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Little is known about the genetic causes of stillbirth. In this study, investigators used exome sequencing analysis to identify a genetic cause in a relatively small percentage of cases and to provide some interesting clues as to where to look for more genes that, when mutated, cause stillbirth. The article is accompanied by interactive tables and an illustrated glossary.

In a large, systematic study of genetic diagnosis in stillborn infants, microarray analysis provided a higher likelihood of obtaining an interpretable result and revealed pathogenic variants in more stillborn infants than did karyotype analysis. Stillbirth, which is defined as fetal death at or after 20 weeks of gestation, occurs in 1 of every 160 births in the United States. 1 Despite extensive evaluation, 25 to 60% of stillbirths remain unexplained. 2 Karyotypic abnormalities are detected in 6 to 13% of stillbirths with a successful karyotype analysis. 3 , 4 Some stillbirths may have chromosomal imbalances below the resolution of conventional cytogenetic analysis, which is typically 5 to 10 Mb. Single-nucleotide polymorphism (SNP) oligonucleotide microarray analysis detects almost all genomic imbalances recognized by karyotyping, as well as smaller deletions and duplications in the kilobase range, termed copy-number variants. Microarray . . .

Stillbirth is strongly related to impaired fetal growth. However, the relationship between fetal growth and stillbirth is difficult to determine because of uncertainty in the timing of death and confounding characteristics affecting normal fetal growth. We conducted a population-based case-control study of all stillbirths and a representative sample of live births in 59 hospitals in five geographic areas in the US. Fetal growth abnormalities were categorized as small for gestational age (SGA) (<10th percentile) or large for gestational age (LGA) (>90th percentile) at death (stillbirth) or delivery (live birth) using population, ultrasound, and individualized norms. Gestational age at death was determined using an algorithm that considered the time-of-death interval, postmortem examination, and reliability of the gestational age estimate. Data were weighted to account for the sampling design and differential participation rates in various subgroups. Among 527 singleton stillbirths and 1,821 singleton live births studied, stillbirth was associated with SGA based on population, ultrasound, and individualized norms (odds ratio [OR] [95% CI]: 3.0 [2.2 to 4.0]; 4.7 [3.7 to 5.9]; 4.6 [3.6 to 5.9], respectively). LGA was also associated with increased risk of stillbirth using ultrasound and individualized norms (OR [95% CI]: 3.5 [2.4 to 5.0]; 2.3 [1.7 to 3.1], respectively), but not population norms (OR [95% CI]: 0.6 [0.4 to 1.0]). The associations were stronger with more severe SGA and LGA (<5th and >95th percentile). Analyses adjusted for stillbirth risk factors, subset analyses excluding potential confounders, and analyses in preterm and term pregnancies showed similar patterns of association. In this study 70% of cases and 63% of controls agreed to participate. Analysis weights accounted for differences between consenting and non-consenting women. Some of the characteristics used for individualized fetal growth estimates were missing and were replaced with reference values. However, a sensitivity analysis using individualized norms based on the subset of stillbirths and live births with non-missing variables showed similar findings. Stillbirth is associated with both growth restriction and excessive fetal growth. These findings suggest that, contrary to current practices and recommendations, stillbirth prevention strategies should focus on both severe SGA and severe LGA pregnancies. Please see later in the article for the Editors' Summary.

