Search

Stillbirth, defined as fetal death at 20 weeks gestation or later, is a devastating pregnancy outcome affecting 1 in 175 pregnancies in the United States. Although efforts to understand the etiology of stillbirth have expanded, 25 % of cases remain unexplained and some cases previously thought to be explained may have additional unknown causative factors. Determining an etiology for stillbirth is important for clinical management and for grieving families to obtain closure, to find meaning, and to understand recurrence risks. However, the evaluation of stillbirth is not completed uniformly despite American College of Obstetrics and Gynecology (ACOG) guidelines and stillbirth data is frequently incomplete due to lack of genomic analysis, fetal autopsy, and placental pathology. Karyotype and chromosomal microarray have been the gold standard in genetic analysis in perinatal medicine for many years, but next generation sequencing holds promise towards improving diagnostic yields and providing clarity for both clinicians and patients., (Copyright © 2023 Elsevier Inc. All rights reserved.)

New genetic tests have rapidly entered clinical care with little consistency in laboratory testing and reporting. Non-invasive prenatal screening using cell free DNA (cfDNA) may either screen for common aneuploidies alone or include chromosomal microdeletions. All cfDNA screening tests have false positives and false negatives, and accordingly laboratories should report positive and negative predictive values. In addition, since fetal fraction plays a significant role in the reliability of results, this should also be reported with all test results. Chromosomal microarray addresses significant clinically relevant information beyond that detected with standard karyotype testing but may, in less than one percent of cases, result in a variant of uncertain significance (VUS). Laboratories should indicate their policies for reporting these VUS findings. In addition, physicians using this testing should be aware of the advantages and disadvantages of the laboratory platforms. Whole-exome and whole-genome sequencing are just entering clinical care and issues of VUS, incidental findings, and phenotype/genotype correlations need to be investigated before these techniques enter routine clinical care., (Copyright © 2018. Published by Elsevier Inc.)

Given the rapid advances in genomics, translating new genomic tests effectively into prenatal clinical practice remains challenging. We discuss emerging genetic tests, considerations for their use, how tests should ideally be validated prior to use in clinical practice, and the role of the Federal Drug Administration, Clinical Laboratory Improvement Amendments (CLIA) laboratories, commercial laboratories, insurers, and professional societies such as the American College of Obstetricians and Gynecologists (ACOG), and the Society for Maternal-Fetal Medicine (SMFM) in the introduction of new prenatal genetic tests. After the introduction of new tests into the prenatal clinic, it is critical to utilize shared databases with measured outcomes to improve clinical care as well as to advance science., (Copyright © 2018. Published by Elsevier Inc.)

Administration of antenatal corticosteroids has been standard of care for women between 24 and 34 weeks of gestation who are at risk for preterm delivery for more than 20 years longer in other parts of the world. Although the benefit of steroids in this population has been confirmed, there remain many questions including the frequency of dosing and whether it is possible to expand the gestational age criteria to women likely to deliver before 24 weeks or after 34 weeks. The MFMU Network has played a major role in answering some of these questions., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Antenatal corticosteroids have been proven to accelerate fetal lung development and reduce neonatal morbidity and mortality when given between 28 and 34 weeks of gestation. However, there is only limited research to guide their use in the periviable period (22-26 weeks). Laboratory studies suggest that it is biologically plausible for antenatal steroids to be effective in this gestational period. In addition, cohort studies have demonstrated the efficacy of antenatal corticosteroids in reducing neonatal mortality and IVH. Follow-up studies performed between 18 and 22 months of age also suggest a long-term benefit to antenatal use in this period. Based on this information, antenatal corticosteroids should be used in appropriate patients at high risk for preterm birth at 23-26 weeks of gestation. An advantageous outcome to treatment at 22 weeks is less certain., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Though the preterm birth rate in the United States has finally begun to decline, preterm birth remains a critical public health problem. The administration of antenatal corticosteroids to improve outcomes after preterm birth is one of the most important interventions in obstetrics. This article summarizes the evidence for antenatal corticosteroid efficacy and safety that has accumulated since Graham Liggins and Ross Howie first introduced this therapy. Although antenatal corticosteroids have proven effective for singleton pregnancies at risk for preterm birth between 26 and 34 weeks’ gestation, questions remain about the utility in specific patient populations such as multiple gestations, very early preterm gestations, and pregnancies complicated by IUGR. In addition, there is still uncertainty about the length of corticosteroid effectiveness and the need for repeat or rescue courses. Though a significant amount of data has accumulated on antenatal corticosteroids over the past 40 years, more information is still needed to refine the use of this therapy and improve outcomes for these at-risk patients.

