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Maternal Preeclampsia Protects Preterm Infants against Severe Joa˜o Borges Fortes Filho, MD, PhD, Marlene C. Costa, RN, Gabriela U. Eckert, MD, Paula G. B. Santos, MD, Rita C. Silveira, MD, Objective To study the influence of maternal preeclampsia on the occurrence of retinopathy of prematurity.
Study design A prospective cohort study of 324 preterm neonates with birth weight #1500 g and gestational age#32 weeks. Multiple maternal and perinatal factors were analyzed for association and confounding by multiplelogistic regression analysis.
Results Mean birth weight was 1128 Æ 240 g, and mean gestational age 29.7 Æ 1.9 weeks. Twenty-four newborns(7.4%) had severe retinopathy of prematurity; 97 had any stage of retinopathy, and 227 had no retinopathy of pre-maturity. Preeclampsia and complete antenatal steroid treatment course reduced the risk for any stage of retinop-athy of prematurity by 60% and 54%, respectively. Preeclampsia reduced the risk for severe retinopathy ofprematurity by 80%.
Conclusions Preeclampsia lowered the risk for occurrence of any stage and severe retinopathy of prematurity invery low birth weight infants. (J Pediatr 2011;158:372-6).
Maternalpreeclampsiaisafrequentcauseofprematurity.Retinopathyofprematurity(ROP)remainsoneoftheleading causes of preventable childhood blindness. ROP occurs frequently in middle-income countries where improvementsin the perinatal care have increased survival rates of very low birth weight (VLBW) infants. ROP pathogenesis has evolved over 50 years. Initially the uncontrolled use of oxygen therapy was mainly responsible for ROP. More recently, riskfactors for ROP are low birth weight and short gestational age.1 ROP rates differ perhaps related to geographic areas, geneticsdifferences, or environmental susceptibility.2-7 Many studies have evaluated postnatal factors that contribute to ROP. On theother hand, antenatal or maternal risk factors have been minimally studied.8,9 Gotsch et al10 reported an antiangiogenic state in patients with preeclampsia resulting from changes in the concentrations of circulating angiogenic factors. Because ROP is a vasoproliferative disease, an antiangiogenic state in mothers with preeclampsiamight protect the infant for ROP. An association between preeclampsia and ROP has not been reported. We evaluated maternaland perinatal factors for their association with the development of any stage and severe ROP, and if these factors were inde-pendent of the birth weight and gestational age.
A prospective cohort study included all preterm infants screened for ROP with birth weight #1500 g and gestational age #32weeks at birth. The mothers were admitted to Hospital de Clı´nicas de Porto Alegre between October 2002 and July 2009.
The study included all preterm infants screened for ROP who survived until the initial ophthalmologic examination per- formed between the 4th and 6th week after birth. The infants were examined at 45 weeks postmenstrual age (postmenstrualage = gestational age at birth + weeks of life) or until effective stabilization of retinopathy was achieved after treatment. Thedata were prospectively collected, and there were no exclusion criteria. All patients had eye examinations, consisting of binoc-ular indirect ophthalmoscopy after pupil dilation in both eyes with 0.5% tropicamide and 2.5% phenylephrine eye drops, witha 28-diopter lens (Nikon, Melville, New York), and a newborn infant eyelid speculum (Alfonso Eye Speculum; Storz, Bausch &Lomb Inc, San Dimas, California). Scleral indentation was performed when necessary. Screening sessions were performed andscheduled according to the Brazilian guidelines to detect and treat ROP. Subsequent examinations were determined by the find-ings in the first examination.11,12 Clinical outcomes included the onset of any stage of ROP and development of ROP requiring treatment. ROP was classified according to the 1984/1987 International Classification of ROP in stages 1 to 5.13,14 Threshold ROP was defined as 5 contiguousor 8 cumulative clock hours of stage 3 ROP with plus disease in zone I or II, From the Departments of Pediatrics and Ophthalmology Newborn Section, Universidade Federal do Rio Grandedo Sul and Hospital de Clinicas de Porto Alegre, Porto The authors declare no conflicts of interest.
0022-3476/$ - see front matter. Copyright ª 2011 Mosby Inc.
All rights reserved. 10.1016/j.jpeds.2010.08.051 Table I. Univariate analysis of the risk factors for any stage of ROP and for severe ROP N (%); mean Æ standard deviation.
Obs: If Bonferroni corrections for multiples variables were applied the new corrected P value for significance should be P < .002.