Worldwide, stillbirth is one of the leading causes of death. Altered fetal growth and placental abnormalities are the strongest and most prevalent known risk factors for stillbirth. The aim of this study was to identify patterns of association between placental abnormalities, fetal growth, and stillbirth. Population-based case-control study of all stillbirths and a representative sample of live births in 59 hospitals in 5 geographic areas in the U.S. Fetal growth abnormalities were categorized as small (<10th percentile) and large (>90th percentile) for gestational age at death (stillbirth) or delivery (live birth) using a published algorithm. Placental examination by perinatal pathologists was performed using a standardized protocol. Data were weighted to account for the sampling design. Among 319 singleton stillbirths and 1119 singleton live births at ≥24 weeks at death or delivery respectively, 25 placental findings were investigated. Fifteen findings were significantly associated with stillbirth. Ten of the 15 were also associated with fetal growth abnormalities (single umbilical artery; velamentous insertion; terminal villous immaturity; retroplacental hematoma; parenchymal infarction; intraparenchymal thrombus; avascular villi; placental edema; placental weight; ratio birth weight/placental weight) while 5 of the 15 associated with stillbirth were not associated with fetal growth abnormalities (acute chorioamnionitis of placental membranes; acute chorioamionitis of chorionic plate; chorionic plate vascular degenerative changes; perivillous, intervillous fibrin, fibrinoid deposition; fetal vascular thrombi in the chorionic plate). Five patterns were observed: placental findings associated with (1) stillbirth but not fetal growth abnormalities; (2) fetal growth abnormalities in stillbirths only; (3) fetal growth abnormalities in live births only; (4) fetal growth abnormalities in stillbirths and live births in a similar manner; (5) a different pattern of fetal growth abnormalities in stillbirths and live births. The patterns of association between placental abnormalities, fetal growth, and stillbirth provide insights into the mechanism of impaired placental function and stillbirth. They also suggest implications for clinical care, especially for placental findings amenable to prenatal diagnosis using ultrasound that may be associated with term stillbirths.

Background Preeclampsia is characterized by decreased trophoblastic angiogenesis leading to abnormal invasion of spiral arteries, shallow implantation and resulting in compromised placentation with poor uteroplacental perfusion. Vitamin D plays an important role in pregnancy influencing implantation, angiogenesis and placental development. The objective of this study was to determine whether there is an association between serum vitamin D levels, and anti-angiogenic factors at the time of delivery and the occurrence of preeclampsia. Methods This nested case control study analyzed frozen serum samples at the time of delivery and related clinical data from women with singleton liveborn pregnancies who had participated in studies of the NICHD Stillbirth Collaborative Research Network. Women with a recorded finding of preeclampsia and who had received magnesium sulfate treatment prior to delivery were considered index cases ( N  = 56). Women without a finding of preeclampsia were controls ( N  = 341). Results Women with preeclampsia had 14.5% lower serum vitamin D levels than women in the control group (16.5 ng/ml vs. 19 ng/ml, p  = 0.014) with 64.5% higher sFlt-1 levels (11,600 pg/ml vs. 7050 pg/ml, p  < 0.001) and greater than 2 times higher endoglin levels (18.6 ng/ml vs. 8.7 ng/ml, < 0.001). After controlling for gestational age at delivery and maternal BMI, vitamin D levels were 0.88 times lower ( P  = 0.051), while endoglin levels were 2.5 times higher and sFlt-1 levels were 2.1 times higher than in control pregnancies ( P  < 0.001). Conclusions Women with preeclampsia at time of delivery have higher maternal antiangiogenetic factors and may have lower maternal serum vitamin D levels. These findings may lead to a better understanding of the underlying etiology of preeclampsia as well as possible modifiable treatment options which could include assuring adequate levels of maternal serum vitamin D prior to pregnancy.

