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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)
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.
hyperoxia experienced by the neonate after a preterm birth
5. Phan MH, Nguyen PN, Reynolds JD. Incidence and severity of retinop-
promotes a reduction in VEGF expression and induces a vaso-
athy of prematurity in Vietnam, a developing middle-income country.
obliteration state due to endothelial cell apoptosis. As the ret-
J Pediatr Ophthalmol Strabismus 2003;40:208-12.
ina matures and becomes hypoxic because of vascular growth
6. Holmstrom G, van Wijngaarden P, Coster DJ, Williams KA. Genetic sus-
interruption, VEGF level increases progressively to cause the
ceptibility to retinopathy of prematurity: the evidence from clinical andexperimental animal studies. Br J Ophthalmol 2007;91:1704-8.
undesired retinal neovascularization (phase 2 of ROP). Inhi-
7. Bizzarro MJ, Hussain N, Jonsson B, Feng R, Ment LR, Gruen JR, et al.
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.
angiogenic factors concentrations, especially soluble Tie-2.
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).
We suggest that those circulatory changes plus modifications
Graefes Arch Clin Exp Ophthalmol 2010;248:893-900.
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.
velocity and Doppler indexes of the ophthalmic arteries from
birth to hospital discharge of inborn infants with birth
15. Multicenter trial of cryotherapy for retinopathy of prematurity. Prelim-
inary results. Cryotherapy for Retinopathy of Prematurity Cooperative
weights between 500 and 1500 g and gestational age # 32
Group. Arch Ophthalmol 1988;106:471-9.
weeks were just published and could be used as standard
16. The International Classification of Retinopathy of Prematurity revisited.
for the study population.35 The importance of our study is
the demonstration that VLBW infants delivered by pre-
17. Report of the National High Blood Pressure Education Program Work-
eclamptic mothers have 60% reduction in risk for any stage
ing Group on High Blood Pressure in Pregnancy. Am J Obstet Gynecol2000;183:S1-22.
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18. Fortes Filho JB, Barros CK, da Costa MC, Procianoy RS. Results of a pro-
gram for the prevention of blindness caused by retinopathy of prematu-rity in southern Brazil. J Pediatr (Rio J) 2007;83:209-16.
We thank Vania Hirakata for statistical analysis and Isaura Riedel for
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20. Fortes Filho JB, Valiatti FB, Eckert GU, Costa MC, Silveira RC,
Procianoy RS. Is being small for gestational age a risk factor for retinop-
Submitted for publication Apr 21, 2010; last revision received Aug 17, 2010;accepted Aug 27, 2010.
athy of prematurity? A study with 345 very low birth weight preterm in-fants. J Pediatr (Rio J) 2009;85:48-54.
Reprint requests: Renato S. Procianoy, MD, PhD, Rua Tobias da Silva 99 conj
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302, Porto Alegre, RS 90570-020, Brazil. E-mail: email@example.com
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THE JOURNAL OF PEDIATRICS www.jpeds.com
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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.
No Estudo de Proteção do Coração - Heart Protection Study (HPS), sinvastatina os efeitos do tratamento com sinvastatina durante um período de acompanhamento de 5,3 anos, em média, foram avaliados em Medicamento genérico 20.536 pacientes com ou sem hiperlipidemia e alto risco de even- Lei nº 9.787, de 1999 tos coronarianos, em decorrência de diabetes, antecedentes de acide
Begoña Ansorena Psicóloga-Psicoanalista. CDIAP Sant Boi de Llobregat Introducción El siguiente caso fue presentado en un ciclo de sesiones clínicas bajo el título “La desinserción en la infancia: modalidades clínicas”, organizado por el CDIAP de Sant Boi de Llobregat (Barcelona) en colaboración con la Sección Clínica de Bar- celona del Instituto del Campo Freudiano. Elegí es