CPAP, continuous positive airway pressure.
according to the Multicenter Trial of Cryotherapy for Retinop- presence of three or more of the following: apnea, difficult athy of Prematurity.15 During data collection, the Revisited In- breathing, cyanosis, tachycardia, or bradycardia, shock; ternational Classification of ROP was published. Subsequently irritability, lethargy, hypotonia, and seizures; abdominal dis- all treated patients had a retrospective ROP classification ac- tention, vomiting, dietary intolerance, gastric residue, hepa- cording to this new classification.16 All treatments were per- tomegaly, idiopathic jaundice, thermal instability, petechiae, formed at threshold ROP. Severe ROP meant treatable ROP or purpura; and general poor appearance.
at any stage 3 with plus, or threshold ROP, and stages 4 or 5.
All eye examinations were performed by a single author.
Maternal variables were age, number of prenatal visits, use We used SPSS software (version 14.0 for Windows; SPSS Inc, of antenatal steroid, occurrence of preeclampsia, essential hy- Chicago, Illinois). Student’s t test, 2 pertension, type of delivery, and previous preterm birth. An- were used to compare patients with versus without ROP. We tenatal steroid treatment was defined as the completion of 2 included clinical variables that were statistically significantly doses of betamethasone 24 hours apart or 4 doses of dexa- associated with ROP (P < .05) in multiple logistic regression methasone given 12 hours apart more than 24 hours before models. Bonferroni correction for the P value was not used in delivery. The diagnosis of preeclampsia required arterial this study. The study protocol was approved by the Research hypertension (blood pressure $140 mm Hg systolic and Ethics Committee of Hospital de Clı´nicas de Porto Alegre.
$90 mm Hg diastolic) developing after 20 weeks gestationand proteinuria >300 mg in a 24-hour urine sample in theabsence of previous hypertension or kidney disease.17 Postnatal variables were birth weight, gestational age (eval- uated by obstetric history, early obstetric ultrasound, and During the period of the study 515 patients with birth weight confirmed by newborn infant clinical examination), small # 1500 g and gestational age #32 weeks were admitted to the for gestational age (SGA) (<10th percentile), sex, single or neonatal intensive care unit. Before the initial ophthalmo- multiple gestations, Apgar score at 5 minutes, oxygen therapy logic examination, 158 died. Of the 357 surviving VLBW by nasal continuous positive airway pressure or mechanical infants, 324 (91%) were included in the study. The infants ventilation, erythropoietin, indomethacin, surfactant, blood had a mean birth weight 1.128 Æ 240 g and a mean gesta- transfusions, and presence of sepsis, meningitis, persistent tional age 29.7 Æ 1.9 weeks. One hundred forty-two ductus arteriosus, and any grade of intraventricular hemor- (43.8%) were male, and 136 were SGA (42%). One hundred rhage (IVH) diagnosed by cerebral ultrasonography. Sepsis thirty-seven (42.3%) received a complete antenatal steroid and meningitis were defined by clinical examination and/or course, 222 (75.5%) were delivered by cesarean-section, microbiological culture. Clinical sepsis was based on the and 92 (28.4%) had maternal preeclampsia. Mean gestational THE JOURNAL OF PEDIATRICS  www.jpeds.com ages of newborns delivered of non-preeclamptic and pre- eclamptic mothers were similar (29.6 Æ 1.9 weeks and 30.0Æ 1.6 weeks, respectively; P = .95).
The incidence of any stage of ROP and severe ROP was 29.9% We diagnosed any stage of ROP in 97 (29.9%) patients: 41 and 7.4%, respectively. This ROP rate is low, even for coun- stage 1, 32 stage 2, 22 stage 3, 1 stage 4, and 1 stage 5. Severe tries with established standards of excellence in perinatal ROP developed in 24 patients, and 22 were from nonpree- care.18,19 Complete antenatal steroid treatment and maternal clamptic pregnancies (P = .024). Only 23 patients were preeclampsia were protective factors for any stage of ROP, treated by transpupillary diode laser photocoagulation for and maternal preeclampsia was the only significant protective threshold ROP; one had progression to stage 4A ROP despite factor for severe ROP needing treatment in VLBW infants.
two laser photocoagulation treatments. This patient required The high prevalence of SGA in our study was the result of scleral buckle to stop ROP progression. One patient missed using birth weight as a cutoff point even for newborns with the treatment appointment and developed stage 5. None of 32 weeks’ gestational age. In this study, SGA was not indepen- the treated patients had ROP in zone 1.
dently associated with development of any stage of ROP After univariate analysis any stage of ROP was associated (Table II) as we previously reported.20 It was, however, with less antenatal steroid treatment, less maternal pre- independently associated with severe ROP (Table II), as eclampsia, and essential hypertension. Lower gestational age and birth weight, use of mechanical ventilation, indo- Low gestational age and birth weight was associated with methacin, blood transfusions, and any grade of IVH were as- ROP in most studies. Both are considered the most impor- sociated with more ROP (Table I). By univariate analysis tant risk factors for ROP in different populations and in dif- VLBW infants with severe ROP had less maternal ferent countries.1,23 Our results agree; they also provide preeclampsia, lower gestational age and birth weight, more information about antenatal risk factors that associate with blood transfusions, and more any grade of IVH (Table I).
