ABSTRACT
Importance: Uterus transplant in women with absolute uterine-factor infertility offers the possibility of carrying their own pregnancy. Objective: To determine whether uterus transplant is feasible and safe and results in births of healthy infants. Design, Setting, and Participants: A case series including 20 participants with uterine-factor infertility and at least 1 functioning ovary who underwent uterus transplant in a large US tertiary care center between September 14, 2016, and August 23, 2019. Intervention: The uterus transplant (from 18 living donors and 2 deceased donors) was surgically placed in an orthotopic position with vascular anastomoses to the external iliac vessels. Participants received immunosuppression until the transplanted uterus was removed following 1 or 2 live births or after graft failure. Main Outcomes and Measures: Uterus graft survival and subsequent live births. Results: Of 20 participants (median age, 30 years [range, 20-36]; 2 Asian, 1 Black, and 16 White), 14 (70%) had a successful uterus allograft; all 14 recipients gave birth to at least 1 live-born infant. Eleven of 20 recipients had at least 1 complication. Maternal and/or obstetrical complications occurred in 50% of the successful pregnancies, with the most common being gestational hypertension (2 [14%]), cervical insufficiency (2 [14%]), and preterm labor (2 [14%]). Among the 16 live-born infants, there were no congenital malformations. Four of 18 living donors had grade 3 complications. Conclusions and Relevance: Uterus transplant was technically feasible and was associated with a high live birth rate following successful graft survival. Adverse events were common, with medical and surgical risks affecting recipients as well as donors. Congenital abnormalities and developmental delays have not occurred to date in the live-born children. Trial Registration: ClinicalTrials.gov Identifier: NCT02656550.
ABSTRACT
Carrier screening has historically assessed a relatively small number of autosomal recessive and X-linked conditions selected based on frequency in a specific subpopulation and association with severe morbidity or mortality. Advances in genomic technologies enable simultaneous screening of individuals for several conditions. The American College of Medical Genetics and Genomics recently published a clinical practice resource that presents a framework when offering screening for autosomal recessive and X-linked conditions during pregnancy and preconception and recommends a tier-based approach when considering the number of conditions to screen for and their frequency within the US population in general. This laboratory technical standard aims to complement the practice resource and to put forth considerations for clinical laboratories and clinicians who offer preconception/prenatal carrier screening.
Subject(s)
Genetic Carrier Screening , Genetic Testing , Genetics, Medical , Genomics , Prenatal Diagnosis , Humans , Genetic Carrier Screening/methods , Genetic Carrier Screening/standards , Pregnancy , Female , Genomics/methods , Genomics/standards , Prenatal Diagnosis/methods , Prenatal Diagnosis/standards , Genetic Testing/standards , Genetic Testing/methods , Genetics, Medical/standards , United States , Preconception Care/methods , Preconception Care/standards , Genetic Counseling/standards , Genetic Counseling/methodsABSTRACT
STUDY QUESTION: Do characteristics of the lower uterine segment and cervix modify the risk of preterm delivery in uterus transplant (UTx) recipients? SUMMARY ANSWER: The cervical length showed little association with preterm delivery, however, cervical inflammation deserves further exploration as a cause of preterm delivery. WHAT IS KNOWN ALREADY: UTx recipients do not have the risk factors normally used to stratify pregnancies that would benefit from cervical length assessment. In addition, unique factors related to absent tissues, a different blood supply, inflammatory processes of rejection, cervical biopsies, and a different microbiome challenge the normal progressive remodeling of the cervix and thus cervical competence. STUDY DESIGN, SIZE, DURATION: This is a subanalysis of a clinical trial of 20 women undergoing uterus transplantation at Baylor University Medical Center from 2016 to 2020, in addition to two women who received transplantation outside of a research protocol at our institution through September 2022. In this report, the first 16 UTx recipients that achieved live birth are included. PARTICIPANTS/MATERIALS, SETTING, METHODS: The focus of this study was 20 pregnancies that reached the second trimester in 16 women following UTx. We analyzed recipient, transplant, and donor factors to determine if characteristics were associated with delivery outcome. We compared obstetrical outcomes, including planned versus unplanned delivery, by factors such as number of superior venous anastomoses, warm ischemia and cold ischemia times, donor factors including cesarean sections, cervical biopsy results, and cervical ultrasound results. MAIN RESULTS AND THE ROLE OF CHANCE: Planned term deliveries occurred in 44% (8/18) of live births. Of the preterm births, 30% (3/10) were planned and 70% (7/10) were unplanned. Unplanned deliveries occurred in women with spontaneous preterm labor, severe rejection, subchorionic hematoma, and placenta previa. Cervical length in UTx recipients averaged 33.5 mm at 24 weeks and 31.5 mm at 28 weeks, comparable to values from the general population. No relationship was seen between delivery outcome and number of veins used, ischemic time, or number of previous cesarean sections. LIMITATIONS, REASONS FOR CAUTION: The study's small size allows limited conclusions. The obstetric history of all donors was limited to mode of delivery. WIDER IMPLICATIONS OF THE FINDINGS: Cervical length measurements in the UTx population are not expected to deviate from those with a native uterus. While cervical length surveillance remains important, attention must be paid to the results of cervical biopsies which are obtained to monitor rejection. Inflammatory processes seem most predictive of preterm delivery. STUDY FUNDING/COMPETING INTEREST(S): No funding was provided for this study. The authors report no conflicts of interest. TRIAL REGISTRATION NUMBER: NCT02656550.
