Risk of uterine rupture and placenta accreta with prior uterine surgery outside of the lower segment.

OBJECTIVE: Women with a prior myomectomy or prior classical cesarean delivery often have early delivery by cesarean because of concern for uterine rupture. Although theoretically at increased risk for placenta accreta, this risk has not been well-quantified. Our objective was to estimate and compare the risks of uterine rupture and placenta accreta in women with prior uterine surgery. METHODS: Women with prior myomectomy or prior classical cesarean delivery were compared with women with a prior low-segment transverse cesarean delivery to estimate rates of both uterine rupture and placenta accreta. RESULTS: One hundred seventy-six women with a prior myomectomy, 455 with a prior classical cesarean delivery, and 13,273 women with a prior low-segment transverse cesarean delivery were evaluated. Mean gestational age at delivery differed by group (P<.001), prior myomectomy (37.3 weeks), prior classical cesarean delivery (35.8 weeks), and low-segment transverse cesarean delivery (38.6 weeks). The frequency of uterine rupture in the prior myomectomy group (P-MMX group) was 0% (95% confidence interval [CI] 0-1.98%). The frequency of uterine rupture in the low-segment transverse cesarean delivery group (LTC group) (0.41%) was not statistically different from the risk in the P-MMX group (P>.99) or in the prior classical cesarean delivery group (PC group) (0.88%; P=.13). Placenta accreta occurred in 0% (95% CI 0-1.98%) of the P-MMX group compared with 0.19% in the LTC group (P>.99) and 0.88% in the PC group (P=.01 relative to the LTC group). The adjusted odds ratio for the PC group (relative to LTC group) was 3.23 (95% CI 1.11-9.39) for uterine rupture and 2.09 (95% CI 0.69-6.33) for accreta. The frequency of accreta for those with previa was 11.1% for the PC group and 13.6% for the LTC group (P>.99). CONCLUSION: A prior myomectomy is not associated with higher risks of either uterine rupture or placenta accreta. The absolute risks of uterine rupture and accreta after prior myomectomy are low.

Elective repeat cesarean delivery compared with spontaneous trial of labor after a prior cesarean delivery: a propensity score analysis.

OBJECTIVE: The purpose of this study was to determine outcomes, after the use of propensity score techniques, to create balanced groups according to whether a woman undergoes elective repeat cesarean delivery (ERCD) or trial of labor (TOL). STUDY DESIGN: Women who were eligible for a TOL with 1 previous low transverse incision were categorized according to whether they underwent an ERCD or TOL. A propensity score technique was used to develop ERCD and TOL groups with comparable baseline characteristics. Outcomes were assessed with conditional logistic regression. RESULTS: The rates of endometritis, operative injury, respiratory distress syndrome, and newborn infant infection were lower and the rates of hysterectomy and wound complication were higher in the ERCD group. CONCLUSION: Propensity score techniques can be used to generate comparable ERCD and TOL groups. Some types of maternal morbidity (such as hysterectomy) are higher; other types (such as operative injury) are lower in the ERCD group. Although the absolute risk is low, neonatal morbidity appears to be lower in the ERCD group.

Effect of antenatal corticosteroids on respiratory morbidity in singletons after late-preterm birth.

OBJECTIVE: To evaluate whether neonates born to women who previously had received antenatal corticosteroids and then delivered a late-preterm-birth neonate had less respiratory morbidity compared with those not exposed to antenatal corticosteroids. METHODS: This is a secondary analysis from a multicenter observational study regarding mode of delivery after previous cesarean delivery. We compared women who received one course of antenatal corticosteroids with unexposed parturients and evaluated various respiratory outcomes among those having a singleton, late-preterm-birth neonate. We controlled for potential confounders including gestational age at delivery, diabetes, mode of delivery, and maternal race. RESULTS: Five thousand nine hundred twenty-four patients met the inclusion criteria; 550 received steroids and 5,374 did not. In the univariable model, compared with unexposed women, those who received antenatal corticosteroids appeared more likely to have neonates who required ventilatory support (11.5% compared with 8.6%, P=.022), had respiratory distress syndrome (RDS) (17.1% compared with 12.2%, P=.001), developed transient tachypnea of the newborn (12.9% compared with 9.8%, P=.020), or required resuscitation in the delivery room (55.8% compared with 49.7%, P=.007). After controlling for confounding factors, we found no significant differences among the groups regarding all of the above outcomes with an odds ratio for RDS of 0.78 (95% confidence interval, 0.60-1.02) and ventilator support of 0.75 (95% confidence interval, 0.55-1.03). CONCLUSION: Exposure to antenatal corticosteroids does not significantly affect respiratory outcomes among those with a subsequent late-preterm birth.