ROP. Preeclampsia or antenatal steroid treatment was pro- Variables included in the multiple logistic regression model for any stage of ROP were gestational age and SGA, Preeclampsia is linked to maternal and perinatal rates of maternal preeclampsia, antenatal steroid treatment, essential mortality, morbidity, and prematurity.24 Holmstro¨m et al,25 hypertension, any stage of intraventricular hemorrhage, me- in a population-based study, reported that maternal pre- chanical ventilation, indomethacin, blood transfusion, and eclampsia was less frequent in the non-ROP group, but the vaginal delivery. Low gestational age and blood transfusion difference was not statistically significant. Seibert and Linder- were significant risk factors; maternal preeclampsia; and an- kamp9 reported that maternal preeclampsia and lung matura- tenatal steroid treatment reduced risk by 60% and 54%, re- tion induced with antenatal betamethasone were associated spectively (Table II). Variables included in a multiple with lower incidence of ROP. They suggested that maternal logistic regression model for severe ROP were gestational preeclampsia and hypertension mature VLBW infants and age and SGA, maternal preeclampsia, any stage of maternal stress increases cortisol.9 A retrospective study in- intraventricular hemorrhage, and blood transfusion. Low cluded maternal preeclampsia as a main risk factor for devel- gestational and SGA were risk factors; and maternal opment of ROP, although none of the newborns delivered by preeclampsia reduced risk by 80% (Table II).
preeclamptic mothers needed surgical treatment.26 The Ital-ian ROP Study Group reported the importance of antenatalsteroid treatment for respiratory distress syndrome inVLBW infants and the highly significant protective effect of Table II. Adjusted logistic regression for any stage and this therapy for ROP.27 Improvement of respiratory function would decrease the need of oxygen therapy and secondarily the occurrence of ROP. Our data showed decreased develop- ment of ROP in VLBW infants delivered by preeclamptic mothers or after antenatal steroid therapy, independently of oxygen therapy. We suggest that intrauterine stress matures neonatal retinal vasculature preventing ROP.
Any grade of intraventricular hemorrhage 1.251 0.628-2.492 A hypothesis for the pathogenesis of preeclampsia is the ‘‘is- chemic model’’; a reduced placental blood flow causes de- creased fetal growth and intrauterine growth restriction28,29 in patients who are likely to have development of ROP, pe- ripheral retinal vessel growth, or are totally interrupted after premature birth, resulting in a nonvascular and hypoxic pe- ripheral retina (phase 1 of ROP). The proliferative phase of Any stage of intraventricular hemorrhage 1.936 0.708-5.294 disease occurs because of ischemia. Lack of retinal perfusion in the early phase of ROP determines the subsequent degreeof neovascularization, i.e., the severity of disease.30 Vascular endothelial growth factor (VEGF) is a potent angiogenic fac- birth: ten year data from a tertiary care center in a developing country.
tor necessary for normal growth of blood vessels that is asso- ciated with undesired retinal neovascularization.31 The 4. Mayet I, Cockinos C. Retinopathy of prematurity in South Africans at a tertiary hospital: a prospective study. Eye (London) 2006;20:29-31.
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obliteration state due to endothelial cell apoptosis. As the ret- J Pediatr Ophthalmol Strabismus 2003;40:208-12.
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bition of VEGF at this phase cannot prevent retinal neovascu- Genetic susceptibility to retinopathy of prematurity. Pediatrics 2006; larization proving that ROP is a multifactorial disease.31-33 Gotsch et al10 reported an antiangiogenic state in patients 8. Holmstrom G, Broberger U, Thomassen P. Neonatal risk factors for ret- with preeclampsia. They detected changes in the circulating inopathy of prematurity–a population-based study. Acta OphthalmolScand 1998;76:204-7.