As aneuploid screening evolves to the first trimester a complimentary diagnostic procedure becomes increasingly important. Chorionic villus (CVS) sampling has emerged as the only safe invasive prenatal diagnostic procedure prior to the 14(th) week of gestation. Over 2 decades of experience have demonstrated the accuracy, efficacy and safety of CVS. The karyotype is identical to that of the fetus in over 98% of cases. In the remaining 1 to 2% confined placental mosaicism (CPM) occurs. Current knowledge of the etiology of CPM allows accurate clinical interpretation, the recognition of cases of fetal uniparental disomy, and identification of pregnancies at risk for poor perinatal outcome. Prospective comparative studies have demonstrated that with equally experienced operators, CVS and second trimester amniocentesis have similar procedure induced miscarriage rates. When CVS procedures are performed after 10 weeks gestation, no increased risk of fetal anomalies has been demonstrated.

First trimester risk assessment for trisomies 21 and 18 is rapidly transitioning from an investigational procedure performed at a few major centers to the clinical arena. The BUN study (Biochemistry, Ultrasound, Nuchal translucency) was conceived to evaluate the performance of first trimester screening using PAPP-A, free beta HCG, and ultrasound measurement of the nuchal translucency when introduced into practice. Over a 4-year period, 13 prenatal diagnostic centers evaluated over 8500 patients and reported an 85.2% trisomy 21 detection rate with a 9.4% false positive rate. Further evaluation of the data revealed that, once training and experience were accomplished, sonographers could perform NT measurements consistent with reported standards. In approximately half of the patients enrolled in the study, second trimester serum analytes were obtained leading to additional trisomy 21 detection but with an unacceptably high false positive rate. A "sequential contingency" screening approach using both first and second trimester values in some patients may provide the additional detection afforded by measuring second trimester analytes with a limited invasive procedure rate.

Amniocentesis and Chorionic Villus Sampling have been the two most common prenatal diagnostic procedures for decades. There are wide variations in utilization, operator skills, quoted procedure risks, actual observed risks, and patient choices that come from highly variable counseling as to those risks. The compilation of published data suggests procedure risks of amniocentesis to be about 1/200 and in very skilled hands to be slightly lower. The risks of CVS in very experienced hands may also be about 1/200. Most studies comparing CVS to amniocentesis in skilled hands have found equivalency of risks. No well controlled studies support claims of amniocentesis risk at 1/1000 or lower. There is no increased risks of limb reduction defects following CVS at 10 weeks or greater, but there is an increase in Talipes from "Early Amniocentesis." In the first trimester CVS is the safer procedure.

Approximately 25% of stillbirths have been attributed to cytogenetic, mendelian, or biochemical causes with 75% still unknown. The most common autosomal trisomies are 21, 18, and 13, and the most common karyotypic abnormality is 45x. The remaining are sporadic multiple malformation syndromes and single organ malformations. Little is known about the genetic and metabolic causes of stillbirth; however, with new cytogenetic techniques such as fluorescent in situ hybridization, comparative genomic hybridization, and telomeric probes, cytogenetic errors will be identified more accurately. Advances in diagnosis will provide additional information for appropriate genetic counseling.

Chorionic villus sampling has been used successfully for first trimester diagnosis of genetic disorders for over 14 years. When performed between 10 and 14 weeks' gestation, it is both safe and effective in the diagnosis of fetal chromosomal, biochemical, and molecular disorders, with risks comparable to those of second trimester amniocentesis. Cytogenetic results have been confirmed to be reliable and accurate. Although confined placental mosaicism occurs in approximately 1% of cases requiring interpretation, and occasionally additional invasive testing, its finding adds additional information about perinatal outcome and can alert the practitioner to fetal genetic disorders. Earlier concerns about procedure-induced limb defects have been reduced with the accumulation of additional data, showing minimal to no risk when chorionic villus sampling is performed after 70 days of gestation. In experienced hands, it may be the procedure of choice for sampling multiple gestations. Secondary to the advantage of safe, early diagnosis, chorionic villus sampling appears to be the optimal choice for first trimester testing.

Chorionic villus sampling (CVS) has been used a successful and safe first-trimester prenatal diagnostic technique for over 12 years. Developed to avoid the medical and psychological complications of later prenatal diagnosis by amniocentesis, CVS rapidly has become a primary tool for the diagnosis of fetal cytogenetic, molecular, and biochemical disorders. In addition, its development has led to an improved understanding of several biological processes, including confined placental mosaicism and uniparental disomy.

A twin gestation presents unique problems in both genetic counseling and prenatal diagnosis. This article describes the specific genetic counseling concerns for a twin gestation and outlines the available techniques for genetic prenatal diagnosis. The technical aspects, risks and benefits to the pregnancy of amniocentesis and of chorionic villi sampling are compared. Although the risk of miscarriage after amniocentesis in a twin gestation is at least double that for a singleton, much of this additional risk is secondary to the inherent hazards of twins and not procedure-related. In experienced centers, chorionic villi sampling is equally safe and efficacious, and allows an earlier diagnosis that may be beneficial when discordant results are found. The aspects of serum screening unique to twin gestations are also outlined. Prenatal diagnosis by both chorionic villus sampling and amniocentesis can be safely performed in twin gestations and higher-order multiple gestations. Serum screening is also useful, but appears to have a lower sensitivity and specificity than in singletons.