COVID-19 grave y embarazo: a propósito de dos casos alrededor de la viabilidad fetal / Severe COVID-19 and pregnancy: on purpose of 2 cases around fetal viability

Resumen El presente trabajo describe la evolución de dos casos clínicos graves de COVID-19 en pacientes embarazadas con 27 y 24 semanas de amenorrea. A partir de estos casos se resume la evidencia disponible en la literatura en relación con el curso grave de la enfermedad durante el embarazo y se sugieren guías para considerar en la reflexión multidisciplinaria que permite manejar y resolver casos similares.

Abstract The present article describes the evolution of two clinical cases of severe COVID-19 in pregnant patients with 27 and 24 weeks of gestational weeks. The available up-to-date evidence about severe course of the disease during pregnancy is resumed. Management guides are suggested for the multidisciplinary approach of similar cases.

En mujeres embarazadas con rotura prematura de membranas y edad gestacional entre 34 y 37 semanas: ¿Es la interrupción del embarazo (manejo activo) mejor que el manejo expectante para reducir la sepsis neonatal? / In pregnant women with premature rupture of membranes and gestational age between 34 and 37 weeks: Is termination of pregnancy (active management) better than expectant management to reduce neonatal sepsis?

INTRODUCCIÓN: La rotura prematura de membranas (RPM) ocurre en un 8 a 10% de las embarazadas, y de ellas, un 20% corresponde a embarazos de pretérmino. El mayor riesgo para el feto luego de una RPM pretérmino son las complicaciones propias de la prematurez. Por debajo de las 34 semanas se favorece el manejo expectante, y el uso de antibióticos y corticoides. Entre las 34 y 37 semanas, sin embargo, las prácticas varían, no habiendo un consenso claro sobre la conducta óptima. OBJETIVO: El objetivo de esta revisión es explorar la evidencia actualmente disponible respecto de la conducta activa versus la expectante en embarazos con RPM entre las 34 y 37 semanas (36 semanas más 6 días). METODOLOGÍA: Se realizó una búsqueda de literatura médica en distintas bases de datos, dentro de las cuales se incluye "PubMed" y "Cochrane", usando los siguientes términos: "Fetal Membranes, Premature Rupture", "Premature Birth", "34 and 37 weeks" y "Clinical Trial". Se limitó la búsqueda a artículos que fueran ensayos clínicos aleatorizados. De un total de 31 trabajos, se seleccionaron 3, a los cuales se les aplicó la pauta de análisis crítico para evaluación de estudios de terapia. RESULTADOS: Se incluyeron 3 estudios que respondían a la pregunta planteada. En el primer estudio se concluyó que en pacientes en que hay interrupción inmediata la incidencia de sepsis neonatal es baja y no es posible demostrar que esta conducta mejore los resultados en comparación con el manejo expectante (2.6% vs. 4.1%). El manejo activo en este estudio se asoció a mayor incidencia de hiperbilirrubinemia, hipoglicemia, y mayor estadía hospitalaria neonatal. En el segundo artículo se planteó que la incidencia de sepsis neonatal sigue siendo baja, lo cual no disminuyó con la inducción del trabajo de parto. Esta tampoco disminuyó el riesgo de otros resultados neonatales o maternos. Finalmente, el tercer estudio concluyó que la interrupción inmediata aumenta las complicaciones neonatales sin disminución de la sepsis neonatal, pero a expensas de mayor frecuencia de fiebre materna y de hemorragia intraparto. CONCLUSIONES: El manejo expectante no es inferior al manejo activo en el contexto de RPM entre las semanas 34 a 37 de edad gestacional.

