Delivery outcomes in the subsequent pregnancy following the conservative management of placenta accreta spectrum disorder: a systematic review and meta-analysis.

OBJECTIVE: Cesarean hysterectomy is generally presumed to decrease maternal morbidity and mortality secondary to placenta accreta spectrum disorder. Recently, uterine-sparing techniques have been introduced in conservative management of placenta accreta spectrum disorder to preserve fertility and potentially reduce surgical complications. However, despite patients often expressing the intention for future conception, few data are available regarding the subsequent pregnancy outcomes after conservative management of placenta accreta spectrum disorder. Thus, we aimed to perform a systematic review and meta-analysis to assess these outcomes. DATA SOURCES: PubMed, Scopus, and Web of Science databases were searched from inception to September 2022. STUDY ELIGIBILITY CRITERIA: We included all studies, with the exception of case studies, that reported the first subsequent pregnancy outcomes in individuals with a history of placenta accreta spectrum disorder who underwent any type of conservative management. METHODS: The R programming language with the "meta" package was used. The random-effects model and inverse variance method were used to pool the proportion of pregnancy outcomes. RESULTS: We identified 5 studies involving 1458 participants that were eligible for quantitative synthesis. The type of conservative management included placenta left in situ (n=1) and resection surgery (n=1), and was not reported in 3 studies. The rate of placenta accreta spectrum disorder recurrence in the subsequent pregnancy was 11.8% (95% confidence interval, 1.1-60.3; I2=86.4%), and 1.9% (95% confidence interval, 0.0-34.1; I2=82.4%) of participants underwent cesarean hysterectomy. Postpartum hemorrhage occurred in 10.3% (95% confidence interval, 0.3-81.4; I2=96.7%). A composite adverse maternal outcome was reported in 22.7% of participants (95% confidence interval, 0.0-99.4; I2=56.3%). CONCLUSION: Favorable pregnancy outcome is possible following successful conservation of the uterus in a placenta accreta spectrum disorder pregnancy. Approximately 1 out of 4 subsequent pregnancies following conservative management of placenta accreta spectrum disorder had considerable adverse maternal outcomes. Given such high incidence of adverse outcomes and morbidity, patient and provider preparation is vital when managing this population.

Outcomes of pregnancies at high-risk for placenta accreta spectrum following negative diagnostic imaging.

OBJECTIVES: To assess the pretest and negative post-test probability for placenta accreta spectrum (PAS) in a group of patients with high-risk clinical factors. METHODS: We included patients with suspected and/or confirmed PAS at our institution over 8 years. Sonography performed by maternal-fetal medicine specialists, and selected patients underwent MRI. Imaging was considered positive if either sonography or MRI suggested PAS. Histopathology was the gold standard for diagnosis of PAS. We assessed the pretest and negative imaging-test probability, and resources required. RESULTS: We identified 82 high-risk patients with the following: (1) a history of ≥1 cesarean section and/or intrauterine gynecologic procedure and placenta previa in the index pregnancy; (2) a history of >3 cesarean deliveries and/or gynecologic procedures regardless of placental location; (3) prior PAS disorder, or retained placenta requiring manual extraction and/or curettage, complicated by postpartum hemorrhage; and (4) suspected cesarean section scar pregnancy. Histopathology confirmed PAS in 52 patients, with pretest probability of 63%. Imaging correctly identified 44/50 cases with PAS, and excluded this condition in 24/30 cases. Thus, the positive and negative post-test probability for PAS following negative imaging was 88 and 20%, respectively. Of the six patients with false-negative imaging, all had either surgical complications or required care beyond that for routine cesarean section. CONCLUSIONS: Although diagnostic imaging is sensitive, the negative posttest probability remains high in women with high pretest probability for PAS. Therefore, women at high risk for PAS should be managed in experienced centers by a multidisciplinary team even if imaging is negative.

Improved management of placenta accreta spectrum disorders: experience from a single institution.