The antibiotic treatment of PPROM study: systemic maternal and fetal markers and perinatal outcomes.

OBJECTIVE: We sought to correlate maternal and cord blood cytokine and intercellular adhesion molecule-1 levels with antibiotic exposure and perinatal outcomes after conservatively managed preterm premature rupture of the membranes. STUDY DESIGN: Conservatively managed women with preterm premature rupture of the membranes at 24-32 weeks had blood sampling at randomization (n = 222) and delivery (n = 121). Plasma from these, and umbilical cord blood (n = 196), was stored at -70°C. Interleukin (IL)-6, IL-10, granulocyte colony-stimulating factor (G-CSF), tumor necrosis factor-α, and intercellular adhesion molecule-1 levels were assessed for associations with antibiotic treatment, latency, amnionitis, neonatal sepsis, pneumonia, and composite neonatal morbidity. RESULTS: Cord blood IL-6 and G-CSF were higher than maternal levels. Antibiotic treatment lowered only maternal G-CSF (P = .01). Elevated maternal cytokine levels were associated with delivery within 7 days and with development of chorioamnionitis. All umbilical cord blood markers were increased with amnionitis (P ≤ .01 for each). No maternal marker was associated with neonatal morbidities. Cord G-CSF and IL-6 were increased with neonatal sepsis within 72 hours of birth (P = .004 for both), and with composite neonatal morbidity (P = .001 and .002, respectively). Maternal and umbilical cord cytokine levels demonstrated low predictive values for perinatal outcomes. CONCLUSION: Umbilical cord blood cytokine values are higher than maternal levels, suggesting significant fetal/placental contribution. Maternal and umbilical cord cytokine levels are not adequately predictive to be used clinically.

Progesterone receptor polymorphisms and clinical response to 17-alpha-hydroxyprogesterone caproate.

OBJECTIVE: Seventeen-alpha-hydroxyprogesterone caproate (17-OHPC) reduces recurrent preterm birth (PTB). We hypothesized that single nucleotide polymorphisms in the human progesterone receptor (PGR) affect response to 17-OHPC in the prevention of recurrent PTB. STUDY DESIGN: We conducted secondary analysis of a study of 17-OHPC vs placebo for recurrent PTB prevention. Twenty PGR gene single nucleotide polymorphisms were studied. Multivariable logistic regression assessed for an interaction between PGR genotype and treatment status in modulating the risk of recurrent PTB. RESULTS: A total of 380 women were included; 253 (66.6%) received 17-OHPC and 127 (33.4%) received placebo. In all, 61.1% of women were African American. Multivariable logistic regression demonstrated significant treatment-genotype interactions (either a beneficial or harmful treatment response) for African Americans delivering<37 weeks' gestation for rs471767 and rs578029, and for Hispanics/Caucasians delivering<37 weeks' gestation for rs500760 and <32 weeks' gestation for rs578029, rs503362, and rs666553. CONCLUSION: The clinical efficacy and safety of 17-OHPC for recurrent PTB prevention may be altered by PGR gene polymorphisms.

Admixture mapping to identify spontaneous preterm birth susceptibility loci in African Americans.