Background Audit and classification of stillbirths is an essential part of clinical practice and a crucial step towards stillbirth prevention. Due to the limitations of the ICD system and lack of an international approach to an acceptable solution, numerous disparate classification systems have emerged. We assessed the performance of six contemporary systems to inform the development of an internationally accepted approach. Methods We evaluated the following systems: Amended Aberdeen, Extended Wigglesworth; PSANZ-PDC, ReCoDe, Tulip and CODAC. Nine teams from 7 countries applied the classification systems to cohorts of stillbirths from their regions using 857 stillbirth cases. The main outcome measures were: the ability to retain the important information about the death using the InfoKeep rating; the ease of use according to the Ease rating (both measures used a five-point scale with a score <2 considered unsatisfactory); inter-observer agreement and the proportion of unexplained stillbirths. A randomly selected subset of 100 stillbirths was used to assess inter-observer agreement. Results InfoKeep scores were significantly different across the classifications ( p ≤ 0.01) due to low scores for Wigglesworth and Aberdeen. CODAC received the highest mean (SD) score of 3.40 (0.73) followed by PSANZ-PDC, ReCoDe and Tulip [2.77 (1.00), 2.36 (1.21), 1.92 (1.24) respectively]. Wigglesworth and Aberdeen resulted in a high proportion of unexplained stillbirths and CODAC and Tulip the lowest. While Ease scores were different ( p ≤ 0.01), all systems received satisfactory scores; CODAC received the highest score. Aberdeen and Wigglesworth showed poor agreement with kappas of 0.35 and 0.25 respectively. Tulip performed best with a kappa of 0.74. The remainder had good to fair agreement. Conclusion The Extended Wigglesworth and Amended Aberdeen systems cannot be recommended for classification of stillbirths. Overall, CODAC performed best with PSANZ-PDC and ReCoDe performing well. Tulip was shown to have the best agreement and a low proportion of unexplained stillbirths. The virtues of these systems need to be considered in the development of an international solution to classification of stillbirths. Further studies are required on the performance of classification systems in the context of developing countries. Suboptimal agreement highlights the importance of instituting measures to ensure consistency for any classification system.

Background There is limited information on potentially modifiable risk factors for stillbirth, such as gestational weight gain (GWG). Our purpose was to explore the association between GWG and stillbirth using the GWG z−score. Methods We analyzed 479 stillbirths and 1601 live births from the Stillbirth Collaborative Research Network case−control study. Women with triplets or monochorionic twins were excluded from analysis. We evaluated the association between GWG z−score (modeled as a restricted cubic spline with knots at the 5th, 50th, and 95th percentiles) and stillbirth using multivariable logistic regression with generalized estimating equations, adjusting for pre − pregnancy body mass index (BMI) and other confounders. In addition, we conducted analyses stratified by pre − pregnancy BMI category (normal weight, overweight, obese). Results Mean GWG was 18.95 (SD 17.6) lb. among mothers of stillbirths and 30.89 (SD 13.3) lb. among mothers of live births; mean GWG z−score was − 0.39 (SD 1.5) among mothers of cases and − 0.17 (SD 0.9) among control mothers. In adjusted analyses, the odds of stillbirth were elevated for women with very low GWG z−scores (e.g., adjusted odds ratio (aOR) and 95% Confidence Interval (CI) for z−score − 1.5 SD versus 0 SD: 1.52 (1.30, 1.78); aOR (95% CI) for z−score − 2.5 SD versus 0 SD: 2.36 (1.74, 3.20)). Results differed slightly by pre − pregnancy BMI. The odds of stillbirth were slightly elevated among women with overweight BMI and GWG z−scores ≥1 SD (e.g., aOR (95% CI) for z−score of 1.5 SD versus 0 SD: 1.84 (0.97, 3.50)). Conclusions GWG z−scores below − 1.5 SD are associated with increased odds of stillbirth.