OBJECTIVES: To assess the applicability of a standardized multidisciplinary protocol for managing placenta accreta spectrum (PAS) disorders and its impact on the outcomes. METHODS: We compared patients with PAS manage by a standardized multidisciplinary protocol (T2) to historic controls managed on a case-by-case basis by individual physicians between (T1). The primary outcome is composite maternal morbidity. Secondary outcomes were the rates of surgical complications, estimated blood loss, number of blood products transfused, intensive care unit admissions, ventilator use, and birth weight. Multivariate logistic analysis was used to identify independent predictors of composite maternal morbidity. RESULTS: During T1 and T2, we managed 39 and 36 patients with confirmed PAS, respectively. During T2, the protocol could be implemented in 21 cases (58%). Compared to T1, patients managed during T2 had 70% less composite maternal morbidity (95% CI: 0.11-0.82) and lower blood loss (median, 2,000 vs. 1,100 mL, p=0.008). Also, they were 68% less likely to require transfusion of blood products (95% CI: 0.12-0.81; p=0.01), including fewer units of packed red blood cells (median, 2 vs. 0, p=0.02). Management following the protocol was the only independent factor associated with lower composite maternal morbidity (OR: 0.22; 95% CI: 0.05-0.95; p=0.04). Selected maternal and neonatal outcomes were not different among 12 and 15 patients with suspected but unconfirmed PAS disorders managed during T1 and T2, respectively. CONCLUSIONS: Most patients can be managed under a standardized multidisciplinary protocol for PAS disorders, leading to improved outcomes.

The value of amniotic fluid analysis in patients with suspected clinical chorioamnionitis.

Objective To assess the value of incorporating amniotic fluid (AF) analysis in the management of patients with clinical chorioamnionitis. Methods This was a retrospective cohort study of all women carrying a singleton fetus and managed at our center between 2000 and 2009. We included only those women suspected of chorioamnionitis based on one or more of the following: (1) uterine tenderness, (2) maternal fever, (3) maternal and/or fetal tachycardia and (4) purulent discharge. The management was deemed to be justified if (1) pregnancy was terminated <24 weeks and histology confirmed chorioamnionitis; (2) delivery was performed expeditiously after initial assessment and histology confirmed chorioamnionitis; (3) delivery was delayed for 2-7 days and the patient completed a course of antenatal steroids before 34 weeks; and (4) delivery was delayed ≥7 days and histology was not indicative of chorioamnionitis, or delivery occurred after 37 weeks. Univariate and logistic regression analyses were used as appropriate. Results Of the 77 women with suspected chorioamnionitis, AF analysis was performed in 43 (55.8%) cases, and the management was justified in 63 (81.8%) cases based on the aforementioned criteria. Stepwise regression analysis confirmed AF analysis as a predictor of justified management. The rates of composite morbidity, neonatal sepsis, neonatal death and admissions to neonatal intensive care unit were lower in the justified management group. Conclusion Incorporation of AF analysis into clinical assessment does improve the management of suspected chorioamnionitis.

Pregnancy in a woman with chronic neutrophilic leukemia.

BACKGROUND: Chronic neutrophilic leukemia is a rare myeloproliferative disorder in women of reproductive age. CASE: A pregnant woman with an established diagnosis of chronic neutrophilic leukemia presented at 26 weeks of gestation with splenomegaly, thrombocytopenia, leukocytosis, and anemia. Thrombocytopenia was refractory to medical treatment and, in part, was attributed to splenic sequestration. She delivered a healthy neonate at 35 weeks of gestation by repeat cesarean delivery under general anesthesia. Her preoperative platelet count was 30,000/mL and she was transfused platelets throughout the perioperative period. Her postpartum course was complicated by intraabdominal hemorrhage and severe preeclampsia. She recovered with intensive medical and surgical management. CONCLUSION: Chronic neutrophilic leukemia poses difficult challenges during pregnancy and requires a multidisciplinary approach.

Optimized amniotic fluid analysis in patients suspected of intrauterine infection/inflammation.