INTRODUCTION: Premature rupture of membranes (PROM) occur in eight to ten percent of pregnancies, and 20 percent of them occur in preterm pregnancies. Biggest fetal risks after preterm PROM are complications due to prematurity. Before 34 weeks of gestation it is preferred an expectant management, and the use of antibiotics and steroids. Between 34 and 37 weeks, however, practices are variable without a clear consensus about the best management. OBJECTIVE: The objective of this review is to explore the available evidence about active versus expectant management in pregnancies with PROM between 34 and 37 weeks (36 weeks plus 6 days). METHODS: Different databases were searched for medical literature, including 'PubMed' and 'Cochrane', using the following terms: 'Fetal Membranes, Premature Rupture', 'Premature Birth', '34 and 37 weeks' and 'Clinical Trial'. The search was limited to clinical randomized trials. From a total of 31 studies, three were selected, in which critical analysis guidelines for evaluation of therapy studies were applied. RESULTS: Three clinical trials which answered our question were included in this review. The first study concluded that in patients whose pregnancies were interrupted immediately, the incidence of neonatal sepsis was low but is was not able to demonstrate that this action improved outcomes compared to expectant management (2.6% vs 4.1%). Active management in this study was associated to greater incidences of hyperbilirubinemia, hypoglycemia and longer neonatal hospital stay. In the second article the incidence of neonatal sepsis was low and didn't decrease with induction of labor. It also didn't reduce the risk of other maternal nor neonatal outcomes. Finally, the third study concluded that induction of labor increased neonatal complications without reducing neonatal sepsis, but at the expense of increased frequency of intrapartum hemorrhage and maternal fever. CONCLUSION: After analyzing the selected articles, it is possible to conclude that there is enough evidence to say that expectant management is not inferior to active management in relation to PROM between 34 and 37 weeks of gestational age.

CORONIS - International study of caesarean section surgical techniques: the follow-up study.

BACKGROUND: The CORONIS Trial was a 2×2×2×2×2 non-regular, fractional, factorial trial of five pairs of alternative caesarean section surgical techniques on a range of short-term outcomes, the primary outcome being a composite of maternal death or infectious morbidity. The consequences of different surgical techniques on longer term outcomes have not been well assessed in previous studies. Such outcomes include those related to subsequent pregnancy: mode of delivery; abnormal placentation (e.g. accreta); postpartum hysterectomy, as well as longer term pelvic problems: pain, urinary problems, infertility. The Coronis Follow-up Study aims to measure and compare the incidence of these outcomes between the randomised groups at around three years after women participated in the CORONIS Trial. METHODS/DESIGN: This study will assess the following null hypotheses: In women who underwent delivery by caesarean section, no differences will be detected with respect to a range of long-term outcomes when comparing the following five pairs of alternative surgical techniques evaluated in the CORONIS Trial: 1. Blunt versus sharp abdominal entry. 2. Exteriorisation of the uterus for repair versus intra-abdominal repair. 3. Single versus double layer closure of the uterus. 4. Closure versus non-closure of the peritoneum (pelvic and parietal). 5. Chromic catgut versus Polyglactin-910 for uterine repair. The outcomes will include (1) women's health: pelvic pain; dysmenorrhoea; deep dyspareunia; urinary symptoms; laparoscopy; hysterectomy; tubal/ovarian surgery; abdominal hernias; bowel obstruction; infertility; death. (2) Outcomes of subsequent pregnancies: inter-pregnancy interval; pregnancy outcome; gestation at delivery; mode of delivery; pregnancy complications; surgery during or following delivery. DISCUSSION: The results of this follow-up study will have importance for all pregnant women and for health professionals who provide care for pregnant women. Although the results will have been collected in seven countries with limited health care resources (Argentina, Chile, Ghana, India, Kenya, Pakistan, Sudan) any differences in outcomes associated with different surgical techniques are likely to be generalisable throughout the world. TRIAL REGISTRATION: ISRCTN31089967.

