10.17843/rpmesp.2020.372.4779

ORIGINAL ARTICLE

Risk of brain damage in premature infants under 34 weeks of gestational age exposed to histological chorioamnionitis Lima, Peru

Noelia Guillén ¹, Physician
Carolina Llerena ¹, Physician
Susan Samalvides ¹, Pediatric Neurologist
Judith Vila ^1,2, Pediatric Neurologist
Tania Juárez ², Pediatric Neurologist
Jaime Cáceres ², Pathologist
Daniel Guillén-Pinto ^1,2, Pediatric Neurologist

¹ Universidad Peruana Cayetano Heredia, Lima, Perú.
² Hospital Cayetano Heredia, Lima, Perú.

ABSTRACT

Objectives: To assess the risk of brain damage in premature infants under 34 weeks of gestational age exposed to histological chorioamnionitis (HCA).

Materials and methods: A cohort study was conducted at the Hospital Cayetano Heredia, during 2015. Premature infants under 34 weeks of gestational age, who had histopathological examination of the placenta, were included. The types of HCA evaluated were sub-chorionitis, chorionitis, chorioamnionitis, with or without funisitis. Brain damage was evaluated in three age periods, between 0 and 7 days, between 7 and 30 days and at 40 weeks of corrected gestational age. A neurological follow-up and regular controls were performed with brain ultrasound.

Results: A total of 85 premature infants were included, 47.1% were women and the mean gestational age was 30.9 weeks. From the total, 42% (36/85) were born exposed to HCA. Premature rupture of membranes was the main cause of sepsis, which was related to neurological damage. HCA was associated with intraventricular hemorrhage (IVH) during the first week and with white matter lesions between 7 and 30 days of age (p = 0.035). The chorioamnionitis type of HCA was associated with neurological damage during the first week (RR = 2.11, 95% CI: 1.09-4.11) and between 7 and 30 days of age (RR = 2.72, 95% CI: 1.07-6.88).

Conclusions: Chorioamnionitis was a risk factor for developing brain injuries in premature infants under 34 weeks of gestational age. It was also a risk factor for HIV during the first 7 days and for white matter injuries between 7 and 30 days of age. At 40 weeks of corrected gestational age, extreme premature infants with HCA had more extensive brain damage.

Keywords: Histological Chorioamnionitis; Preterm; Intraventricular Hemorrhage; White Matter; Periventricular Leucomalacia; Lenticulostriate Vasculopathy; Neurology; Neonatology (Source: MeSH NLM).

INTRODUCTION

Five decades ago, Eastman and DeLeon ⁽¹⁾ linked maternal fever to cerebral palsy (CP) in full-term infants. Since then, it has been known that chorioamnionitis (CA) can induce preterm birth and potentially cause brain damage in the infant ⁽²⁾.

    CA is produced by bacterial invasion of the placenta with subsequent infiltration of polymorphonuclears (PMN) ⁽³⁾, and is considered one of the main causes of obstetric morbidity in Lima ⁽⁴⁾. Clinical CA (CCA) affects 0.5% to 10% of all pregnancies, and increases the risk of premature birth by three times ⁽⁵⁾. Meanwhile, histological CA (HCA) is present in 25-40% of all preterm births and up to 80% in preterm births under 30 weeks ⁽⁶⁾. In this regard, several studies have demonstrated the poor correlation between clinical and histological diagnosis ^(2,5,7).

    In Peru, brain lesions prevalent in premature infants under 34 weeks have been reported. The diagnosis was made using clinical ad serial ultrasound examinations; lesions found were more severe as the gestational age decreased ⁽⁸⁾. Likewise, experimental studies and clinical observations have shown that CA can produce brain damage by direct invasion of pathogenic bacteria (sepsis/meningitis) ^(9-11) or by the effect of inflammatory products (cytokines) generated during placental infection ^(6,12). In this process, cytokines could pass the blood-brain barrier (BBB), injure the cerebral white matter ^(6,11) and sometimes generate intraventricular hemorrhage ⁽²⁾.