OBJECTIVE: To determine the combination of amniotic fluid (AF) tests with the best diagnostic accuracy for predicting intrauterine infection/inflammation (IUI) in patients with clinical suspicion of chorioamnionitis. STUDY DESIGN: This is a retrospective study of 34 pregnant women who presented with uterine tenderness, maternal fever, maternal tachycardia, and/or fetal tachycardia and underwent AF analysis. IUI diagnosis was based on placental histology, positive AF bacterial cultures, and/or Gram stain. RESULT: Logistic regression analysis revealed a significant relationship between IUI and AF glucose. Glucose is more sensitive than culture or Gram stain (64% vs. 40% and 20%, respectively). Culture and glucose combined achieved the best diagnostic accuracy (sensitivity, 71%; specificity, 100%; positive and negative predictive values, 100-83%, respectively). CONCLUSION: Positive AF Gram stain or glucose <15 mg/dL strongly suggests IUI in symptomatic patients. If both tests are negative, the result of culture should aid the management.

The clinical use of inflammatory markers during pregnancy.

PURPOSE OF REVIEW: There is overwhelming evidence that intrauterine infection and inflammation play an important role in the pathogenesis of spontaneous preterm labor, preterm prelabor rupture of the membranes and fetal injury resulting in long-term sequelae. Early diagnosis of subclinical infection and inflammation may therefore aid clinicians institute interventions focusing on such adverse outcomes. RECENT FINDINGS: Biomarkers of intrauterine inflammation such as interleukin-6, although sensitive, are not specific. Thus, decision to deliver remote from term because of intrauterine infection and/or inflammation should be based on clinical signs and/or bacterial culture or Gram stain of amniotic fluid. In patients with preterm contractions and intact membranes, the risk of delivery is 1% within the week following a negative fetal fibronectin in cervicovaginal secretions. This aids to decide whether antenatal steroids should be administered to patients presenting with preterm contractions between 24 and 34 weeks' gestation. Biomarkers in cervical secretions and amniotic fluid identify those who may benefit from cerclage when the cervix is shortened (<25 mm) and dilated in the second trimester. SUMMARY: So far, few interventions utilizing inflammatory biomarkers have shown clinical benefit. Future efforts should focus on the quest for accurate biomarkers that can be obtained noninvasively and allow early prediction of subclinical disease to initiate appropriate risk-specific intervention.

The role of gene-environment interaction in predicting adverse pregnancy outcome.

This article focuses on the influence of gene-environment interaction on pregnancy outcome. In particular, we focus on those adverse outcomes related to subclinical infection and the resultant inflammation of gestational tissues. We identify genetic association studies on pregnancy-related disorders with an infectious/inflammatory etiology. All studies in this field have focused on spontaneous preterm delivery and/or preterm and premature rupture of membranes. We discuss those articles where an environmental (infectious) exposure was studied in relation to genetic variability. In these studies, infectious exposure was defined as altered vaginal flora or bacterial vaginosis (BV). Maternal genomic variations influence both tumor necrosis factor-alpha and interleukin-1beta response to BV-related organisms (anaerobic Gram-negative bacteria and Gardnerella vaginalis in particular) in the vagina and the risk of spontaneous preterm birth. Further studies are warranted to confirm these associations, stratify disease risk, and delineate interventions for achieving population health benefits.

TNFA-308G>A polymorphism influences the TNF-alpha response to altered vaginal flora.

OBJECTIVE: To investigate the association between a tumor necrosis factor-alpha (TNF-alpha) gene polymorphism, vaginal TNF-alpha level, and microbial flora in pregnant women. METHODS: Vaginal samples from 203 women at 18-22 weeks' gestation were analyzed for microflora. TNFA-308G>A polymorphism was analyzed by polymerase chain reaction and restriction endonuclease analysis and TNF-alpha concentration was determined by ELISA. Outcome data were subsequently obtained. RESULTS: The vaginal TNF-alpha concentration was elevated in TNFA-308A carriers only in the presence of abnormal vaginal flora. A median TNF-alpha level of 10.94 pg/ml in TNFA-308A carriers with bacterial vaginosis (BV) was significantly higher than that of 1.77 pg/ml in TNFA-308A carriers without BV (P=.02), and 1.72 pg/ml in TNF-308G homozygotes with BV (P=.01). CONCLUSION: The TNFA-308G>A polymorphism influences the local TNF-alpha response to altered vaginal microflora. This suggests that the nature of the host response to microbial invasion in the lower female genital is genetically determined.

Vaginal nitric oxide in pregnant women with bacterial vaginosis.

