By Ahizechukwu C. Eke, MD, PhD, MPH
Associate Professor in Maternal Fetal Medicine, Division of Maternal Fetal Medicine, Department of Gynecology & Obstetrics, Johns Hopkins University School of Medicine, Baltimore
SYNOPSIS: About 1 in 40 females who underwent reproductive carrier screening were found to be carriers for a disease that could cause maternal symptoms during pregnancy. Healthcare providers should be aware of the potential for complications among carriers of genetic conditions during pregnancy and the best practices for handling such cases.
SOURCE: Souter V, Prigmore B, Becraft E, et al. Reproductive carrier screening results with maternal health implications during pregnancy. Obstet Gynecol 2023; Aug 10. doi: 10.1097/AOG.0000000000005318. [Online ahead of print].
The pathway to motherhood is an extraordinary and transformative experience, filled with hope, anticipation, and, at times, unexpected challenges. For couples planning to start or expand their families, the process of conception and pregnancy often is accompanied by a multitude of decisions and considerations. Among these is reproductive carrier screening, a powerful tool in contemporary medicine that provides valuable insights into the genetic health of prospective parents and their potential offspring.1 This is critically important because an estimated 1 in 300 pregnancies in the United States are affected by significant recessive and X-linked genetic disorders.2 This has prompted the American College of Obstetricians and Gynecologists (ACOG) and the American College of Medical Genetics and Genomics (ACMG) both to recommend reproductive carrier screening for monogenic genetic disorders with moderate to severe phenotypes to be made available to expectant mothers.3,4
Reproductive carrier screening is a genetic testing process that assesses individuals for the presence of gene mutations associated with hereditary conditions, such as cystic fibrosis, sickle cell anemia, and Tay-Sachs disease, among others.5 Its primary goal is to identify carriers of these genetic mutations, who, while not manifesting symptoms themselves, may pass on the mutation to their offspring. When both prospective parents are carriers of the same mutation for a specific condition, the risk of having a child affected by that condition significantly increases. Reproductive carrier screening is invaluable in the context of family planning, since it provides couples with the knowledge to make informed decisions about their reproductive options. For many, this may involve pursuing prenatal testing, in vitro fertilization with preimplantation genetic testing, or adoption as viable pathways to parenthood while minimizing the risk of passing on a serious genetic disorder. However, some genetic disorders discovered during carrier screening may develop during pregnancy, and there may be instances in which having a fetus with a disorder will have an effect on the mother's health.6,7 In this paper, Souter and colleagues set out to identify conditions identifiable through a commercially available reproductive carrier screening panel with potential for carrier manifestations during pregnancy and the implications for obstetric care.7
This was a retrospective, cross-sectional study conducted between January 2020 and September 2022 in the United States. Reproductive carrier screening test request forms were used to collect information on patient demographic characteristics, such as maternal age, race/ethnicity, and pregnancy status (pregnant, not pregnant, or pregnancy status not reported). Inclusion criteria were females aged 18-55 years who gave informed consent to the study. Consecutive blood samples were tested at Natera, Inc., using a 274-gene reproductive carrier screening panel. All genetic disorders in affected people in the Natera gene panels could result in physical or cognitive impairment, requirement for postnatal surgical or medical intervention, or an effect on quality of life.
Of the 274 genes in the Natera panel, ACOG currently recommends providing pan-ethnic carrier screening to all couples, regardless of their race or ethnicity, for only three diseases: cystic fibrosis (CF), hemoglobinopathies, and spinal muscular atrophy (SMA), while the ACMG recommends pan-ethnic carrier screening for 113 of the 274 conditions tested in the Natera panel. According to the ACMG criteria, test results were deemed positive if a pathogenic or likely pathogenic variant was found that increased the risk of a genetic disorder during pregnancy, increased the risk of a particular health condition in the person being screened, or was linked to another potentially relevant finding. The number of samples with two variants in the same gene, and the prevalence of carriers for pathogenic or potentially pathogenic mutations in more than one of these genes, were reported. Samples that yielded variants of uncertain significance (VUS); those that did not yield a result; conditions where an abnormal phenotype would only be expressed in the fetus; conditions where carriers show late-onset disease or would not routinely require additional testing or clinical management of the pregnant persons; and carriers for sickle cell disease, alpha thalassemia trait, and other mild hemoglobinopathy variants were excluded.
The investigators performed a literature search for genetic disorders with carrier manifestations in pregnancy for each of the 274 Natera genes in the panel, and considered whether female carriers or heterozygotes who had a pathogenic or likely pathogenic variation in one copy of the gene would be at risk for pregnancy complications. Management options for reproductive carriers were evaluated by the investigators, and a summary of the frequency, type, and signs of affected carriers during pregnancy were extracted. Together with 95% confidence intervals (CIs) for each condition and for all conditions combined, the prevalence of at least one pathogenic or likely pathogenic mutation in any of the genes with potential for maternal pregnancy manifestation was calculated.
During the period spanning from January 2020 to September 2022, a total of 2,852 women were studied. Twelve genes were identified by the investigators as having the potential to manifest as carriers during pregnancy, nine of which manifested regardless of the fetal genetic status (ABCB11 [familial cholestasis], COL4A3 [Alport syndrome], COL4A4 [Alport syndrome, keratoconus], COL4A5 [Alport syndrome], DMD [Duchenne muscular dystrophy], F9 [hemophilia], F11 [factor XI deficiency], GLA [Fabry disease], and OTC [ornithine transcarbamylase deficiency]) and three of which manifested only if the fetus was affected (CPT1A [carnitine palmitoyltransferase 1 deficiency], CYP19A1 [aromatase deficiency], and HADHA [long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency]). Cardiomyopathy, antepartum hemorrhage, gestational hypertension, cholestasis of pregnancy, acute fatty liver, hyperammonemic crisis, and maternal virilization were some of the manifestations. Eleven of the 12 genes had carrier management advice published in the literature. There were 2,139 (2.3%) positive tests for a pathogenic or potentially pathogenic variant over the research period, yielding a carrier frequency of 1 in 43 (95% CI, 1/41; 1/45) across all 12 genes. Carriers for one of the nine genes with the potential for carrier symptoms were found in 1,826 (2.0%) subjects of the research population.