Subject(s)
Premature Birth , Female , Humans , Infant, Newborn , Pregnancy , Cervix Uteri/diagnostic imaging , Premature Birth/etiology , Risk Factors , Transplant Recipients , Uterus/diagnostic imagingABSTRACT
Recipients of uterus transplantation have unique factors that may increase their risk of cervical insufficiency. This report describes a uterus transplant recipient with cervical insufficiency resulting in two second-trimester miscarriages. After McDonald cerclages (one that failed), she underwent an interval transabdominal cerclage and delivered a healthy term child in her third pregnancy. The longitudinal information of this case provides observations from which we can propose testable hypotheses that address venous outflow and inflammation. This case also suggests that there could be a role for prophylactic cerclage placement at the time of transplantation.
ABSTRACT
OBJECTIVE: Doppler velocimetry of the uterine and umbilical arteries is used to predict preeclampsia and monitor fetal outcomes. There have been no reports of Doppler velocimetry indices in pregnancies conceived after uterus transplantation, which differ from traditional pregnancies because of different uterine vascular inflow and outflow and exposure to immunosuppressive agents. We sought to examine whether Doppler indices can be used to predict embryo transfer success after uterus transplantation and whether Doppler indices across pregnancy predict fetal growth restriction. STUDY DESIGN: This was a single-center cohort observational study of 14 uterus transplant recipients who underwent embryo transfer. Of these, 12 women successfully delivered 14 babies. Five Doppler investigations were performed within the cohort: (1) prepregnancy; (2) uterine artery assessment across pregnancy; (3) umbilical artery assessment across pregnancy; (4) successive pregnancies; and (5) fetal growth. RESULTS: Prepregnancy uterine artery Doppler indices did not correlate with successful implantation after embryo transfer. Uterine artery Doppler indices in uterus transplant recipients decreased across pregnancy as described in pregnancies without uterus transplantation. The umbilical artery systolic/diastolic velocity ratio was lower at all weeks of gestation after uterus transplantation compared with values described in pregnancies without uterus transplantation. In those women who delivered two successive babies after uterus transplant, umbilical artery Doppler indices were significantly lower during the second pregnancy. There was always forward flow throughout diastole in the umbilical arteries, and no babies experienced fetal growth restriction. CONCLUSION: In our study, uterus transplantation was not associated with abnormal blood flow indices in either the uterine or umbilical arteries. Although Doppler indices were not predictive of embryo transfer success, they supported the expectation that pregnancies after uterus transplantation at our center result in normally grown babies. KEY POINTS: · Uterus transplantation is not associated with abnormal blood flow indices.. · Prepregnancy uterine artery Doppler indices did not correlate with successful embryo implantation.. · Doppler assessment supports the expectation of normal placentation, fetal growth, and healthy live births after uterus transplantation..