PROBLEM: To evaluate vaginal nitric oxide (NO) production in response to alterations in the vaginal microbial flora. METHOD OF STUDY: Cervicovaginal lavage samples from 206 women at 18-22 weeks of gestation were tested for NO, interleukin-1beta (IL-1beta), IL-1 receptor antagonist (IL-1ra), tumor necrosis factor-alpha and the inducible 70 kDa heat shock protein (hsp70). Bacterial vaginosis (BV) was diagnosed based on gram staining of vaginal smears. RESULTS AND CONCLUSIONS: Elevated NO (>2.14 mmol/L) was associated with a diagnosis of BV (38% versus 11%, P < 0.008) as well as an increased median vaginal IL-1ra concentration (72.5 ng/ml versus 36.6 ng/ml, P = 0.041). Elevated vaginal NO was also associated with vaginal hsp70 and this relationship was independent of BV status or IL-1ra concentrations (P < 0.026). We conclude that vaginal hsp70 release in response to abnormal vaginal microflora may trigger NO production in an attempt to minimize the pathological consequences of this altered milieu.

Association between vaginal 70-kd heat shock protein, interleukin-1 receptor antagonist, and microbial flora in mid trimester pregnant women.

OBJECTIVE: This study investigated the association among the inducible 70-kd heat shock protein, cytokines, and microbial flora in the vagina in mid trimester pregnant women and subsequent preterm delivery. STUDY DESIGN: Vaginal samples from 205 pregnant women, which were collected at 18 to 22 weeks of gestation, were analyzed for qualitative and quantitative vaginal microflora and for 70-kd heat shock protein, interleukin-1beta, interleukin-1 receptor antagonist, and tumor necrosis factor-alpha by enzyme-linked immunosorbent assay. Pregnancy outcome data were obtained subsequently. RESULTS: The 70-kd heat shock protein was detected in 38 vaginal samples (18.5%). Its presence was associated with elevated vaginal pH, a diagnosis of bacterial vaginosis, and elevated interleukin-1 receptor antagonist levels (P < .001). Among women with bacterial vaginosis, 70-kd heat shock protein-positive subjects had a >80% increase in median vaginal concentration of interleukin-1 receptor antagonist (P < .05). CONCLUSION: Vaginal 70-kd heat shock protein expression is associated with the down-regulation of the proinflammatory immune response to abnormal vaginal flora in mid trimester pregnant women.

Innate Immune System Gene Polymorphisms in Women with Vulvovaginal Infections.

The innate immune responses at mucosal surfaces of the lower female genital tract play a central role in preventing the establishment of infection. Variability in the genes regulating innate immune recognition or response to infectious microorganisms could explain interindividual differences in susceptibility to infection and severity of infectious disorders. Of the numerous genetic variations identified within immunoregulatory genes, only a few have so far been studied in relation to infectious disorders of the lower female genital tract. Although these studies broaden our understanding of the genetic influence on mucosal innate immunity and microbiologic outcome, they also highlight the complexity of links between genotypical and phenotypical features, ie, the influence of a single genetic marker on the phenotype is at best moderate and is not constant in every ethnic/racial group. Such inconsistency is primarily attributed to gene-to-gene interactions and demographic genetic variability. Large case-control studies evaluating multiple genetic markers simultaneously in well-defined subgroups will characterize patients more accurately and pave the way to personalized medicine.

Hormonal monitoring of the first trimester of pregnancy.

The hormonal changes and maternal adaptations of human pregnancy are among the most remarkable phenomena in nature. Endocrinologic parameters in the early gestation period have been used to predict abnormal pregnancies and to identify fetuses that have chromosomal aberrations. This article focuses on the changes in hormones that are secreted by the maternal-fetal-placental unit that are unique for the first trimester of pregnancy and their impact on clinical outcome.

Polymorphism in intron 2 of the interleukin-1 receptor antagonist gene, local midtrimester cytokine response to vaginal flora, and subsequent preterm birth.