Background Participation in the Special Supplemental Nutrition Program for Women, Infants and Children (WIC) has been associated with lower risk of stillbirth. We hypothesized that such an association would differ by race/ethnicity because of factors associated with WIC participation that confound the association. Methods We conducted a secondary analysis of the Stillbirth Collaborative Research Network’s population-based case-control study of stillbirths and live-born controls, enrolled at delivery between March 2006 and September 2008. Weighting accounted for study design and differential consent. Five nested models using multivariable logistic regression examined whether the WIC participation/stillbirth associations were attenuated after sequential adjustment for sociodemographic, health, healthcare, socioeconomic, and behavioral factors. Models also included an interaction term for race/ethnicity x WIC. Results In the final model, WIC participation was associated with lower adjusted odds (aOR) of stillbirth among non-Hispanic Black women (aOR: 0.34; 95% CI 0.16, 0.72) but not among non-Hispanic White (aOR: 1.69; 95% CI: 0.89, 3.20) or Hispanic women (aOR: 0.91; 95% CI 0.52, 1.52). Conclusions Contrary to our hypotheses, control for potential confounding factors did not explain disparate findings by race/ethnicity. Rather, WIC may be most beneficial to women with the greatest risk factors for stillbirth. WIC-eligible, higher-risk women who do not participate may be missing the potential health associated benefits afforded by WIC.

A carefully classified dataset of perinatal mortality will retain the most significant information on the causes of death. Such information is needed for health care policy development, surveillance and international comparisons, clinical services and research. For comparability purposes, we propose a classification system that could serve all these needs, and be applicable in both developing and developed countries. It is developed to adhere to basic concepts of underlying cause in the International Classification of Diseases (ICD), although gaps in ICD prevent classification of perinatal deaths solely on existing ICD codes. We tested the Causes of Death and Associated Conditions (Codac) classification for perinatal deaths in seven populations, including two developing country settings. We identified areas of potential improvements in the ability to retain existing information, ease of use and inter-rater agreement. After revisions to address these issues we propose Version II of Codac with detailed coding instructions. The ten main categories of Codac consist of three key contributors to global perinatal mortality (intrapartum events, infections and congenital anomalies), two crucial aspects of perinatal mortality (unknown causes of death and termination of pregnancy), a clear distinction of conditions relevant only to the neonatal period and the remaining conditions are arranged in the four anatomical compartments (fetal, cord, placental and maternal). For more detail there are 94 subcategories, further specified in 577 categories in the full version. Codac is designed to accommodate both the main cause of death as well as two associated conditions. We suggest reporting not only the main cause of death, but also the associated relevant conditions so that scenarios of combined conditions and events are captured. The appropriately applied Codac system promises to better manage information on causes of perinatal deaths, the conditions associated with them, and the most common clinical scenarios for future study and comparisons.

Impingement by the distal fascicle of the anterior inferior tibiofibular ligament (AITFL) is a relatively new entity among the known causes of anterolateral impingement syndromes of the ankle. This study investigated the anatomy of the anterior inferior tibiofibular ligament and its possible role in talar impingement in 47 ankles of 27 cadavers. The length, width, insertion point to the fibula and the interactions with talus were noted, as was the relationship of the fascicle and talus during different ankle movements before and after incision of the lateral ligaments. A distal fascicle of the AITFL was found in 39 of the 47 ankles (83%) and appeared as a single‐complete ligament in the remaining 8 ankles (17%). The fascicle averaged 16.1±2.94 mm in length (range 10–21) and 4.2±1.00 mm in width (range, 3–7). The insertion point of the fascicle on the fibula averaged 10.3±2.27 mm (5–13) distal to the joint level. Contact between the ligament and the lateral dome of the talus was observed in 42 specimens (89.3%). Bending of the fascicle was observed in 8 of these 42 ankles with forced dorsiflexion. These 8 specimens were significantly wider and longer than the specimens without bending of the fascicle. Incision of the anterior talofibular ligament led to bending in dorsiflexion in additional 11 ankles. The total 19 fascicles with bending after incision of the anterior talofibular ligament were significantly longer and inserted more distally than the remaining 20 fascisles without bending. Manual traction simulating distraction during arthroscopic procedures relieved the contact. These findings show that the presence of the distal fascicle of the AITFL and its contact with the talus is a normal finding. However, it may become pathological due to anatomical variations and/or instability of the ankle resulting from torn lateral ligaments. When observed during an ankle arthroscopy, the surgeon should look for the criteria described in the present study to decide whether it is pathological and needs to be resected.