfate in utero were less likely to develop PVL, whereas PE was not associated with a reduced risk of PVL. (34) A worrisome aspect of the neurologic repercussions of PE was documented in a large cohort study; PE was considered to be an independent risk factor for encephalopathy in term newborns. The authors speculated that this nding could be due to increased fetal inammatory response to hypoxia and oxidative stress in pregnancy complicated by PE. (35) Short-term outcomes are summarized in Table 1.

Late Outcomes
The long-term impact of PE on health status and on growth and development is still not well established, but ongoing evidence suggests that PE increases the risk of diabetes and cardiovascular disease in adulthood. (6) It has been speculated that vasculotoxic factors released by the diseased placenta could pass the placental barrier and determine a persistent defect in the circulation of the offspring that may predispose them to cardiovascular disease later in life. (36)
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Table 1.

Short-term Neonatal Outcome in Preeclampsia: What Is Expected and What Is Uncertain

Outcome Respiratory morbidity RDS BPD Thrombocytopenia Neutropenia Sepsis NEC Feeding problems Cerebral injury in preterm (PVL and IVH) Encephalopathy in term infants Risk Increased Increased May be increased Increased Increased Uncertain May be increased Increased Not increased or decreased Increased Commentary In preterm and late preterm infants The role of PE in lung maturation is not established Results are not uniform Mainly in intrauterine growth restriction Related to severity of maternal disease Prolonged neutropenia may increase the risk Mainly in infants who have abnormal antenatal umbilical Doppler ow Few studies Lower risk of PVL compared to preterm rupture of membranes; magnesium sulfate decreases risk of PVL Studies on the effect of PE in newborns at term are scarce

BPDbronchopulmonary dysplasia; IVHintraventricular hemorrhage; NECnecrotizing enterocolitis; PE preeclampsia; PVLperiventricular leukomalacia; RDSrespiratory distress syndrome.

GROWTH. At present, there is a paucity of data on the growth of infants born to mothers who have PE. A cohort study evaluated growth outcome at 12 and 18 months corrected age of very low birthweight infants born to preeclamptic mothers (n 40) and normotensive mothers (n 46). The PE group had higher rates of subnormal growth at 12 and 18 months corrected age, and catch-up of bodyweight did not occur. Head circumference was signicantly lower in these infants at 18 months corrected age. (37) Ongoing research in our service aimed to evaluate growth in a cohort of low birthweight preterm infants who were managed up to 2 years of corrected age. There were no differences in weight, length, and head circumference between infants of hypertensive mothers (n 80) and normotensive mothers (n 100), and in both groups, growth was compatible with values from World Health Organization standard curves. At the end of the second year, however, children born to hypertensive mothers presented twice the risk of being overweight than controls. In early puberty, daughters of obese women who had PE had higher BMIs and larger waist measurements, whereas no differences were found in boys. (38) In young adulthood there were no differences in height, BMI, and waist-to-hip ratio between female offspring of women who did or did not have PE. (39) NEURODEVELOPMENT. Data on long-term development are scarce and inconclusive. In the literature, there are conicting results on the neurodevelopmental outcome of preterm infants born to preeclamptic mothers. Some
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evidence suggests a protective role of maternal hypertension on the neurodevelopmental outcome of preterm infants, with a reduced risk of IVH (8)(40) and cerebral palsy, (41) whereas some authors report similar rates of disabilities in the rst 2 years after birth. (42) Poorer neurodevelopment owing to maternal PE was documented in a retrospective study of 89 very low birthweight infants delivered before 32 weeks gestation. These infants were assessed by using the Bayley Scales at 2 years corrected age and had lower Mental Developmental Index scores compared with infants of normotensive mothers. In this study, PE was a risk factor for impaired cognitive development. (43) In contrast, a prospective study of 86 very low birthweight infants (40 born to preeclamptic mothers) evaluated at 12 and 18 months of corrected age by using Bayley Scales showed similar Mental Developmental Index scores in both groups, and at 18 months of corrected age, preterm infants of preeclamptic mothers had a signicantly higher Psychomotor Developmental Index score. (37) A recent Australian cohort study of 1,389 children (25% born to hypertensive mothers) demonstrated that offspring of pregnancies complicated by gestational hypertension or PE had a mild impairment in their verbal abilities at age 10 years. Hypertensive disorders of pregnancy were a risk factor for a reduction in verbal ability of the offspring. (44) Divergence in the literature could be due to differences in patients, methods, main outcome measures, and time of follow-up. But it must be considered that PE is a complex and heterogeneous disease that can have