OBJECTIVE: This study investigated the association between polymorphism in intron 2 of the interleukin-1 receptor antagonist gene, midtrimester vaginal microflora, vaginal interleukin receptor antagonist and interleukin-1beta levels and subsequent spontaneous preterm birth. STUDY DESIGN: Vaginal samples from 212 women, collected at 18-22 weeks' gestation, were analyzed for the polymorphism in intron 2 of the interleukin-1 receptor antagonist gene by polymerase chain reaction, qualitative and quantitative vaginal microflora, and interleukin-1beta and interleukin-1ra concentrations by enzyme-linked immunosorbent assay. Pregnancy outcome data were subsequently obtained. RESULTS: Carriage of intron 2 of the interleukin-1 receptor antagonist allele 2 (IL1RN * 2) was associated with an elevated vaginal pH in black ( P < .001) and white ( P = .005) women, a reduced interleukin-1beta response to anaerobic Gram-negative rods and/or Gardnerella vaginalis ( P < .01), and a decreased rate of spontaneous preterm deliveries (6% versus 18%, P = .02). In black women, IL1RN * 2 carriage was associated with increased anaerobic Gram-negative rods, Mycoplasma, and Peptostreptococci and decreased Lactobacilli colonization. CONCLUSION: IL1RN * 2 carriage was associated with a blunted proinflammatory interleukin-1beta response to abnormal vaginal flora. This property may decrease susceptibility to infection-related preterm birth.

Relationship between a toll-like receptor-4 gene polymorphism, bacterial vaginosis-related flora and vaginal cytokine responses in pregnant women.

OBJECTIVE: The relationship between a single nucleotide polymorphism (TLR4 896 A > G) in the toll-like receptor-4 (TLR4) gene, qualitative and quantitative changes in vaginal micro-flora and vaginal interleukin (IL)-1beta and IL-1 receptor antagonist (IL-1ra) concentrations in pregnant women were evaluated. STUDY DESIGN: Qualitative and quantitative microbial methods were used to characterize vaginal micro-flora of 238 women at 18-22 weeks gestation. Polymerase chain reaction was used to determine TLR4 genotype. IL-1beta and IL-1ra concentrations in vaginal lavage samples were measured by ELISA. RESULTS: The TLR4 variant was identified in 10.3% of women. Carriage of this variant was associated with a median increase in vaginal pH (P = 0.05), a greater than 10-fold increase in vaginal Gardnerella vaginalis levels (P < 0.0001) and a 10-fold increase in the vaginal concentration of three species of anaerobic Gram-negative rods, Prevotella, Bacteroides, and Porphyromonas (P = 0.08 ). Colonization with G. vaginalis and/or the anaerobic Gram-negative rods resulted in elevated vaginal IL-1 (P = 0.01) and IL-1ra (P < 0.0002) concentrations in women who were TLR4 896A homozygotes, but not in TLR4 896G carriers. CONCLUSION: The TLR4 896 A > G polymorphism contributes to inter-individual differences in the vaginal immune defense against G. vaginalis and anaerobic Gram-negative rods.

A disproportionate increase in IL-1beta over IL-1ra in the cervicovaginal secretions of pregnant women with altered vaginal microflora correlates with preterm birth.

OBJECTIVE: This purpose of this study was to investigate the association between vaginal microflora, concentrations of interleukin-1beta (IL-1beta), and its natural receptor antagonist (IL-1ra) in the cervicovaginal discharge, and spontaneous preterm birth. Study design Vaginal samples collected at 18 to 22 weeks' gestation from 207 women were analyzed to study qualitative and quantitative microbiologic aspects of vaginal microflora and IL-1beta and IL-1ra concentrations. RESULTS: Among women colonized with anaerobic Gram-negative rods and/or Gardnerella vaginalis, an elevated IL-1beta concentration, or a diminished IL-1ra:IL-1beta ratio were associated with preterm delivery. A cut-off IL-1ra:IL-1beta ratio of <8632:1 optimally discriminated the subjects with subsequent spontaneous preterm deliveries from subjects who delivered at term, with a sensitivity of 78%, specificity of 51%, positive predictive value of 21%, and negative predictive value of 95%. CONCLUSION: A disproportionate increase in IL-1beta over IL-1ra in response to vaginal colonization with anaerobic Gram-negative rods and/or G. vaginalis at 18 to 22 weeks' gestation is associated with spontaneous preterm delivery.