    In the long term, it has been observed that infants exposed to HCA are at increased risk of developing CP and other neurodevelopmental disorders ^(6,13). However, recent studies have questioned these findings and propose the development of new research methodologies to resolve the possible underlying mechanism ^(14,15).

    The histopathological study of the placenta and the clinical follow-up offer more evidence to characterize the possible association between HCA and brain damage in the preterm infant. Therefore, the objective of this study was to explore the risk of brain damage in preterm infants under 34 weeks of age exposed to HCA, identified sequentially by age, up to 40 weeks of corrected gestational age. As a secondary objective, due to their relevance in intensive care, maternal and neonatal characteristics were analyzed according to the condition of HCA.

MATERIALSAND METHODS

Designand population

A prospective cohort study of preterm infants under 34 weeks conducted at the Cayetano Heredia Hospital (Lima, Peru). Subtypes of HCA were related to types of brain damage by age, up to 40 weeks of corrected gestational age. The sample size was estimated at 36 preterm infants without a history of HCA and 36 preterm infants with past history of HCA. For the calculation, a 95% confidence level, power of 80% and precision of 0.133 was assumed, which is the difference in the anticipated probabilities of neurological disease between exposed (0.583) and unexposed (0.450) preterm infants, based on an exploratory pilot in the same setting and under the same conditions.

    Premature infants under 34 weeks of age born during the year 2015 with histological examination of the placenta were included. Gestational age was recorded in the following certainty order, by date of last menstruation, first trimester ultrasound or Ballard’s scale. Newborns with severe malformations and those whose mothers had uncontrolled neuropsychiatric pathologies were excluded.

Variables

Maternal, neonatal, anthropometric data, clinical evolution, ultrasounds and histopathological examination of the placenta were recorded in a clinical file. All placentas had macroscopic and microscopic examination performed. HCA was defined as the presence of diffuse or parceled PMN infiltrate in the placenta (≥10 PMN/field). Pathological findings were classified according to the inflammation progression, and the following types were defined: sub-chorionitis, chorionitis and chorioamnionitis. Funisitis was also studied, and it was defined as the presence of PMN infiltration in the umbilical cord.

    According to the highest probability of brain injury by age of the premature infant, brain damage ⁽⁷⁾ was defined as any type of identifiable brain injury during the first week (0 to 7 days), between the first and fourth week (7 to 30 days), and at 40 weeks of corrected age. The types of damage were classified as intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), neonatal encephalopathy (NE), meningitis (MEC), striated lenticule vasculopathy (SLV), parenchymal hemorrhage (PH), cerebral infarction (CI) and cerebral hypoplasia (CH). Hemorrhagic and ischemic lesions tend to be much more frequent in the first week; white substance lesions, between the third and fourth week; and brain trophic effects, at 40 gestational weeks of corrected age ^(8,16).

    Probable sepsis was considered in those cases with clinical signs and evidence of leukocytosis, C‑reactive protein or procalcitonin positive. Confirmed sepsis was considered in cases with positive clinical signs and blood cultures ⁽¹⁷⁾.

    Cases of meningitis required demonstration of pleocytosis (≥30 leukocytes per milliliter in CSF), cases of encephalopathy were defined as the presence of clinical manifestations (hypoactivity, hypotonia, epileptic seizures) and metabolic acidosis.

    All patients underwent neurological examination, head circumference measurement and brain ultrasound, during the first three days, then weekly for three weeks, and then every four weeks until 40 weeks of corrected age. Tests were performed by a neuropediatrics specialist. All ultrasounds were reviewed a second time by a neonatal brain ultrasound specialist.

Ethical considerations

All infants received neonatal care in intensive care units in accordance to both, the hospital protocol and the Peruvian Ministry of Health protocol ⁽¹⁸⁾. In all cases, informed consent was requested; in addition, when the mother was under 18 years old, the assent and consent of an adult family member was requested. The study was approved by the Ethics Committees of Universidad Peruana Cayetano Heredia and the Cayetano Heredia Hospital.

Statistical analysis

The information collected was stored in a protected database and analyzed with STATA 13. Numerical variables with normal distribution were analyzed with the Student’s T-test, and numerical variables without normal distribution, with the Mann-Whitney U test.