Trasplante alogénico de precursores hematopoyéticos de sangre de cordón umbilical de donante no emparentado: primera experiencia, en tres casos, con donantes del banco público chileno de células de cordón / Allogenic hematopoietic stem cell transplantation with unrelated cord blood: Report of three cases from the Chilean cord blood bank

Public cord blood banks are a source of hematopoietic stem cells for patients with hematological diseases who lack a family donor and need allogeneic transplantation. In June 2007 we started a cord blood bank with units donated in three maternity wards in Santiago, Chile. We report the first three transplants done with cord blood units form this bank. Cord blood units were obtained by intrauterine collection at delivery. They were depleted of plasma and red cells and frozen in liquid nitrogen. Tests for total nucleated cells, CD34 cell content, viral serology, bacterial cultures and HLA A, B and DRB1 were done. Six hundred cord blood units were stored by March 2012. Three patients received allogeneic transplant with cord blood from our bank, two with high risk lymphoblastic leukemia and one with severe congenital anemia. They received conditioning regimens according to their disease and usual supportive care for unrelated donor transplantation until full hematopoietic and immune reconstitution was achieved. The three patients had early engraftment of neutrophils and platelets. The child corrected his anemia and the leukemia patients remain in complete remission. The post-transplant course was complicated with Epstein Barr virus, cytomegalovirus and BK virus infection. Two patients are fully functional 24 and 33 months after transplant, the third is still receiving immunosuppression.

[Allogenic hematopoietic stem cell transplantation with unrelated cord blood: report of three cases from the Chilean cord blood bank]. / Trasplante alogénico de precursores hematopoyéticos de sangre de cordón umbilical de donante no emparentado: primera experiencia, en tres casos, con donantes del banco público chileno de células de cordón.

Public cord blood banks are a source of hematopoietic stem cells for patients with hematological diseases who lack a family donor and need allogeneic transplantation. In June 2007 we started a cord blood bank with units donated in three maternity wards in Santiago, Chile. We report the first three transplants done with cord blood units form this bank. Cord blood units were obtained by intrauterine collection at delivery. They were depleted of plasma and red cells and frozen in liquid nitrogen. Tests for total nucleated cells, CD34 cell content, viral serology, bacterial cultures and HLA A, B and DRB1 were done. Six hundred cord blood units were stored by March 2012. Three patients received allogeneic transplant with cord blood from our bank, two with high risk lymphoblastic leukemia and one with severe congenital anemia. They received conditioning regimens according to their disease and usual supportive care for unrelated donor transplantation until full hematopoietic and immune reconstitution was achieved. The three patients had early engraftment of neutrophils and platelets. The child corrected his anemia and the leukemia patients remain in complete remission. The post-transplant course was complicated with Epstein Barr virus, cytomegalovirus and BK virus infection. Two patients are fully functional 24 and 33 months after transplant, the third is still receiving immunosuppression.

Polymorphisms in maternal and fetal genes encoding for proteins involved in extracellular matrix metabolism alter the risk for small-for-gestational-age.

OBJECTIVE: To examine the association between maternal and fetal genetic variants and small-for-gestational-age (SGA). METHODS: A case-control study was conducted in patients with SGA neonates (530 maternal and 436 fetal) and controls (599 maternal and 628 fetal); 190 candidate genes and 775 SNPs were studied. Single-locus, multi-locus and haplotype association analyses were performed on maternal and fetal data with logistic regression, multifactor dimensionality reduction (MDR) analysis, and haplotype-based association with 2 and 3 marker sliding windows, respectively. Ingenuity pathway analysis (IPA) software was used to assess pathways that associate with SGA. RESULTS: The most significant single-locus association in maternal data was with a SNP in tissue inhibitor of metalloproteinase 2 (TIMP2) (rs2277698 OR = 1.71, 95% CI [1.26-2.32], p = 0.0006) while in the fetus it was with a SNP in fibronectin 1 isoform 3 preproprotein (FN1) (rs3796123, OR = 1.46, 95% CI [1.20-1.78], p = 0.0001). Both SNPs were adjusted for potential confounders (maternal body mass index and fetal sex). Haplotype analyses resulted in associations in α 1 type I collagen preproprotein (COL1A1, rs1007086-rs2141279-rs17639446, global p = 0.006) in mothers and FN1 (rs2304573-rs1250204-rs1250215, global p = 0.045) in fetuses. Multi-locus analyses with MDR identified a two SNP model with maternal variants collagen type V α 2 (COL5A2) and plasminogen activator urokinase (PLAU) predicting SGA outcome correctly 59% of the time (p = 0.035). CONCLUSIONS: Genetic variants in extracellular matrix-related genes showed significant single-locus association with SGA. These data are consistent with other studies that have observed elevated circulating fibronectin concentrations in association with increased risk of SGA. The present study supports the hypothesis that DNA variants can partially explain the risk of SGA in a cohort of Hispanic women.