ABSTRACT
OBJECTIVE: Limited data are available on the outcome of infants born after uterus transplantation. Our aim was to describe the hospital course and laboratory findings in the first 2 months of life of the 12 infants born in the Dallas UtErus Transplant Study (DUETS). STUDY DESIGN: Based on the trial protocol, information about infants was collected in a prospective fashion, including infant demographics, hospital course, and laboratory values. RESULTS: Twelve infants were delivered, all by cesarean section, from 11 mothers who had undergone uterus transplantation (one mother had two pregnancies and delivered two babies). All pregnancies were singleton. The mothers received immunosuppressive therapy, and one had a rejection episode that was detected during pregnancy. The rejection episode resolved after steroid treatment. The infants had a median gestational age of 366/7 weeks (range: 306/7-380/7 weeks) and median birth weight of 2,920 g (range: 1,770-3,470 g). The lowest Apgar's score at 5 minutes was 8. All infants were appropriate size for gestational age. Two infants presented with bandemia but negative blood cultures. At 2 months of age, all infants achieved the developmental and behavioral milestones outlined by the American Academy of Pediatrics. CONCLUSION: The 12 infants born from mothers with uterus transplants had a neonatal course that reflected the gestational age at delivery. No baby was born with an identified malformation or organ dysfunction. Longer follow-up and a larger number of infants are needed to confirm these observations. KEY POINTS: · Normal fetal development after uterus transplantation.. · No baby was born with malformations or showed any organ dysfunction.. · At 2 months, all infants achieved appropriate developmental and behavioral milestones..
Subject(s)
Cesarean Section , Multiple Organ Failure , Infant, Newborn , Infant , Pregnancy , Humans , Female , Child , Retrospective Studies , Birth Weight , Uterus/transplantationABSTRACT
An equitable approach by the American College of Medical Genetics and Genomics (ACMG) has recently recommended carrier screening for genes associated with moderate to severe autosomal recessive conditions with a carrier frequency of ≥1/200 in the Genome Aggregation Database exomes (gnomADv2.0.2). We analyzed carrier frequencies in gnomADv3.1.1 genomes representing diverse populations. ClinVar data on 35 996 pathogenic/likely pathogenic variants in 419 genes were used to estimate the gnomAD frequency of heterozygous carriers. We found that ninety-two genes had a carrier frequency of ≥1/200, of which 63 were shared between v3.1.1 and v2.0.2 and 29 were new in v3.1.1. Addition of new populations (Amish, Finnish and Middle Eastern) increased the number of new genes with a carrier frequency of ≥1/200 to 71. Changes in carrier frequencies were attributed to new gnomAD populations, different sample sizes, new ClinVar data, and technical differences between exomes and genomes. This study highlights the dynamic changes in carrier frequencies due to new datasets from diverse populations and provides updated carrier frequencies based on the combined data from 184 352 genomes and exomes in gnomAD. We recommend a periodic review for inclusion of new population data to update carrier screening panels in the future.
Subject(s)
Exome , Genetic Variation , Genes, Recessive , Genomics , Heterozygote , HumansABSTRACT
Counseling the uterus transplant patient requires an enhanced knowledge of unique genetic challenges that include an understanding of the spectrum of Mayer-Rokitansky-Küster-Hauser syndrome. Patients should understand their options for genetic screening and testing including preimplantation genetic testing for aneuploidy, genetic screening, and diagnostic testing. This patient population is potentially at risk for fetal anomalies due to the increased susceptibility to infections, such as cytomegalovirus. There are management strategies to minimize this risk. The risk of teratogenicity from mycophenolate is eliminated by a washout period before embryo transfer.
Subject(s)
46, XX Disorders of Sex Development , Congenital Abnormalities , 46, XX Disorders of Sex Development/genetics , Female , Genetic Testing , Humans , Male , Teratogens/toxicity , Uterus/abnormalities , VaginaABSTRACT
We offer consensus recommendations for the antepartum management of the uterus transplant pregnancy based on our experience at 3 US centers. Patient access to accurate information is important to manage expectations and make informed decisions. Unique aspects of medical management include monitoring tacrolimus levels and performing cervical biopsies for rejection. Low-dose aspirin for preeclampsia is routinely used. Vigilant screening for gestational diabetes and preeclampsia allows for the prompt diagnosis and treatment of these common complications. We aim to deliver patients at 37 to 38 weeks by cesarean section. Shared decision making dominates whether to consider future pregnancies and timing of hysterectomy.
Subject(s)
Cesarean Section , Pre-Eclampsia , Aspirin , Female , Humans , Pre-Eclampsia/prevention & control , Pregnancy , Prenatal Care , UterusABSTRACT
Carrier screening began 50 years ago with screening for conditions that have a high prevalence in defined racial/ethnic groups (e.g., Tay-Sachs disease in the Ashkenazi Jewish population; sickle cell disease in Black individuals). Cystic fibrosis was the first medical condition for which panethnic screening was recommended, followed by spinal muscular atrophy. Next-generation sequencing allows low cost and high throughput identification of sequence variants across many genes simultaneously. Since the phrase "expanded carrier screening" is nonspecific, there is a need to define carrier screening processes in a way that will allow equitable opportunity for patients to learn their reproductive risks using next-generation sequencing technology. An improved understanding of this risk allows patients to make informed reproductive decisions. Reproductive decision making is the established metric for clinical utility of population-based carrier screening. Furthermore, standardization of the screening approach will facilitate testing consistency. This practice resource reviews the current status of carrier screening, provides answers to some of the emerging questions, and recommends a consistent and equitable approach for offering carrier screening to all individuals during pregnancy or preconception.