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variable effects on the fetus, so the neurodevelopmental outcome for the infant born to a preeclamptic woman can be variable. NEUROLOGIC ALTERATIONS AND MENTAL HEALTH. There is some evidence that bad prenatal experiences such as adverse obstetric events can be associated with behavioral problems throughout childhood and adolescence, and that maternal psychopathology plays a role in the etiology of PE. This nding suggests a link between hypertensive disease and mental health of the offspring. (45) PE has been highlighted as a risk factor for epilepsy in infancy, mainly in children born at term, and although the mechanism underlying this association is not fully understood, PE may cause fetal brain ischemia and cerebral vascular lesions mediated by placental dysfunction. (46) According to a large Australian cohort study, children and adolescents born to women who had gestational hypertension were more likely to have behavioral problems (externalizing and internalizing behavior), whereas in the PE group, reduced internalizing behavior in infancy was demonstrated. (45) Epidemiological studies showed an association between PE and mental health problems in offspring, including anorexia nervosa (47) and symptoms of depression in adults (48); however, these studies do not prove the existence of a causal relationship in this association. HEALTH CONDITION AND THE RISK OF FUTURE DISEASES. A population-based cohort study showed that children born preterm and exposed to PE had an increased risk of hospitalization during the rst year after

birth, whereas children born at term to preeclamptic mothers had an increased risk of being hospitalized for metabolic, nutritional, endocrine, and hematologic diseases from infancy through adulthood. These results suggest a direct effect from the maternal disease on fetal programming. (49) To conrm this hypothesis, in the same cohort, the risk of metabolic or respiratory disease was compared between children who were exposed to PE and their nonexposed siblings. The risk of metabolic diseases was similar between siblings, whereas the risk of respiratory disease was higher when the second child was exposed to PE. These ndings suggest that genetic factors or maternal complications associated with PE can contribute to the risk of future diseases in the descendants, although one cannot rule out some effect from PE in fetal programming. (50) There is increasing evidence that PE is a risk factor for adverse cardiac and vascular events in future life. PE and cardiovascular disease may share several pathophysiological mechanisms. Understanding the cardiovascular phenotype of women and their children exposed to PE may allow the identication of potential targets for preventive strategies. (51) Offspring of hypertensive pregnancies have been shown to have elevated blood pressure in childhood and adolescence, (52) and an increased risk of hypertension and stroke in adulthood. (53) Long-term outcomes are summarized in Table 2.

Final Considerations
Despite all the obstetric attempts to improve assessment and surveillance of women who have hypertension in pregnancy, PE continues to be a common and serious complication of pregnancy, a cause of great concern because of the high rates of maternal and fetal adverse

Table 2.

Long-term Outcomes in Children Born to Preeclamptic Women

Risk Subnormal in the rst 2 years; increased risk of overweight in infancy and puberty Uncertain; lower risk of cerebral palsy; impaired cognitive development; increased risk of epilepsy Impairment of verbal abilities Increased risk in children and adolescents Increased risk of anorexia and depression Increased risk of hospitalization Increased risk Commentary Few studies Conicting results on Bayley Scales Few studies Epidemiological studies Not conrmed as causal relationship Mainly children born at term Suggesting an effect of PE in fetal programming

Outcome Growth Neurodevelopment in the rst years At school age Behavioral problems Adult mental health Health status Hypertension and adult cardiovascular disease
PEpreeclampsia.

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outcomes. Studies aimed at improving our understanding of its pathophysiology are needed urgently so that preventive strategies can be adopted in the future. Regarding the newborn infant born to a preeclamptic woman, although the results from studies on short- and long-term outcomes are inconclusive, the surveillance of complications is necessary. Follow-up of these patients is fundamental in understanding the repercussions of PE for growth and development and for health status in adulthood. Studies involving infants born to mothers who have PE must be encouraged.

