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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Congenital heart defects &#40;CHD&#41; are the most prevalent congenital malformation and the leading cause of childhood mortality and morbidity&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">1</span></a> Preterm birth&#44; which occurs in 5&#8211;18&#37; of newborns worldwide&#44; is also a leading cause of childhood mortality and morbidity and is associated with an increased risk of neurodevelopmental disorders&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">2</span></a> The combination of CHD and preterm birth results in even higher mortality and morbidity&#44; with preterm children born with CHD having a 2&#8211;4-fold higher mortality<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">3</span></a> and an increased risk of neurodevelopmental disorders&#46; Additionally&#44; some CHD types are associated with delayed brain maturation&#44; potentially exacerbating the negative effects of preterm birth on the brain&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">The study by Palma et al&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">4</span></a> aims to clarify the crosstalk between CHD and preterm birth further&#46; Using data from a single center&#44; the authors found that 23&#37; of newborns with CHD were preterm infants&#44; and the presence of CHD increased the likelihood of being preterm by two-fold&#46; The preterm group did not have a statistically different neonatal mortality compared to the term group with CHD&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">It is worth mentioning that the authors&#8217; estimate of the relationship between CHD and preterm birth may be biased due to the use of only live births in the analysis&#46; The study assumes that preterm births only happen from live births when the true risk set is all pregnancies &#40;including fetuses still in-utero&#41;&#46; By only looking at live births&#44; the study ignores pregnancies that end in miscarriage&#44; elective termination&#44; or fetal death&#44; which can be related to exposure and lead to biased results&#46; Additionally&#44; it is also important to note that a significant number of CHD cases may have been missed in this study&#44; as only 40&#8211;50&#37; of CHD cases are diagnosed within the first week and 50&#8211;60&#37; within the first month of life&#46; The study only included cases diagnosed during prenatal and neonatal periods&#44; which could have resulted in missing cases&#44; particularly in term neonates who typically have a shorter hospital stay&#46; To reduce ascertainment bias&#44; the authors excluded mild cardiac defects&#44; but this may have also introduced selection bias&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">We should point out&#44; however&#44; that even though these possible selection biases&#44; the estimates presented by Palma et al&#46; are in line with previous reports that found an association between any CHD and an approximately two-fold increased risk of preterm birth&#46; For example&#44; Laas et al&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">5</span></a> conducted a population-based study on CHD&#44; including 2189 live births with CHD &#40;excluding isolated atrial septal defects&#41; born between 2005 and 2008 and found that 13&#46;5&#37; of newborns with CHD were preterm&#46; The likelihood of preterm birth was two times higher in the CHD group compared to the general population &#40;odds ratio 2&#46;0&#44; 95&#37; confidence interval 1&#46;6&#8211;2&#46;5&#41;&#44; mainly due to a higher rate of spontaneous preterm birth&#46; The increased risk of preterm birth in the CHD group remained even after excluding newborns with chromosomal or other anomalies&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">Matthiesen et al&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">6</span></a> also reported similar results&#44; with a sample size of 1<span class="elsevierStyleHsp" style=""></span>040<span class="elsevierStyleHsp" style=""></span>474 births from Denmark&#46; CHD was associated with an increased risk of spontaneous preterm birth&#44; with an adjusted hazard ratio of 2&#46;1 &#40;95&#37; CI&#44; 1&#46;9&#8211;2&#46;4&#41; compared to the general population&#46; Specific subtypes of CHD were associated with even higher risks&#44; including pulmonary stenosis combined with a septal defect&#44; pulmonary stenosis or atresia&#44; tetralogy of Fallot&#44; coarctation or interrupted aortic arch&#44; and hypoplastic left heart syndrome&#46; The majority of the association was attributed to preterm pre-labour rupture of membranes&#46; The study found no other explanation for this association&#44; particularly from maternal genetics&#44; polyhydramnios&#44; or indicators of fetal or placental growth&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">No definitive cause for this increased risk for preterm birth in CHD could be found&#44; and several mechanisms have been speculated&#46; It likely results from a combination of genetic predispositions and environmental exposures&#46; Preterm birth in infants with CHD could also occur due to abnormal blood flow patterns in the fetus&#46; Regarding other possible confounders&#44; including multiple births&#44; congenital syndromes or extracardiac malformations&#44; in the present study&#44; only the last one had a statistical significance between term and PTB congenital heart disease patients&#46; Further research is needed to examine the connection between changes in fetal circulation and the risk of spontaneous preterm birth in fetuses with CHD&#46;</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflicts of interest</span><p id="par0035" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare&#46;</p></span></span>"
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Spontaneous preterm birth and congenital heart defects: What is known?
Prematuridade e cardiopatia congénita: o que sabemos?