Subject(s)
Anemia, Sickle Cell , Cystic Fibrosis , Genetics, Medical , Tay-Sachs Disease , Anemia, Sickle Cell/genetics , Cystic Fibrosis/genetics , Female , Genetic Carrier Screening , Genetic Testing , Genomics , Humans , Pregnancy , Tay-Sachs Disease/genetics , United StatesABSTRACT
BACKGROUND: The clinical pregnancy rates among patients with uterus transplantation have been reported by only a limited number of centers, and those centers have not used preimplantation genetic testing for aneuploidy in their protocol. OBJECTIVE: This study examined clinical pregnancy rates among women with absolute uterine-factor infertility undergoing in vitro fertilization using good-quality, expanded-blastocyst-stage, euploid embryos after uterus transplantation. STUDY DESIGN: This cohort observational study involved 20 women who underwent uterus transplantation over 3 years. Notably, 14 of these patients had successful transplants and were followed prospectively for a median of 14.1 months (range, 11-34.8 months). In vitro fertilization was performed before subjects underwent uterus transplantation, and good-quality expanded-blastocyst-stage euploid embryos were obtained and frozen for future embryo transfer. Interventions consisted of in vitro fertilization, preimplantation genetic testing for aneuploidy, uterus transplantation, and frozen embryo transfer. RESULTS: All 14 subjects with successful transplants underwent single embryo transfer of a warmed, good-quality, euploid, expanded blastocyst and had at least 1 documented clinical pregnancy within the uterus. In 71.4%, the first embryo transfer resulted in clinical pregnancy. The median time from successful uterus transplantation to first embryo transfer was 4.5 months; from successful uterus transplantation to first clinical pregnancy, 7.3 months; and from successful uterus transplantation to first live birth, 14.1 months. A total of 13 live births have occurred in 12 subjects. CONCLUSION: Women with absolute uterine-factor infertility who have surgically successful uterus transplantation and in vitro fertilization using preimplantation genetic testing for aneuploidy can achieve high clinical pregnancy rates. We have reduced the time interval from uterus transplantation to embryo transfer by at least 50% and the interval from uterus transplantation to clinical pregnancy by >6 months compared with previous studies. We believe our approach may shorten the time from transplant to clinical pregnancy and therefore decrease patient exposure to immunosuppressant therapies.
Subject(s)
46, XX Disorders of Sex Development/complications , Fertilization in Vitro , Infertility, Female/therapy , Mullerian Ducts/abnormalities , Ovulation Induction/methods , Pregnancy Rate , Single Embryo Transfer/methods , Uterus/transplantation , Adult , Congenital Abnormalities , Female , Humans , Hysterectomy , Infertility, Female/etiology , Pregnancy , Preimplantation Diagnosis , Time Factors , Young AdultABSTRACT
OBJECTIVE: To describe aggregated pregnancy outcomes after uterus transplantation from a single, experienced center. METHODS: This prospective study reports on live births among 20 women who received a uterus transplant from 2016 to 2019 at Baylor University Medical Center at Dallas. These live births occurred between November 2017 and September 2020. The main measures were live birth, maternal complications, and fetal and newborn outcomes. RESULTS: There were six graft failures (four surgical complications and two with poor perfusion postoperatively). Of the 14 technically successful transplants, at least one live birth occurred in 11 patients. Thus far, the live birth rate per attempted transplant is 55%, and the live-birth rate per technically successful transplant is 79%. Ten uteri were from nondirected living donors and one uterus was from a deceased donor. In vitro fertilization was performed to achieve pregnancy. Ten recipients delivered one neonate, and one recipient delivered two neonates. One organ rejection episode was detected during pregnancy and was resolved with steroids. The median birth weight was 2,890 g (range 1,770-3,140 g [median 68th percentile]). Maternal weight gain was higher than Institute of Medicine recommendations. Maternal medical complications were observed in five recipients (elevated creatinine level, gestational diabetes, gestational hypertension [n=2], and preeclampsia). In five recipients, maternal medical or obstetric complications led to an unplanned preterm delivery (elevated creatinine level, preeclampsia; preterm labor [n=3]). The median gestational age at delivery was 36 6/7 weeks (range 30 6/7-38 weeks). All neonates were liveborn, with Apgar scores of 8 or higher at 5 minutes. CONCLUSION: Over the first 3 years, our program experienced a live-birth rate per attempted transplant of 55% and a live-birth rate per technically successful transplant of 79%. In our experience, uterus transplantation resulted in a third-trimester live birth in all cases in which pregnancies reached 20 weeks of gestation. Maternal medical and obstetric complications can occur; however, these were manageable by applying principles of generally accepted obstetric practice. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02656550.