American Board of Pediatrics Neonatal-Perinatal Content Specications

Know the effects on the fetus and/or newborn infant of maternal chronic hypertension and its management. Know the effects on the fetus and/or newborn infant of mild preeclampsia and its management. Know the effects on the fetus and/or newborn infant of severe preeclampsia, including HELLP syndrome, and its management. Recognize the effects of fetal programming and nutrition on the prevalence and types of adult onset disorders. Know the etiology, pathophysiology, and differential diagnosis of neonatal leukopenia. Know the causes and pathophysiology of neonatal thrombocytopenia and thrombocytosis.

References
1. Rugolo LMSS, Bentlin MR, Trindade CEP. Preeclampsia: effect on the fetus and newborn. NeoReviews. 2011;12(4):e198e206 2. National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy. Report of National High Blood Pressure Education Program working group on high blood pressure in pregnacy.Am J Obstet Gynecol. 2000;183(suppl 1): S1S22 3. Cruz MO, Gao W, Hibbard JU. Obstetrical and perinatal outcomes among women with gestational hypertension, mild preeclampsia, and mild chronic hypertension. Am J Obstet Gynecol. 2011; 205(3):260.e19 4. Ferrazzani S, Luciano R, Garofalo S, et al. Neonatal outcome in hypertensive disorders of pregnancy. Early Hum Dev. 2011;87(6): 445449 5. Valenzuela FJ, Prez-Seplveda A, Torres MJ, Correa P, Repetto GM, Illanes SE. Pathogenesis of preeclampsia: the genetic component. J Pregnancy. 2012;2012:632732 6. Backes CH, Markham K, Moorehead P, Cordero L, Nankervis CA, Giannone PJ. Maternal preeclampsia and neonatal outcomes. J Pregnancy. 2011;2011:214365 7. Langenveld J, Ravelli AC, van Kaam AH, et al. Neonatal outcome of pregnancies complicated by hypertensive disorders between 34 and 37 weeks of gestation: a 7 year retrospective
e538 NeoReviews Vol.13 No.9 September 2012

analysis of a national registry. Am J Obstet Gynecol. 2011; 205(6): 540.e17 8. Shah DM, Shenai JP, Vaughn WK. Neonatal outcome of premature infants of mothers with preeclampsia. J Perinatol. 1995;15(4):264267 9. Friedman SA, Schiff E, Kao L, Sibai BM. Neonatal outcome after preterm delivery for preeclampsia. Am J Obstet Gynecol. 1995;172 (6):17851788, discussion 17881792 10. Kurkinen-Rty M, Koivisto M, Jouppila P. Preterm delivery for maternal or fetal indications: maternal morbidity, neonatal outcome and late sequelae in infants. BJOG. 2000;107(5):648655 11. Chang EY, Menard MK, Vermillion ST, Hulsey T, Ebeling M. The association between hyaline membrane disease and preeclampsia. Am J Obstet Gynecol. 2004;191(4):14141417 12. Lewis DF, McCann J, Wang Y, Cormier C, Groome L. Hospitalized late preterm mild preeclamptic patients with mature lung testing: what are the risks of delivery? J Perinatol. 2009;29(6): 413415 13. Habli M, Levine RJ, Qian C, Sibai B. Neonatal outcomes in pregnancies with preeclampsia or gestational hypertension and in normotensive pregnancies that delivered at 35, 36, or 37 weeks of gestation. Am J Obstet Gynecol. 2007;197(4):406.e17 14. Buchbinder A, Sibai BM, Caritis S, et al; National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. Adverse perinatal outcomes are signicantly higher in severe gestational hypertension than in mild preeclampsia. Am J Obstet Gynecol. 2002;186(1):6671 15. Tang JR, Karumanchi SA, Seedorf G, Markham N, Abman SH. Excess soluble vascular endothelial growth factor receptor-1 in amniotic uid impairs lung growth in rats: linking preeclampsia with bronchopulmonary dysplasia. Am J Physiol Lung Cell Mol Physiol. 2012;302(1):L36L46 16. Hansen AR, Barns CM, Folkman J, McElrath TF. Maternal preeclampsia predicts the development of bronchopulmonary dysplasia. J Pediatr. 2010;156(4):532536 17. OShea JE, Davis PG, Doyle LW; Victorian Infant Collaborative Study Group. Maternal preeclampsia and risk of bronchopulmonary dysplasia in preterm infants. Pediatr Res. 2012;71(2): 210214 18. Gruslin A, Lemyre B. Pre-eclampsia: fetal assessment and neonatal outcomes. Best Pract Res Clin Obstet Gynaecol. 2011;25 (4):491507 19. Kush ML, Gortner L, Harman CR, Baschat AA. Sustained hematological consequences in the rst week of neonatal life secondary to placental dysfunction. Early Hum Dev. 2006;82(1): 6772 20. Roberts I, Murray NA. Neonatal thrombocytopenia. Semin Fetal Neonatal Med. 2008;13(4):256264 21. Mouzinho A, Rosenfeld CR, Sanchez PJ, Risser R. Effect of maternal hypertension on neonatal neutropenia and risk of nosocomial infection. Pediatrics. 1992;90(3):430435 22. Sharma G, Nesin M, Feuerstein M, Bussel JB. Maternal and neonatal characteristics associated with neonatal neutropenia in hypertensive pregnancies. Am J Perinatol. 2009;26(9):683689 23. Procianoy RS, Silveira RC, Mussi-Pinhata MM, et al; Brazilian Network on Neonatal Research. Sepsis and neutropenia in very low birth weight infants delivered of mothers with preeclampsia. J Pediatr. 2010;157(3):434438, 438, e1 24. Kim HY, Sohn YS, Lim JH, et al. Neonatal outcome after preterm delivery in HELLP syndrome. Yonsei Med J. 2006;47(3): 393398