A genetic association study of maternal and fetal candidate genes that predispose to preterm prelabor rupture of membranes (PROM).

OBJECTIVE: We sought to determine whether maternal/fetal single-nucleotide polymorphisms (SNPs) in candidate genes are associated with preterm prelabor rupture of membranes (pPROM). STUDY DESIGN: A case-control study was conducted in patients with pPROM (225 mothers and 155 fetuses) and 599 mothers and 628 fetuses with a normal pregnancy; 190 candidate genes and 775 SNPs were studied. Single locus/haplotype association analyses were performed; false discovery rate was used to correct for multiple testing (q* = 0.15). RESULTS: First, a SNP in tissue inhibitor of metalloproteinase 2 in mothers was significantly associated with pPROM (odds ratio, 2.12; 95% confidence interval, 1.47-3.07; P = .000068), and this association remained significant after correction for multiple comparisons. Second, haplotypes for Alpha 3 type IV collagen isoform precursor in the mother were associated with pPROM (global P = .003). Third, multilocus analysis identified a 3-locus model, which included maternal SNPs in collagen type I alpha 2, defensin alpha 5 gene, and endothelin 1. CONCLUSION: DNA variants in a maternal gene involved in extracellular matrix metabolism doubled the risk of pPROM.

Viral infection of the placenta leads to fetal inflammation and sensitization to bacterial products predisposing to preterm labor.

Pandemics pose a more significant threat to pregnant women than to the nonpregnant population and may have a detrimental effect on the well being of the fetus. We have developed an animal model to evaluate the consequences of a viral infection characterized by lack of fetal transmission. The experiments described in this work show that viral infection of the placenta can elicit a fetal inflammatory response that, in turn, can cause organ damage and potentially downstream developmental deficiencies. Furthermore, we demonstrate that viral infection of the placenta may sensitize the pregnant mother to bacterial products and promote preterm labor. It is critical to take into consideration the fact that during pregnancy it is not only the maternal immune system responding, but also the fetal/placental unit. Our results further support the immunological role of the placenta and the fetus affecting the global response of the mother to microbial infections. This is relevant for making decisions associated with treatment and prevention during pandemics.

Identification of fetal and maternal single nucleotide polymorphisms in candidate genes that predispose to spontaneous preterm labor with intact membranes.

OBJECTIVE: The purpose of this study was to determine whether maternal/fetal single nucleotide polymorphisms (SNPs) in candidate genes are associated with spontaneous preterm labor/delivery. STUDY DESIGN: A genetic association study was conducted in 223 mothers and 179 fetuses (preterm labor with intact membranes who delivered <37 weeks of gestation [preterm birth (PTB)]), and 599 mothers and 628 fetuses (normal pregnancy); 190 candidate genes and 775 SNPs were studied. Single locus/haplotype association analyses were performed; the false discovery rate was used to correct for multiple testing. RESULTS: The strongest single locus associations with PTB were interleukin-6 receptor 1 (fetus; P=.000148) and tissue inhibitor of metalloproteinase 2 (mother; P=.000197), which remained significant after correction for multiple comparisons. Global haplotype analysis indicated an association between a fetal DNA variant in insulin-like growth factor F2 and maternal alpha 3 type IV collagen isoform 1 (global, P=.004 and .007, respectively). CONCLUSION: An SNP involved in controlling fetal inflammation (interleukin-6 receptor 1) and DNA variants in maternal genes encoding for proteins involved in extracellular matrix metabolism approximately doubled the risk of PTB.

Microbial invasion of the amniotic cavity in pregnancies with small-for-gestational-age fetuses.