OBJECTIVE: Preterm birth is 1.5 times more common in African American (17.8%) than European American women (11.5%), even after controlling for confounding variables. We hypothesize that genetic factors may account for this disparity and can be identified by admixture mapping. METHODS: This is a secondary analysis of women with at least one prior spontaneous preterm birth enrolled in a multicenter prospective study. DNA was extracted and whole-genome amplified from stored saliva samples. Self-identified African American patients were genotyped with a 1,509 single nucleotide polymorphism (SNP) commercially available admixture panel. A logarithm of odds locus-genome score of 1.5 or higher was considered suggestive and 2 or higher was considered significant for a disease locus. RESULTS: One hundred seventy-seven African American women with one or more prior spontaneous preterm births were studied. One thousand four hundred fifty SNPs were in Hardy-Weinberg equilibrium and passed quality filters. Individuals had a mean of 78.3% to 87.9% African American ancestry for each SNP. A locus on chromosome 7q21-22 was suggestive of an association with spontaneous preterm birth before 37 weeks of gestation (three SNPs with logarithm of odds scores 1.50-1.99). This signal strengthened when women with at least one preterm birth before 35.0 (eight SNPs with logarithm of odds scores greater than 1.50) and before 32.0 weeks of gestation were considered (15 SNPs with logarithm of odds scores greater than 1.50). No other areas of the genome had logarithm of odds scores higher than 1.5. CONCLUSION: Spontaneous preterm birth in African American women may be genetically mediated by a susceptibility locus on chromosome 7. This region contains multiple potential candidate genes, including collagen type 1-α-2 gene and genes involved with calcium regulation.

Timing of elective repeat cesarean delivery at term and maternal perioperative outcomes.

OBJECTIVE: Elective repeat cesarean delivery at 37 or 38 weeks compared with 39 completed weeks of gestation is associated with adverse neonatal outcomes. We assessed whether delivery before 39 weeks is justifiable on the basis of decreased adverse maternal outcomes. METHODS: We conducted a cohort study of women with live singleton pregnancies delivered by prelabor elective repeat cesarean delivery from 1999 through 2002 at 19 U.S. academic centers. Gestational age was examined by completed weeks (eg, 37 completed weeks=37 0/7-37 6/7 weeks). Maternal outcomes included a primary composite of death, hysterectomy, uterine rupture or dehiscence, blood transfusion, uterine atony, thromboembolic complications, anesthetic complications, surgical injury or need for arterial ligation, intensive care unit admission, wound complications, or endometritis. RESULTS: Of 13,258 elective repeat cesareans performed at 37 weeks of gestation or later, 11,255 (84.9%) were between 37 0/7 and 39 6/7 weeks (6.3% at 37, 29.5% at 38, and 49.1% at 39 completed weeks), and 15.1% were at 40 0/7 weeks or more. The primary outcome occurred in 7.43% at 37 weeks, 7.47% at 38 weeks and 6.56% at 39 weeks (P for trend test=.09). Delivery before 39 weeks was not associated with a decrease in the primary outcome when compared with delivery at 39 weeks (adjusted odds ratio 1.16; 95% confidence interval 1.00-1.34). Early delivery was associated with increased maternal hospitalization of 5 days or more [1.96 (1.54, 2.49)] but not with a composite of death or hysterectomy or with individual maternal morbidities. CONCLUSION: Elective repeat cesarean delivery at 37 or 38 weeks is not associated with decreased maternal morbidity. LEVEL OF EVIDENCE: II.

Absence of mitochondrial progesterone receptor polymorphisms in women with spontaneous preterm birth.

OBJECTIVE: The truncated mitochondrial progesterone receptor (PR-M) is homologous to nuclear PRs with the exception of an amino terminus hydrophobic membrane localization sequence, which localizes PR-M to mitochondria. Given the matrilineal inheritance of both spontaneous preterm birth (SPTB) and the mitochondrial genome, we hypothesized that (a) PR-M is polymorphic and (b) PR-M localization sequence polymorphisms could result in variable progesterone-mitochondrial effects and variable responsiveness to progesterone prophylaxis. METHODS: Secondary analysis of DNA from women enrolled in a multicenter, prospective, study of 17 alpha-hydroxyprogesterone caproate (17OHPC) versus placebo for the prevention of recurrent SPTB. DNA was extracted from stored saliva. RESULTS: The PR-M localization sequence was sequenced on 344 patients. Sequences were compared with the previously published 48 base-pair sequence, and all were identical. CONCLUSIONS: We did not detect genetic variation in the mitochondrial localization sequence of the truncated PR-M in a group of women at high risk for SPTB.

Comparison of transverse and vertical skin incision for emergency cesarean delivery.