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9. Seiberth V, Linderkamp O. Risk factors in retinopathy of prematu- ROP is a vasoproliferative disease and an antiangiogenic state rity. a multivariate statistical analysis. Ophthalmologica 2000;214: in maternal preeclampsia could protect from ROP. We found that maternal preeclampsia was a protective factor for ROP 10. Gotsch F, Romero R, Kusanovic JP, Chaiworapongsa T, Dombrowski M, that reduced the need for laser treatment. We speculate that Erez O, et al. Preeclampsia and small-for-gestational age are associatedwith decreased concentrations of a factor involved in angiogenesis: sol- some antiangiogenic factor produced by preeclamptic mother uble Tie-2. J Matern Fetal Neonatal Med 2008;21:389-402.
may cross the placenta barrier to the fetus. As with maternal 11. Zin A, Florencio T, Fortes Filho JB, Nakanami CR, Gianini N, antibody, it could remain circulating and acting on the retina Graziano RM, et al. [Brazilian guidelines proposal for screening and for several months. There is a temporal sequence of abnormal treatment of retinopathy of prematurity (ROP)]. Arq Bras Oftalmol Doppler changes in the peripheral and central circulatory sys- 12. Fortes Filho JB, Eckert GU, Valiatti FB, Dos Santos PG, da Costa MC, tems of the fetus delivered of preeclamptic mothers, and those Procianoy RS. The influence of gestational age on the dynamic behavior changes also occur in cerebral circulation and retinal vessels.34 of other risk factors associated with retinopathy of prematurity (ROP).
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of factors involved in angiogenesis could prevent the develop- 13. An international classification of retinopathy of prematurity. The Com- mittee for the Classification of Retinopathy of Prematurity. Arch Oph-thalmol 1984;102:1130-4.
The limitation of our study is the lack of information on 14. An international classification of retinopathy of prematurity. II. The retinal circulatory changes that may occur in very preterm in- classification of retinal detachment. The International Committee for fants delivered of preeclamptic mothers. Normal blood flow the Classification of the Late Stages of Retinopathy of Prematurity.
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35. Soares CR, Silveira RC, Procianoy RS. Ophthalmic artery blood flow in 31. Hellstrom A, Perruzzi C, Ju M, Engstrom E, Hard AL, Liu JL, et al. Low very-low-birth-weight preterm infants. Invest Ophthalmol Vis Sci 2010; IGF-I suppresses VEGF-survival signaling in retinal endothelial cells: 50 Years Ago in THE JOURNAL OF PEDIATRICS Turner’s Syndrome in the MaleSteiker DD, Mellman MJ, Bongionvanni AM, Eberlein WR, Leboeuf G. J Pediatr 1961;58:321-9 Although described clinically more than two decades earlier, the recognition that most patients with Turner syn- drome (TS) were ‘‘chromatin negative’’ emerged only 7 years before this report. Using the ‘‘nuclear sexing’’ sys- tem, the interpretation of the absence of Barr bodies (sex chromatin), based on the 1947 Jost experiments in rabbits,was that individuals with TS were genetic males who had undergone prenatal castration resulting in female genitaliaand gonadal dysgenesis. Demonstration of the 45, X karyotype and admonition that such persons be considered femalewith an abnormal genotype rather than a ‘‘chromosomal male’’ or case of ‘‘sex reversal’’ appeared only 2 years beforeSteiker et al reported their five cases of apparent TS in males. Thus, it is easy to understand their confusion regardingthe relationship between these boys and the classic triad of sexual infantilism, congenital webbed neck, and cubitusvalgus that comprised the initial description of girls with TS. Not only is a female phenotype now part of its definition,but the manifestations of TS are believed to be primarily caused by haploinsufficiency of one or more of the multitudeof genes on the X chromosome, such as SHOX.
A likely candidate for what was presumed male Turner syndrome is Noonan syndrome, which is caused by PTPN11 deletions in $50% of cases. Although one or more of the five boys probably had Noonan syndrome, it is unlikely thatthey all did, given the disparate phenotypes. Distinguishing among children with overlapping features such as shortstature, abnormal auricles, high arched palate, low posterior hairline, and short or webbed neck was surely a challenge50 years ago, and, despite advances in molecular and clinical genetics, sometimes remains one to this day. The authorsare to be commended for attempting to reconcile a bewildering set of observations, causing them to go so far as tosuggest that the features of TS were unrelated to the emblematic chromosomal pattern. This insinuation mightseem preposterous to us today, but we should remember the importance of an open mind and consider every conceiv-able explanation for our findings until the inexorable process of scientific discovery allows the ‘‘truth’’ to becomeilluminated.

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