Subject(s)
46, XX Disorders of Sex Development , Congenital Abnormalities , Live Birth , Mullerian Ducts/abnormalities , Postoperative Complications , Pregnancy Complications , Uterus/transplantation , Adult , Female , Humans , Pregnancy , Prospective Studies , Young AdultABSTRACT
OBJECTIVE: We report the results of the first 20 uterus transplants performed in our institution. SUMMARY BACKGROUND DATA: Uterus transplantation (UTx) aims at giving women affected by absolute uterine-factor infertility the possibility of carrying their own pregnancy. UTx has evolved from experimental to an established surgical procedure. METHODS: The Dallas Uterus Transplant Study (DUETS) program started in 2016. The uterus was transplanted in orthotopic position with vascular anastomoses to the external iliac vessels and removed when 1 or 2 live births were achieved. Immunosuppression lasted only for the duration of the uterus graft. RESULTS: Twenty women, median age 29.7 years, enrolled in the study, with 10 in phase 1 and 10 in phase 2. All but 2 recipients had a congenital absence of the uterus. Eighteen recipients received uteri from living donors and 2 from deceased donors. In phase 1, 50% of recipients had a technically successful uterus transplant, compared to 90% in phase 2. Four recipients with a technical success in phase 1 have delivered 1 or 2 babies, and the fifth recipient with a technical success is >30 weeks pregnant. In phase 2, 2 recipients have delivered healthy babies and 5 are pregnant. CONCLUSIONS: UTx is a unique type of transplant; whose only true success is a healthy child birth. Based on results presented here, involving refinement of the surgical technique and donor selection process, UTx is now an established solution for absolute uterine-factor infertility.
Subject(s)
Donor Selection/methods , Fertility/physiology , Infertility, Female/surgery , Living Donors , Organ Transplantation/methods , Uterus/transplantation , Adult , Female , Follow-Up Studies , Humans , Pregnancy , Retrospective Studies , Treatment Outcome , Young AdultABSTRACT
Pathogenic variants in the CFTR gene are causative of classic cystic fibrosis (CF) as well as some nonclassic CF phenotypes. In 2001, CF became the first target of pan-ethnic universal carrier screening by molecular methods. The American College of Medical Genetics and Genomics (ACMG) recommended a core panel of 23 disease-causing variants as the minimal set to be included in pan-ethnic carrier screening of individuals with no family history of the disease, and these variants were usually assessed using targeted methods. The original recommendation also left open the option for laboratories to offer expanded CFTR variant panels; however, at the time, expanded CFTR variant panels were met with some controversy on the basis of the available technologies and the limited phenotypic knowledge of rare variants. Both of those aspects have now evolved, prompting this update of the ACMG technical standards for CFTR variant testing.
Subject(s)
Cystic Fibrosis Transmembrane Conductance Regulator , Genetic Testing/standards , Genetics, Medical , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Genomics , Humans , Mutation , United StatesABSTRACT
Open neural tube defects (ONTDs) include open spina bifida (OSB) and anencephaly. These defects are caused by incomplete closure of the neural tube at about 4 weeks of pregnancy. Levels of early second-trimester maternal serum (ms) alpha-fetoprotein (AFP) are sufficiently elevated in affected pregnancies to be used as a population-based screening test. The basic screening methodology was described in the late 1970s and screening programs were active a few years later. By identifying pregnancies with the highest msAFP levels, about 80% of OSB and 95% of anencephaly can be identified as early as 16 weeks gestation. The interpretation of msAFP levels is complicated by the need to consider multiple factors such as gestational age, maternal weight, maternal race, multiple gestations, and more. Testing for AFP and acetylcholinesterase in amniotic fluid and/or identification of the lesion by targeted ultrasound is considered diagnostic of ONTD. When a diagnosis is made, options include termination, surgery after delivery, or in utero surgery, depending on factors such as location and size of the defect, and the presence of any additional anomalies. Screening for ONTD should be performed as part of a comprehensive program linking primary obstetrical care providers, laboratorians, and high-risk clinicians.