OBJECTIVE: To compare incision-to-delivery intervals and related maternal and neonatal outcomes by skin incision in primary and repeat emergent cesarean deliveries. METHODS: From 1999 to 2000, a prospective cohort study of all cesarean deliveries was conducted at 13 hospitals comprising the Eunice Kennedy Shriver National Institute of Child Health and Human Development's Maternal-Fetal Medicine Units Network. This secondary analysis was limited to emergent procedures, defined as those performed for cord prolapse, abruption, placenta previa with hemorrhage, nonreassuring fetal heart rate tracing, or uterine rupture. Incision-to-delivery intervals, incision-to-closure intervals, and maternal outcomes were compared by skin-incision type (transverse compared with vertical) after stratifying for primary compared with repeat singleton cesarean delivery. Neonatal outcomes were compared by skin-incision type. RESULTS: Of the 37,112 live singleton cesarean deliveries, 3,525 (9.5%) were performed for emergent indications of which 2,498 (70.9%) were performed by transverse and the remaining 1,027 (29.1%) by vertical incision. Vertical skin incision shortened median incision-to-delivery intervals by 1 minute (3 compared with 4 minutes, P<.001) in primary and 2 minutes (3 compared with 5 minutes, P<.001) in repeat cesarean deliveries. Total median operative time was longer after vertical skin incision by 3 minutes in primary (46 compared with 43 minutes, P<.001) and 4 minutes in repeat cesarean deliveries (56 compared with 52 minutes, P<.001). Neonates delivered through a vertical incision were more likely to have an umbilical artery pH of less than 7.0 (10% compared with 7%, P=.02), to be intubated in the delivery room (17% compared with 13%, P=.001), or to be diagnosed with hypoxic ischemic encephalopathy (3% compared with 1%, P<.001). CONCLUSION: In emergency cesarean deliveries, neonatal delivery occurred more quickly after a vertical skin incision, but this was not associated with improved neonatal outcomes. LEVEL OF EVIDENCE: II.

Maternal and neonatal outcomes of repeat cesarean delivery in women with a prior classical versus low transverse uterine incision.

We compared maternal and neonatal outcomes following repeat cesarean delivery (CD) of women with a prior classical CD with those with a prior low transverse CD. The Maternal Fetal Medicine Units Network Cesarean Delivery Registry was used to identify women with one previous CD who underwent an elective repeat CD prior to the onset of labor at ≥36 weeks. Outcomes were compared between women with a previous classical CD and those with a prior low transverse CD. Of the 7936 women who met study criteria, 122 had a prior classical CD. Women with a prior classical CD had a higher rate of classical uterine incision at repeat CD (12.73% versus 0.59%; P < 0.001), had longer total operative time and hospital stay, and had higher intensive care unit admission. Uterine dehiscence was more frequent in women with a prior classical CD (2.46% versus 0.27%, odds ratio 9.35, 95% confidence interval 1.76 to 31.93). After adjusting for confounding factors, there were no statistical differences in major maternal or neonatal morbidities between groups. Uterine dehiscence was present at repeat CD in 2.46% of women with a prior classical CD. However, major maternal morbidities were similar to those with a prior low transverse CD.

Pharmacogenomics of maternal tobacco use: metabolic gene polymorphisms and risk of adverse pregnancy outcomes.

OBJECTIVE: To assess whether functional maternal or fetal genotypes along well-characterized metabolic pathways (ie, CYP1A1, GSTT1, and CYP2A6) may account for varying associations with adverse outcomes among pregnant women who smoke. METHODS: DNA samples from 502 smokers and their conceptuses, alongside women in a control group, were genotyped for known functional allelic variants of CYP1A1 (Ile462Val AA>AG/GG), GSTT1(del), and CYP2A6 (Lys160His T>A). Modification of the association between smoking and outcome by genotype was evaluated. Outcomes included birth weight, pregnancy loss, preterm birth, small for gestational age, and a composite outcome composed of the latter four components plus abruption. RESULTS: No interaction between maternal or fetal genotype of any of the polymorphisms and smoking could be demonstrated. In contrast, the association of smoking with gestational age-adjusted birth weight (birth weight ratio) was modified by fetal GSTT1 genotype (P for interaction=.02). Fetuses with GSTT1(del) had a mean birth weight reduction among smokers of 262 g (P=.01), whereas in fetuses without the GSTT1(del) the effect of tobacco exposure was nonsignificant (mean reduction 87 g, P=.16). After adjusting for confounding, results were similar. CONCLUSION: Fetal GSTT1 deletion significantly and specifically modifies the effect of smoking on gestational age-corrected birth weight.

The effect of 17-alpha hydroxyprogesterone caproate on the risk of gestational diabetes in singleton or twin pregnancies.