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developmental outcomes pre-eclampsia

25. Kamoji VM, Dorling JS, Manktelow B, Draper ES, Field DJ. Antenatal umbilical Doppler abnormalities: an independent risk factor for early onset neonatal necrotizing enterocolitis in premature infants. Acta Paediatr. 2008;97(3):327331 26. Bora R, Mukhopadhyay K, Saxena AK, Jain V, Narang A. Prediction of feed intolerance and necrotizing enterocolitis in neonates with absent end diastolic ow in umbilical artery and the correlation of feed intolerance with postnatal superior mesenteric artery ow. J Matern Fetal Neonatal Med. 2009;22(11): 10921096 27. Kirsten GF, van Zyl N, Smith M, Odendaal H. Necrotizing enterocolitis in infants born to women with severe early preeclampsia and absent end-diastolic umbilical artery doppler ow velocity waveforms. Am J Perinatol. 1999;16(6):309314 28. Bashiri A, Zmora E, Sheiner E, Hershkovitz R, Shoham-Vardi I, Mazor M. Maternal hypertensive disorders are an independent risk factor for the development of necrotizing enterocolitis in very low birth weight infants. Fetal Diagn Ther. 2003;18(6):404407 29. Ersch J, Baenziger O, Bernet V, Bucher HU. Feeding problems in preterm infants of preeclamptic mothers. J Paediatr Child Health. 2008;44(11):651655 30. Ancel PY, Marret S, Larroque B, et al; Epipage Study Group. Are maternal hypertension and small-for-gestational age risk factors for severe intraventricular hemorrhage and cystic periventricular leukomalacia? Results of the EPIPAGE cohort study. Am J Obstet Gynecol. 2005;193(1):178184 31. Bauer M, Fast C, Haas J, Resch B, Lang U, Pertl B. Cystic periventricular leukomalacia in preterm infants: an analysis of obstetric risk factors. Early Hum Dev. 2009;85(3):163169 32. Miller BA, Perez RS, Shah AR, Gonzales ER, Park TS, Gidday JM. Cerebral protection by hypoxic preconditioning in a murine model of focal ischemia-reperfusion. Neuroreport. 2001;12(8): 16631669 33. Zupan V, Gonzalez P, Lacaze-Masmonteil T, et al. Periventricular leukomalacia: risk factors revisited. Dev Med Child Neurol. 1996;38(12):10611067 34. FineSmith RB, Roche K, Yellin PB, et al. Effect of magnesium sulfate on the development of cystic periventricular leukomalacia in preterm infants. Am J Perinatol. 1997;14(5):303307 35. Impey L, Greenwood C, Sheil O, MacQuillan K, Reynolds M, Redman C. The relation between pre-eclampsia at term and neonatal encephalopathy. Arch Dis Child Fetal Neonatal Ed. 2001;85(3):F170F172 36. Jayet PY, Rimoldi SF, Stuber T, et al. Pulmonary and systemic vascular dysfunction in young offspring of mothers with preeclampsia. Circulation. 2010;122(5):488494 37. Silveira RC, Procianoy RS, Koch MS, Benjamin AC, Schlindwein CF. Growth and neurodevelopment outcome of very low birth weight infants delivered by preeclamptic mothers. Acta Paediatr. 2007;96(12):17381742 38. Ogland B, Nilsen ST, Forman MR, Vatten LJ. Pubertal development in daughters of women with pre-eclampsia. Arch Dis Child. 2011;96(8):740743 39. Ros HS, Lichtenstein P, Ekbom A, Cnattingius S. Tall or short? Twenty years after preeclampsia exposure in utero: comparisons of