    For the bivariate analysis of neonatal characteristics, the Fisher’s exact and Chi-square tests were used, depending on the expected frequencies. For multivariate analysis, variables were analyzed by preterm age groups, 0-7 days, 7-30 days, and 40 weeks corrected age, according to the probability of highest risk. The relative risk of developing brain damage in infants exposed to HCA was determined with a generalized linear model, of the Poisson family for dichotomous variables, used by the form of variable distribution response (brain damage), with robust error variance. For this analysis, confounding variables that were associated with brain damage were included in the bivariate analysis.

RESULTS

Patient enrollment

In 2015, 102 premature infants under 34 weeks of age were born. For this study 85 patients were included, 66 of them concluded the follow-up up to 40 weeks of corrected age, 6 abandoned the follow-up (7.1%) and 13 died (15.3%). The study was concluded in March, 2016 at the completion of the last preterm patient follow-up (Figure 1).

Figure 1. Patient inclusion flow chart.

General characteristics of the study population

From the total of preterm infants, 42.4% (36/85) was born exposed to HCA (Figure 1). The average maternal age was 27.6 years (SD: 7); and 45.9% (39/85) had adequate prenatal controls. Urinary tract infection and premature rupture of membranes (PROM) were found in 28.2% and 25.9% of the mothers, respectively; and were also the most common maternal antecedents. Gestational age average was 30.9 weeks (SD: 2.6) and average weight was 1,670 g (SD: 526.1). Most infants had low weight for their gestational age and the average length at birth was 41.3 cm (SD: 4.5) (Table 1).

Table 1. Frequency of maternal and neonatal characteristics

Characteristics associated with histological chorioamnionitis

HCA was distributed as follows: subchorionitis 38.9% (14/36), chorionitis 38.9% (14/36), and chorioamnionitis 22.2% (8/36). All the cases of funisitis 44.4% (16/36) were combined with some type of affectation in the placental layers.

    Maternal education was a factor negatively associated with HCA (p = 0.042). PROM and rupture of membranes for over 18 hours were more frequent in preterm infants exposed to HCA (p = 0.004 and p = 0.033, respectively). Prenatal steroid use was less frequent in the HCA group (p = 0.002). Vaginal delivery was more frequent in the HCA-exposed group (p = 0.044), while caesarean section without labor was more frequent in the non-exposed group (p = 0.044). Other characteristics of the mother, according to the status of the HCA, are detailed in Table 2.

Table 2. Maternal characteristics according to the histological chorioamnionitis status

^a Student’s T-test, ^b Fisher’ s exact test ^c Chi-square test

    The average head circumference percentile for the group with HCA was 47.6 (standard deviation: 28.3), lower (p = 0.035) than the group without HCA (60.7, standard deviation: 27.6). Of the total of patients, 57.6% (49/85) had probable or confirmed sepsis, which was more frequent in preterm infants exposed to HCA (p = 0.013). Other characteristics of the newborn, according to the status of the HCA, are described in Table 3.

Tabla 3. Neonatal characteristics of preterm infants according to the histological chorioamnionitis status

SD: standard deviation, IQC: interquartile range
^a Chi-square test, ^b Student’s T-test, ^c Mann-Whitney U-test, ^d Fisher’s exact test

2. Kaukola T, Herva R, Perhomaa M, Paakko E. Population Cohort Associating Chorioamnionitis, Cord Inflammatory Cytokines and Neurologic Outcome in Very Preterm, Extremely Low Birth Weight Infants. Pediatr Res. 2006;59:478-83.

3. Kim C, Romero R, Chaemsaithong P, Chaiyasit N, Yoon B, Kim Y. Acute chorioamnionitis and funisitis: definition, pathologic features, and clinical significance. Am J Obstet Gynecol. 2015;213(4):S29-S52. doi: 10.1016/j.ajog.2015.08.040.

4. Ministerio de Salud. Análisis de la situación de salud de la provincia de Lima 2011 [Internet]. Lima: Dirección General de Epidemiologia, MINSA; 2011. Available at: http://bvs.minsa.gob.pe/local%20/MINSA/1778.pdf.