OBJECTIVE: To compare the rates of gestational diabetes among women who received serial doses of 17-alpha hydroxyprogesterone caproate vs placebo. STUDY DESIGN: Secondary analysis of 2 double-blind randomized placebo-controlled trials of 17-alpha hydroxyprogesterone caproate given to women at risk for preterm delivery. The incidence of gestational diabetes was compared between women who received 17-alpha hydroxyprogesterone caproate or placebo. RESULTS: We included 1094 women; 441 had singleton and 653 had twin gestations. Combining the 2 studies, 616 received 17-alpha hydroxyprogesterone caproate and 478 received placebo. Among singleton and twin pregnancies, rates of gestational diabetes were similar in women receiving 17-alpha hydroxyprogesterone caproate vs placebo (5.8% vs 4.7%; P = .64 and 7.4% vs 7.6%; P = .94, respectively). In the multivariable model, progesterone was not associated with gestational diabetes (adjusted odds ratio, 1.04; 95% confidence interval, 0.62-1.73). CONCLUSION: Weekly administration of 17-alpha hydroxyprogesterone caproate is not associated with higher rates of gestational diabetes in either singleton or twin pregnancies.

Maternal plasma concentrations of the soluble tumor necrosis factor receptor 2 are increased prior to the diagnosis of preeclampsia.

OBJECTIVE: Soluble receptor levels of tumor necrosis factor (sTNF-R)-1 and -2 are increased during preeclampsia. We postulated the increase preceded overt disease. STUDY DESIGN: Archived plasma from the Eunice Kennedy Shriver National Institute of Child Health and Human Development aspirin to prevent preeclampsia in high risk women trial were used to measure serial sTNF-R1 and sTNF-R2 (enrollment, 24-28 week's gestation) in 986 women (577 also sampled at 34-38 weeks). RESULTS: Preeclampsia incidence was 21.2%. sTNF-R2 levels were higher at enrollment (P = .02) and weeks 24-28 (P = .01) in women who eventually developed preeclampsia. The magnitude of increase from baseline of both receptors was significantly greater in women who developed preeclampsia in the future. Women with week 24-28 sTNF-R2 levels in the highest quartile had significantly increased odds to develop preeclampsia (P = .03 vs quartile 1). This association was observed in the placebo but not the aspirin arm (P

Timing of elective repeat cesarean delivery at term and neonatal outcomes.

BACKGROUND: Because of increased rates of respiratory complications, elective cesarean delivery is discouraged before 39 weeks of gestation unless there is evidence of fetal lung maturity. We assessed associations between elective cesarean delivery at term (37 weeks of gestation or longer) but before 39 weeks of gestation and neonatal outcomes. METHODS: We studied a cohort of consecutive patients undergoing repeat cesarean sections performed at 19 centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network from 1999 through 2002. Women with viable singleton pregnancies delivered electively (i.e., before the onset of labor and without any recognized indications for delivery before 39 weeks of gestation) were included. The primary outcome was the composite of neonatal death and any of several adverse events, including respiratory complications, treated hypoglycemia, newborn sepsis, and admission to the neonatal intensive care unit (ICU). RESULTS: Of 24,077 repeat cesarean deliveries at term, 13,258 were performed electively; of these, 35.8% were performed before 39 completed weeks of gestation (6.3% at 37 weeks and 29.5% at 38 weeks) and 49.1% at 39 weeks of gestation. One neonatal death occurred. As compared with births at 39 weeks, births at 37 weeks and at 38 weeks were associated with an increased risk of the primary outcome (adjusted odds ratio for births at 37 weeks, 2.1; 95% confidence interval [CI], 1.7 to 2.5; adjusted odds ratio for births at 38 weeks, 1.5; 95% CI, 1.3 to 1.7; P for trend <0.001). The rates of adverse respiratory outcomes, mechanical ventilation, newborn sepsis, hypoglycemia, admission to the neonatal ICU, and hospitalization for 5 days or more were increased by a factor of 1.8 to 4.2 for births at 37 weeks and 1.3 to 2.1 for births at 38 weeks. CONCLUSIONS: Elective repeat cesarean delivery before 39 weeks of gestation is common and is associated with respiratory and other adverse neonatal outcomes.

Failed operative vaginal delivery.