nal height, body mass index, waist-to-hip ratio, and age at menarche among women, exposed and unexposed to preeclampsia during fetal life. Pediatr Res. 2001;49(6):763769 40. Pontello D, Ianni A, Driul L, et al. Prenatal risk factors for intraventricular hemorrhage, neonatal death and impaired psychomotor development in very low birth weight infants. Minerva Ginecol. 2008;60(3):223229 41. Gray PH, OCallaghan MJ, Mohay HA, Burns YR, King JF. Maternal hypertension and neurodevelopmental outcome in very preterm infants. Arch Dis Child Fetal Neonatal Ed. 1998;79(2): F88F93 42. van Zeben-van der Aa DM, Verwey RA, Verloove-Vanhorick SP, Brand R, Ruys JH. Maternal hypertension and very preterm infants mortality and handicaps. Eur J Obstet Gynecol Reprod Biol. 1991;39 (2):8792 43. Cheng SW, Chou HC, Tsou KI, Fang LJ, Tsao PN. Delivery before 32 weeks of gestation for maternal pre-eclampsia: neonatal outcome and 2-year developmental outcome. Early Hum Dev. 2004;76(1):3946 44. Whitehouse AJ, Robinson M, Newnham JP, Pennell CE. Do hypertensive diseases of pregnancy disrupt neurocognitive development in offspring? Paediatr Perinat Epidemiol. 2012;26(2): 101108 45. Robinson M, Mattes E, Oddy WH, et al. Hypertensive diseases of pregnancy and the development of behavioral problems in childhood and adolescence: the Western Australian Pregnancy Cohort Study. J Pediatr. 2009;154(2):218224 46. Wu CS, Sun Y, Vestergaard M, et al. Preeclampsia and risk for epilepsy in offspring. Pediatrics. 2008;122(5):10721078 47. Favaro A, Tenconi E, Santonastaso P. Perinatal factors and the risk of developing anorexia nervosa and bulimia nervosa. Arch Gen Psychiatry. 2006;63(1):8288 48. Tuovinen S, Rikknen K, Kajantie E, et al. Depressive symptoms in adulthood and intrauterine exposure to pre-eclampsia: the Helsinki Birth Cohort Study. BJOG. 2010;117(10):12361242 49. Wu CS, Nohr EA, Bech BH, Vestergaard M, Catov JM, Olsen J. Health of children born to mothers who had preeclampsia: a population-based cohort study. Am J Obstet Gynecol. 2009; 201 (3):269.e1269.e10 50. Wu CS, Nohr EA, Bech BH, Vestergaard M, Catov JM, Olsen J. Diseases in children born to mothers with preeclampsia: a population-based sibling cohort study. Am J Obstet Gynecol. 2011;204(2): 157.e15 51. Lazdam M, Davis EF, Lewandowski AJ, Worton SA, Kenworthy Y, Kelly B, Leeson P. Prevention of vascular dysfunction after preeclampsia: a potential long-term outcome measure and an emerging goal for treatment. J Pregnancy. 2012;2012:704146 52. Ferreira I, Peeters LL, Stehouwer CD. Preeclampsia and increased blood pressure in the offspring: meta-analysis and critical review of the evidence. J Hypertens. 2009;27(10): 19551959 53. Kajantie E, Eriksson JG, Osmond C, Thornburg K, Barker DJ. Pre-eclampsia is associated with increased risk of stroke in the adult offspring: the Helsinki birth cohort study. Stroke. 2009;40(4): 11761180

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NeoReviews Quiz New minimum performance level requirements

Per the 2010 revision of the American Medical Association (AMA) Physicians Recognition Award (PRA) and credit system, a minimum performance level must be established on enduring material and journal-based CME activities that are certied for AMA PRA Category 1 CreditTM. In order to successfully complete 2012 NeoReviews articles for AMA PRA Category 1 CreditTM, learners must demonstrate a minimum performance level of 60% or higher on this assessment, which measures achievement of the educational purpose and/or objectives of this activity. Starting with 2012 NeoReviews, AMA PRA Category 1 CreditTM can be claimed only if 60% or more of the questions are answered correctly. If you score less than 60% on the assessment, you will be given additional opportunities to answer questions until an overall 60% or greater score is achieved.