COMMENTARY
There are limits to the current traditional methods of genetic screening for reproductive carriers.8 First, because the workflow depends on knowing both the maternal and paternal carrier status, traditional carrier screening can miss genetic diseases caused by parental carrier status (because the father often is not tested). Second, only around 5% of patients ever get around to having traditional carrier screening done before becoming pregnant, even though doing so would maximize their reproductive possibilities. Third, when carrier screening is done during pregnancy, it typically is done in a sequential fashion (first the mother is screened, then the father), which can take a long time. Finally, misattributed paternity, which happens in about 10% of pregnancies, and low uptake of paternal carrier screening (which is performed in less than half of the times it is indicated) are limitations of traditional carrier screening.8
Excitingly, a number of breakthroughs have been made in reproductive carrier screening. The most significant advance in carrier screening is the reflex single-gene noninvasive prenatal screening (sgNIPS), a method that allows for the assessment of both maternal and fetal carrier status, including genetic transmission risk, from a single maternal blood draw, without the need for paternal carrier screening. Unlike traditional prenatal testing methods, such as amniocentesis or chorionic villus sampling, which carry some risk of miscarriage, sgNIPS is noninvasive, making it very appealing to patients. Furthermore, sgNIPS allows for early detection of genetic mutations and has a high level of accuracy in detecting specific single-gene mutations. The availability of sgNIPS holds significant promise for improving the management of pregnancies at risk for specific single-gene disorders.
Although reproductive carrier screening primarily focuses on the genetic health of the offspring, it also holds crucial implications for maternal health during pregnancy. This particularly is true when carrier screening reveals a potential risk for a child to be born with a severe genetic disorder. In such cases, pregnant women must navigate a complex and emotionally challenging journey, which may involve close monitoring of the pregnancy, specialized medical care, and even difficult decisions regarding the continuation of the pregnancy.
The role of healthcare providers in this intricate landscape of reproductive carrier screening, maternal health, and pregnancy outcomes cannot be overemphasized. Healthcare providers (obstetricians and gynecologists, family medicine and primary care providers, and genetic counselors) not only facilitate genetic counseling and screening but also provide comprehensive support and guidance to pregnant women and their partners facing these complex decisions. It is essential for healthcare professionals to strike a balance between equipping individuals with the knowledge they need to make informed choices and offering the emotional support necessary to navigate the associated challenges.
In conclusion, reproductive carrier screening is a powerful tool that has transformed family planning by offering insights into the genetic health of prospective parents and their potential offspring. However, it is crucial to recognize that the implications of carrier screening extend beyond the realm of genetics; they profoundly affect maternal health and the overall pregnancy experience. As we delve deeper into the complexities of this intersection, we gain a more thorough understanding of the profound choices and challenges faced by pregnant people and their partners, underscoring the need for comprehensive care and support in this critical aspect of reproductive medicine. ACOG recommends that all pregnant individuals and those planning to become pregnant be offered prenatal carrier screening for common single-gene recessive disorders, such as cystic fibrosis, alpha- and beta-hemoglobinopathies, and SMA.9
REFERENCES
- Sagaser KG, Malinowski J, Westerfield L, et al. Expanded carrier screening for reproductive risk assessment: An evidence-based practice guideline from the National Society of Genetic Counselors. J Genet Couns 2023;32:540-557.
- Hogan GJ, Vysotskaia VS, Beauchamp KA, et al. Validation of an expanded carrier screen that optimizes sensitivity via full-exon sequencing and panel-wide copy number variant identification. Clin Chem 2018;64:1063-1073.
- Gregg AR, Aarabi M, Klugman S, et al. Screening for autosomal recessive and X-linked conditions during pregnancy and preconception: A practice resource of the American College of Medical Genetics and Genomics (ACMG). Genet Med 2021;23:1793-1806.
- Wojcik MH, Reimers R, Poorvu T, Agrawal PB. Genetic diagnosis in the fetus. J Perinatol 2020;40:997-1006.
- Edwards S, Laing N. Genetic counselling needs for reproductive genetic carrier screening: A scoping review. J Pers Med 2022;12:1699.
- Harris S, Vora NL. Maternal genetic disorders in pregnancy. Obstet Gynecol Clin North Am 2018;45:249-265.
- Souter V, Prigmore B, Becraft E, et al. Reproductive carrier screening results with maternal health implications during pregnancy. Obstet Gynecol 2023; Aug 10. doi:10.1097/aog.0000000000005318. [Online ahead of print].
- Hoskovec J, Hardisty EE, Talati AN, et al. Maternal carrier screening with single-gene NIPS provides accurate fetal risk assessments for recessive conditions. Genet Med 2023;25:100334.
- [No authors listed]. Committee Opinion No. 690 Summary: Carrier screening in the age of genomic medicine. Obstet Gynecol 2017;129:595-596.
About 1 in 40 females who underwent reproductive carrier screening were found to be carriers for a disease that could cause maternal symptoms during pregnancy. Healthcare providers should be aware of the potential for complications among carriers of genetic conditions during pregnancy and the best practices for handling such cases.
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