5. Edwards RK. Corioamnionitis y parto. Clinic Obstet Ginecol Norteam. 2005;32:287-96.

6. McAdams RM, Juul SE. The Role of Cytokines and Inflammatory Cells in Perinatal Brain Injury. Neurol Res Int. 2012:1-15. doi: 10.1155/2012/561494.

7. Volpe JJ. Neurology of the Newborn. Sixth Edition. Elsevier Health Ed; 2018.

8. Guillén D. Diagnóstico de las Lesiones Cerebrales de los Prematuros Menores de 34 semanas: Incidencia, Factores asociados y Pronóstico [doctoral thesis]. Lima: Universidad Peruana Cayetano Heredia; 2004.

9. Gaudet LM, Smith GN. Cerebral Palsy and chorioamnionitis: The inflammatory cytokine link. Obstet Gynecol Surve. 2001;56(7):433-36.

10. Graham EM, Holcroft CJ, Rai KK, Donohue PK, Allen MC. Neonatal cerebral white matter injury in preterm infants is associated with culture positive infections and only rarely with metabolic acidosis. Am J Obstet Gynecol. 2004;191:1305-10.

11. Hagberg H , Mallard C , Ferriero DM , Vannucci SJ , Levison SW , Vexler ZS , et al. The role of inflammation in perinatal brain injury. Nat Rev Neurol. 2015;11(4):192-208. doi: 10.1038/nrneurol.2015.13.

12. Dammann O, Leviton A. Infection remote from the brain, neonatal white matter damage, and cerebral palsy in the preterm infant. Seminar Pediatr Neurol. 1998;5(3):190-201.

13. Harry GJ, Lawler C, Brunseen SH. Maternal infection and white matter toxicity. Neurotoxicology. 2006; 27: 658-70.

14. Chau V, Poskitt KJ, McFadden D, Bowen-Roberts T, Synnes A, Brant R. Effect of Chorioamnionitis on Brain Development and Injury in Premature Newborns. Ann Neurol. 2009; 66:155-64. doi: 10.1002/ana.21713.

15. Ylijoki M, Ekholm E, Haataja L, Lehtonen L. Is chorioamnionitis harmful for the brain of preterm infants? A clinical overview. Acta Obstet Gynecol Scand. 2012;91(4):403-19. doi: 10.1111/j.1600-0412.2012.01349.x.

16. Medina-Alva P , Duque KR , Zea-Vera A , Bellomo S , Cárcamo C , Guillén-Pinto D , et al. Combined predictors of neurodevelopment in very low birth weight preterm infants. Early Hum Dev. 2019;130:109-15. doi: 10.1016/j.earlhumdev.2019.01.019.

17. Zea-Vera A, Turin CG, Ochoa TJ. Unificar los criterios de sepsis neonatal tardía: propuesta de un algoritmo de vigilancia diagnóstica. Rev Peru Med Exp Salud Publica. 2014;31(2):358-63.

18. Norma técnica para la atención integral de salud neonatal. Resolución N° 828-2013/MINSA [Internet]. Ministerio de Salud; 2015. Available at: http://bvs.minsa.gob.pe/local/minsa/3281.pdf.

19. Volpe JJ. Brain Injury in premature infants: a complex amalgam of destructive and developmental disturbances. Lancet Neurol. 2009; 8:110-24. doi: 10.1016/S1474-4422(08)70294-1.

20. Maisonneuve E, Ancel P, Foix-L’Hélias L, Marret S, Kayem G. Impact of clinical and/or histological chorioamnionitis on neurodevelopmental outcomes in preterm infants: A literature review. J Gynecol Obstet Hum Reprod. 2017;46(4):307-316. doi: 10.1016/j.jogoh.2017.02.007.

21. Shi Z, Ma L, Luo K, Bajaj M, Chawla S, Natarajan G, et al. Chorioamnionitis in the Development of Cerebral Palsy: A Meta-analysis and Systematic Review. Pediatrics 2017;139(6):e20163781.doi: 10.1542/peds.2016-3781.