OBJECTIVE: Microbial invasion of the amniotic cavity (MIAC) has been detected in women with preterm labor, preterm prelabor rupture of membranes (PROM), and in patients at term with PROM or in spontaneous labor. Intrauterine infection is recognized as a potential cause of fetal growth restriction; yet, the frequency of MIAC in pregnancies with small-for-gestational-age (SGA) fetuses is unknown. The aim of this study was to determine the frequency, diversity and relative abundance of microbes in amniotic fluid (AF) of women with an SGA neonate using a combination of culture and molecular methods. METHOD: AF from 52 subjects with an SGA neonate was analyzed with both cultivation and molecular methods in a retrospective cohort study. Broad-range and group-specific PCR assays targeted small subunit rDNA, or other gene sequences, from bacteria, fungi and archaea. Results of microbiologic studies were correlated with indices of the host inflammatory response. RESULTS: 1) All AF samples (n=52) were negative for microorganisms based on cultivation techniques, whereas 6% (3/52) were positive based on PCR; and 2) intra-amniotic inflammation was detected in one of the three patients with a positive PCR result, as compared with three patients (6.1%) of the 49 with both a negative culture and a negative PCR (P=0.2). CONCLUSION: MIAC is detected by PCR in some patients with an SGA fetus who were not in labor at the time of AF collection.

Microbial invasion of the amniotic cavity in preeclampsia as assessed by cultivation and sequence-based methods.

OBJECTIVE: Infection has been implicated in the pathogenesis of preeclampsia, yet the association between microbial invasion of the amniotic cavity (MIAC) and preeclampsia has not been determined. The aim of this study was to determine the prevalence, and microbial diversity associated with MIAC, as well as the nature of the host response to MIAC in patients with preeclampsia. METHOD OF STUDY: Amniotic fluid (AF) from 62 subjects with preeclampsia, not in labor, was analyzed with both cultivation and molecular methods. Broad-range and group-specific PCR assays targeting small subunit ribosomal DNA, or other gene sequences, from bacteria, fungi and archaea were used. Results were correlated with measurements of host inflammatory response, including AF white blood cell count and AF concentrations of glucose, interleukin-6 (IL-6) and MMP-8. RESULTS: 1) The rate of MIAC in preeclampsia was 1.6% (1/62) based on cultivation techniques, 8% (5/62) based on PCR, and 9.6% (6/62) based on the combined results of both methods; 2) among the six patients diagnosed with MIAC, three had a positive PCR for Sneathia/Leptotrichia spp.; and 3) patients with MIAC were more likely to have evidence of an inflammatory response in the amniotic cavity than those without MIAC, as determined by a higher median AF IL-6 [1.65 ng/mL interquartile range (IQR): 0.35-4.62 vs. 0.22 ng/mL IQR: 0.12-0.51; P=0.002). CONCLUSION: The prevalence of MIAC in preeclampsia is low, suggesting that intra-amniotic infection plays only a limited role in preeclampsia. However, the unexpectedly high number of positive AF specimens for Sneathia/Leptotrichia warrants further investigation.

Prevalence and diversity of microbes in the amniotic fluid, the fetal inflammatory response, and pregnancy outcome in women with preterm pre-labor rupture of membranes.

PROBLEM: The role played by microbial invasion of the amniotic cavity (MIAC) in preterm pre-labor rupture of membranes (pPROM) is inadequately characterized, in part because of reliance on cultivation-based methods. METHOD OF STUDY: Amniotic fluid from 204 subjects with pPROM was analyzed with both cultivation and molecular methods in a retrospective cohort study. Broad-range and group-specific polymerase chain reaction (PCR) assays targeted small subunit ribosomal DNA (rDNA), or other gene sequences, from bacteria, fungi, and archaea. Results were correlated with measurements of host inflammation, as well as pregnancy and perinatal outcomes. RESULTS: The prevalence of MIAC was 34% (70/204) by culture, 45% (92/204) by PCR, and 50% (101/204) by both methods combined. The number of bacterial species revealed by PCR (44 species-level phylotypes) was greater than that by culture (14 species) and included as-yet uncultivated taxa. Some taxa detected by PCR have been previously associated with the gastrointestinal tract (e.g., Coprobacillus sp.), the mouth (e.g., Rothia dentocariosa), or the vagina in the setting of bacterial vaginosis (e.g., Atopobium vaginae). The relative risk for histologic chorioamnionitis was 2.1 for a positive PCR [95% confidence interval (CI), 1.4-3.0] and 2.0 for a positive culture (95% CI, 1.4-2.7). Bacterial rDNA abundance exhibited a dose relationship with gestational age at delivery (R(2) = 0.26; P < 0.01). A positive PCR was associated with lower mean birthweight, and with higher rates of respiratory distress syndrome and necrotizing enterocolitis (P < 0.05 for each outcome). CONCLUSION: MIAC in pPROM is more common than previously recognized and is associated in some cases with uncultivated taxa, some of which are typically associated with the gastrointestinal tract. The detection of MIAC by molecular methods has clinical significance.