You are asked to counsel a mother known to be at 28 weeks gestation with a blood pressure of 200/130 mm Hg and severe proteinuria. She presents with loss of vision but is communicative. An immediate computed tomographic scan shows no evidence of stroke, bleeding, or other abnormality in the mother. A cesarean delivery is performed, and the infant has Apgar scores of 4 at 1 minute and 7 at 5 minutes, respectively. 1. For an infant born to a preeclamptic mother, which of the following is correct? A. The infant has a lower risk of being born prematurely. B. Compared to a mother with normotensive pregnancy, if the infant is born late preterm, the infant has a lower rate of admission to NICUs, lower neonatal hospitalizations, lower respiratory morbidity, lower rates of respiratory distress syndrome, and lower need for respiratory assistance. C. The mother exhibits low levels of soluble vascular endothelial factor receptor-1, which stimulates surfactant production. D. It has been shown clearly that these infants have lower incidence of respiratory distress at all stages of pregnancy. E. Preterm delivery owing to maternal or fetal indications is a common pregnancy outcome in women who develop preeclampsia; however, in late-onset preeclampsia, w25% of preterm deliveries are considered iatrogenic. 2. Compared to infants born to non-preeclamptic mothers, this infant: A. B. C. D. E. Is Is Is Is Is less likely to have respiratory morbidity. more likely to have a high white blood cell count. more likely to have thrombocytosis. more likely to have thrombocytopenia that usually resolves by 10 days. more likely to have neutrophilia owing to increased stress and demargination.

3. Studies of infants born to preeclamptic mothers have shown: A. They are at a higher risk for necrotizing enterocolitis and should routinely not be enterally fed for at least 1 week after birth. B. They have a decreased risk of sepsis. C. Their neutropenia should be treated routinely with granulocyte colony stimulating factor. D. They have an increased risk for feeding intolerance and necrotizing enterocolitis in the absence of enddiastolic ow on umbilical artery Doppler. E. They lack hematologic abnormalities related to chronic fetal hypoxia, such as increased erythropoietin, increased nucleated red blood cells, and polycythemia.

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4. Regarding the nervous system and other outcomes of infants born to preeclamptic mothers, which of the following is correct? A. There is a lower risk of intraventricular hemorrhage. B. There is a lower risk for encephalopathy caused by inammatory cytokine responses. C. The risk of periventricular leukomalacia can be reduced with magnesium sulfate administration to the mother. D. There are higher rates of subnormal growth at 12 and 18 months corrected age. Catch-up of bodyweight does not occur. Head circumference is signicantly lower in these infants at 18 months corrected age. E. There is a clear increase in autism-spectrum disorders. 5. Regarding long-term outcomes of infants born to preeclamptic mothers, there is: A. An increased risk of anorexia and depression. B. A decreased risk of hospitalization, especially in children born at term. C. A decreased risk of hypertension and cardiovascular disease owing to reverse programming. D. Improvement in verbal abilities. E. Increased capability in mathematical skills.

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Preeclampsia : Early and Late Neonatal Outcomes Ligia Maria Suppo de Souza Rugolo, Maria Regina Bentlin and Cleide Enoir Petean Trindade Neoreviews 2012;13;e532 DOI: 10.1542/neo.13-9-e532

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including high resolution figures, can be found at: http://neoreviews.aappublications.org/content/13/9/e532 This article cites 44 articles, 8 of which you can access for free at: http://neoreviews.aappublications.org/content/13/9/e532#BIBL This article, along with others on similar topics, appears in the following collection(s): Fetus and Newborn Infant http://neoreviews.aappublications.org/cgi/collection/fetus_newb orn_infant Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: /site/misc/Permissions.xhtml Information about ordering reprints can be found online: /site/misc/reprints.xhtml

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