22. Rincón I, Magdaleno F, Sancha N, Omeñaca F, González A. Corioamnionitis histológica y morbimortalidad neonatal: Aproximación al síndrome de respuesta inflamatoria fetal. Rev Chil Obstet Ginecol. 2010;75(3):172–8.

23. Pugni L, Pietrasanta C, Acaia B, Merlo D, Ronchi A, Ossola M, et al. Chorioamnionitis and neonatal outcome in preterm infants: a clinical overview. J Matern Fetal Neonatal Med. 2016;29(9):1525-29. doi: 10.3109/14767058.2015.1053862.

24. Chaiyasit N , Romero R , Chaemsaithong P , Docheva N , Bhatti G , Kusanovic JP , et al. Clinical chorioamnionitis at term VIII: a rapid MMP-8 test for the identification of intra-amniotic inflammation. J Perinat Med. 2017: 26;45(5):539-550. doi: 10.1515/jpm-2016-0344.

25. Amiya RM , Mlunde LB , Ota E , Swa T , Oladapo OT , Mori R . Antenatal Corticosteroids for Reducing Adverse Maternal and Child Outcomes in Special Populations of Women at Risk of Imminent Preterm Birth: A Systematic Review and Meta-Analysis. PLoS One. 2016;11(2):e0147604. doi: 10.1371/journal.pone.0147604.

26. Ylijoki M, Lehtonen L, Lind A, Ekholm E, Lapinleimu H, Kujari H, et al. Chorioamnionitis and Five-Year Neurodevelopmental Outcome in Preterm Infants. Neonatology. 2016;110(4):286-295.

27. Khwaja O, Volpe JJ. Pathogenesis of Cerebral White matter injury of prematurity. Arch Dis Child Fetal Neonatal Ed. 2008;2:153-61. doi: 10.1136/adc.2006.108837.

28. Instituto Nacional de Estadística e Informática. Encuesta Demográfica y de Salud Familiar 2015 [Internet]. Lima: INEI; 2015. Available at: https://www.inei.gob.pe/media/MenuRecursivo/publicaciones_digitales/Est/Lib1356/ .

29. Pappas A, Kendrick D, Shankaran S, Stoll B, Bell E, Laptook A, et al. Chorioamnionitis and Early Childhood Outcomes Among Extremely Low-Gestational-Age Neonates. JAMA Pediatrics. 2014;168(2):137-47.

30. Chau V, McFadden D, Poskitt KJ, Miller SP. Chorioamnionitis in the Pathogenesis of Brain Injury in Preterm Infants. Clin Perinatol. 2014;41:83-103. doi: 10.1016/j.clp.2013.10.009.

31. Anblagan D, Pataky R, Evans MJ, Telford EJ, Serag A, Sparrow S, et al. Association between preterm brain injury and exposure to choriamnionitis during fetal life. Sci Rep. 2016;6:37932. doi: 10.1038/srep37932.

32. Rocha G, Proenca E, Quintas C, Rodrigues T, Guimaraes H. Chorioamnionitis and brain damage in preterm Newborn. J Matern Fetal Neonatal Med. 2007;20(10):745-9. doi: 10.1080/14767050701580515.

Citation: Guillén N, Llerena C, Samalvides S, Vila J, Juárez T, Cáceres J, et al. Risk of brain damage in premature infants under 34 weeks of gestational age exposed to histological chorioamnionitis Lima, Peru. Rev Peru Med Exp Salud Publica. 2020;37(2):229-38. doi: https://doi.org/10.17843/ rpmesp.2020.372.4779

Correspondence to: Noelia Guillén; calle Modesto Lafuente N° 57, piso 5, puerta A, CP 28003, Madrid, España; noelia.guillen.m@gmail.com

Authors' contributions: DGP, NG and CLl participated in the conception, design and data analysis of the study. NG, CLl participated in the enrollment and data collection. JV, SS andTJ participated in data collection. DGP and NG participated in the writing, JC participated in the collection of anatomopathological data. All authors reviewed and approved the article.

Funding: Self-funded research.

Conflicts of interest: None.

Received: 03/09/2019.

Approved: 29/04/2020.

Online: 12/06/2020