Estimation of individual neonatal survival using birthweight and gestational age: a way to improve neonatal care.

The study was conducted to determine the combined effect of birthweight and gestational age at birth on neonatal mortality using individually-identified livebirths. Logistic regression was used for studying the interactive effect of birthweight and gestational age on the individual probability of neonatal death. All livebirths from Chile in 2000 were included in a linked file. Odds ratio models for birthweight and gestational age were developed for each sex. The probability of neonatal death by sex was presented using contour plots. The models were statistically significant, and odds ratios were different and non-linear for the effects of birthweight and gestational age. Contour plots of constant neonatal mortality according to birthweight and gestational age were presented; they were similar for each sex. A single graph for both sexes that estimates the survival potential of infants born too early or too small would improve neonatal care in developing countries.

[Under diagnosis of fetal growth restriction by the new growth curves of the Chilean Ministry of Health]. / Subdiagnóstico de restricción de crecimiento fetal mediante la aplicación de las curvas de crecimiento intrauterino del Ministerio de Salud.

BACKGROUND: Fetal growth restriction (FGR) is associated with increased risk of perinatal morbidity or death. Nationwide implementation of new fetal growth charts, requires a lower fetal weight for the diagnosis of FGR, compared to previous ones. This may lead to an under diagnosis of FGR in a large proportion of neonates. AIM: To compare the morbidity, mortality and anthropometry of neonates with FGR, diagnosed by MINSAL and Juez curves, with normal weight newborns in the same period (2000-2004). MATERIAL AND METHODS: Revision of medical records of all births occurring in a maternity hospital between 2000 and 2004. The number of neonatal deaths, and the presence of hyperbilirubinemia, polyglobulia, hypoglycemia and hypothermia, were compared among children classified to be below percentile 10 of fetal growth according to both growth charts. RESULTS: FGR was diagnosed in 4,4% (502/11.289) and 9% (1.029/11.289) of newborns by MINSAL and Juez curves respectively. Compared to normal weight controls, the 527 newborns without FGR according to MINSAL curves, but below percentile 10 of Juez curves, had an odds ratio (OR) for polyglobulina of 8.14 (95% confidence intervals (CI): 1.01-65.34), an OR for neonatal hypoglycemia of 5.10 (95% CI: 1.11-23.39) and an OR for a ponderal index below 10th percentile of 10.98 (95% CI: 6.84-17.64). CONCLUSIONS: Newborns without a diagnosis of FGR by MINSAL curves but below 10th percentile by Juez curves, have neonatal outcomes suggesting a true FGR. Juez curves should be maintained as a standard for the evaluation of fetal growth in our population.

Transfusión fetal intravascular en el manejo de la enfermedad hemolítica perinatal / Intravascular fetal transfusion in the management of perinatal hemolytic disease

Cinco fetos con enfermedad hemolítica severa por isoinmunización al factor RH fueron tratados con transfusiones intravasculares repetidas. De 16 transfusiones intentadas, 14 se completaron exitosamente. Los 5 fetos requirieron más de una transfusión. Uno de ellos falleció antes de nacer. Los otros cuatro nacieron vivos y actualmente están sin secuelas aparentes. Se discuten aspectos técnicos del procedimiento, así como sus indicaciones, ventajas y antecedentes históricas