OBJECTIVE: To compare maternal and neonatal outcomes in women undergoing second-stage cesarean delivery after a trial of operative vaginal delivery with those in women undergoing second-stage cesarean delivery without such an attempt. METHODS: This study is a secondary analysis of the women who underwent second-stage cesarean delivery. The maternal outcomes examined included blood transfusion, endometritis, wound complication, anesthesia use, and maternal death. Neonatal outcomes examined included umbilical artery pH less than 7.0, Apgar score of 3 or less at 5 minutes, seizures within 24 hours of birth, hypoxic ischemic encephalopathy, stillbirth, skull fracture, and neonatal death. RESULTS: Of 3,189 women who underwent second-stage cesarean delivery, operative vaginal delivery was attempted in 640. Labor characteristics were similar in the two groups, with the exception of the admission-to-delivery time and cesarean indication. Those with an attempted operative vaginal delivery were more likely to undergo cesarean delivery for a nonreassuring fetal heart rate tracing (18.0% compared with 13.9%, P=.01), have a wound complication (2.7% compared with 1.0%, odds ratio [OR] 2.65, 95% confidence interval [CI] 1.43-4.91), and require general anesthesia (8.0% compared with 4.1%, OR 2.05, 95% CI 1.44-2.91). Neonatal outcomes, including umbilical artery pH less than 7.0, Apgar score of 3 or less at 5 minutes, and hypoxic ischemic encephalopathy, were more common for those with an attempted operative vaginal delivery. This was not significant when cases with a nonreassuring fetal heart rate tracing were removed. CONCLUSION: Cesarean delivery after an attempt at operative vaginal delivery was not associated with adverse neonatal outcomes in the absence of a nonreassuring fetal heart rate tracing. LEVEL OF EVIDENCE: II.

Salivary progesterone and estriol among pregnant women treated with 17-alpha-hydroxyprogesterone caproate or placebo.

OBJECTIVE: The objectives of the study was to determine whether salivary progesterone (P) or estriol (E3) concentration at 16-20 weeks' gestation predicts preterm birth or the response to 17alpha-hydroxyprogesterone caproate (17OHPC) and whether 17OHPC treatment affected the trajectory of salivary P and E3 as pregnancy progressed. STUDY DESIGN: This was a secondary analysis of a clinical trial of 17OHPC to prevent preterm birth. Baseline saliva was assayed for P and E3. Weekly salivary samples were obtained from 40 women who received 17OHPC and 40 who received placebo in a multicenter randomized trial of 17OHPC to prevent recurrent preterm delivery. RESULTS: Both low and high baseline saliva P and E3 were associated with a slightly increased risk of preterm birth. However, 17OHPC prevented preterm birth comparably, regardless of baseline salivary hormone concentrations. 17OHPC did not alter the trajectory of salivary P over pregnancy, but it significantly blunted the rise in salivary E3 as well as the rise in the E3/P ratio. CONCLUSION: 17OHPC flattened the trajectory of E3 in the second half of pregnancy, suggesting that the drug influences the fetoplacental unit.

Sample bias among women with retained DNA samples for future genetic studies.

OBJECTIVE: To evaluate whether women who agree to future use of their biologic specimens for genetic studies reflect the larger study population from which they are derived. METHODS: Women were questioned as to the future disposition of their maternal and fetal DNA samples upon enrollment in a multicenter, observational study originally designed to identify factor V Leiden mutation carriers and prospectively ascertain the estimated rate of pregnancy-related venous thromboembolism and adverse pregnancy outcome. Univariate and multivariate analyses was carried out on the 5,003 of 5,188 enrolled women who indicated their desire regarding future disposition of their DNA samples. RESULTS: Among these 5,003 women, 20.1% desired that their samples be discarded and not available for future genetic studies. Multivariate analysis demonstrated that women who agreed to subsequent use of samples were less likely African-American (odds ratio [OR] 0.6, 95% confidence interval [CI] 0.4-0.7) or Hispanic (OR 0.4, 95% CI 0.3-0.5), and more likely to use tobacco (OR 1.2, 95% CI 1.0-1.6) than those who desired that their samples be discarded. CONCLUSION: Genetic samples from women agreeing to their use in a sample repository may not be representative of the index study cohort. This should be considered in their subsequent interpretation and generalizability. LEVEL OF EVIDENCE: III.