Sérgio Matoso Laranjoa,b,c,d
a Serviço de Cardiologia Pediátrica, Hospital de Santa Marta, Centro Hospital e Universitário de Lisboa Central, Lisboa, Portugal
b Centro de Referência de Cardiopatias Congénitas do Centro Hospital e Universitário de Lisboa Central, Member of the European Reference Network for Rare, Low-prevalence, or Complex Diseases of the Heart (ERN GUARD-Heart), Portugal
c Departamento de Fisiologia, NOVA Medical School, Faculdade de Ciências Medicas, NMS, FCM, Universidade NOVA de Lisboa, Lisboa, Portugal
d Comprehensive Health Research Center, CHRC, NOVA Medical School, Faculdade de Ciências Medicas, NMS, FCM, Universidade NOVA de Lisboa, Lisboa, Portugal
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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Congenital heart defects &#40;CHD&#41; are the most prevalent congenital malformation and the leading cause of childhood mortality and morbidity&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">1</span></a> Preterm birth&#44; which occurs in 5&#8211;18&#37; of newborns worldwide&#44; is also a leading cause of childhood mortality and morbidity and is associated with an increased risk of neurodevelopmental disorders&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">2</span></a> The combination of CHD and preterm birth results in even higher mortality and morbidity&#44; with preterm children born with CHD having a 2&#8211;4-fold higher mortality<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">3</span></a> and an increased risk of neurodevelopmental disorders&#46; Additionally&#44; some CHD types are associated with delayed brain maturation&#44; potentially exacerbating the negative effects of preterm birth on the brain&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">The study by Palma et al&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">4</span></a> aims to clarify the crosstalk between CHD and preterm birth further&#46; Using data from a single center&#44; the authors found that 23&#37; of newborns with CHD were preterm infants&#44; and the presence of CHD increased the likelihood of being preterm by two-fold&#46; The preterm group did not have a statistically different neonatal mortality compared to the term group with CHD&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">It is worth mentioning that the authors&#8217; estimate of the relationship between CHD and preterm birth may be biased due to the use of only live births in the analysis&#46; The study assumes that preterm births only happen from live births when the true risk set is all pregnancies &#40;including fetuses still in-utero&#41;&#46; By only looking at live births&#44; the study ignores pregnancies that end in miscarriage&#44; elective termination&#44; or fetal death&#44; which can be related to exposure and lead to biased results&#46; Additionally&#44; it is also important to note that a significant number of CHD cases may have been missed in this study&#44; as only 40&#8211;50&#37; of CHD cases are diagnosed within the first week and 50&#8211;60&#37; within the first month of life&#46; The study only included cases diagnosed during prenatal and neonatal periods&#44; which could have resulted in missing cases&#44; particularly in term neonates who typically have a shorter hospital stay&#46; To reduce ascertainment bias&#44; the authors excluded mild cardiac defects&#44; but this may have also introduced selection bias&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">We should point out&#44; however&#44; that even though these possible selection biases&#44; the estimates presented by Palma et al&#46; are in line with previous reports that found an association between any CHD and an approximately two-fold increased risk of preterm birth&#46; For example&#44; Laas et al&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">5</span></a> conducted a population-based study on CHD&#44; including 2189 live births with CHD &#40;excluding isolated atrial septal defects&#41; born between 2005 and 2008 and found that 13&#46;5&#37; of newborns with CHD were preterm&#46; The likelihood of preterm birth was two times higher in the CHD group compared to the general population &#40;odds ratio 2&#46;0&#44; 95&#37; confidence interval 1&#46;6&#8211;2&#46;5&#41;&#44; mainly due to a higher rate of spontaneous preterm birth&#46; The increased risk of preterm birth in the CHD group remained even after excluding newborns with chromosomal or other anomalies&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">Matthiesen et al&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">6</span></a> also reported similar results&#44; with a sample size of 1<span class="elsevierStyleHsp" style=""></span>040<span class="elsevierStyleHsp" style=""></span>474 births from Denmark&#46; CHD was associated with an increased risk of spontaneous preterm birth&#44; with an adjusted hazard ratio of 2&#46;1 &#40;95&#37; CI&#44; 1&#46;9&#8211;2&#46;4&#41; compared to the general population&#46; Specific subtypes of CHD were associated with even higher risks&#44; including pulmonary stenosis combined with a septal defect&#44; pulmonary stenosis or atresia&#44; tetralogy of Fallot&#44; coarctation or interrupted aortic arch&#44; and hypoplastic left heart syndrome&#46; The majority of the association was attributed to preterm pre-labour rupture of membranes&#46; The study found no other explanation for this association&#44; particularly from maternal genetics&#44; polyhydramnios&#44; or indicators of fetal or placental growth&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">No definitive cause for this increased risk for preterm birth in CHD could be found&#44; and several mechanisms have been speculated&#46; It likely results from a combination of genetic predispositions and environmental exposures&#46; Preterm birth in infants with CHD could also occur due to abnormal blood flow patterns in the fetus&#46; Regarding other possible confounders&#44; including multiple births&#44; congenital syndromes or extracardiac malformations&#44; in the present study&#44; only the last one had a statistical significance between term and PTB congenital heart disease patients&#46; Further research is needed to examine the connection between changes in fetal circulation and the risk of spontaneous preterm birth in fetuses with CHD&#46;</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflicts of interest</span><p id="par0035" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare&#46;</p></span></span>"
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