Does ART increase the risk for imprinting disorders such as BWS?
BACKGROUND AND PURPOSE:
There have been reports of an association between assisted reproductive techniques (ART) and imprinting disorders, for example (clinical findings and management for syndromes can be found in ‘Learn More – Primary Sources below)
Beckwith-Wiedemann syndrome (BWS)
Mussa et al. (Pediatrics, 2017) examined the prevalence of Beckwith-Wiedemann syndrome (BWS) in children born through ART to further refine relative risk
BWS patients were identified and matched with general demographic data and corresponding regional ART registry
BWS criteria included at least 2 of the following
Abdominal wall defect, macroglossia, macrosomia, embryonal tumor, ear malformations, organ enlargement, nevus flammeus, hemihyperplasia, nephron/urological malformations, hypoglycemia, or family history of BWS
Out of a total population of 379,872 live births, 7884 ART live births were studied
Within the total population, there were 38 patients with BWS (7 from ART and 31 naturally)
BWS birth prevalence was significantly higher in the ART group
In the ART group the relative risk was higher in BWS compared to non-ART at 10.7 (887.9 per 1,000,000 vs 83.3 per 1,000,000 risk)
There is an approximately ten-fold increased risk of BWS in ART children
Does Maternal Subfertility Impact Outcomes in Twin Pregnancies?
BACKGROUND AND PURPOSE:
Multiple gestation associated with assisted reproductive technology (ART) is declining but still accounts for approximately 40% of all twin births.
There is a greater risk of adverse outcomes in twin vs. singleton pregnancies
There is ongoing controversy if adverse outcomes using ART is related to the treatment or parental characteristics such as subfertility and limited data in twin vs. singleton pregnancies
This study by Luke et al. (AJOG, 2017) sought to determine if a mother’s fertility status impacts the risk of adverse outcomes in twin pregnancies
Longitudinal Retrospective Cohort Study
10,352 women with twin pregnancies were included in the study
6,090 ‘fertile’ women who conceived twins naturally
724 ‘subfertile’ women (e.g., use of fertility drugs or ART, diagnosis of infertility) who conceived twins without IVF
3,538 women who conceived twins with IVF
Adverse pregnancy and infant outcomes were examined
Women in the subfertile and IVF group were older and had more chronic health conditions
There were higher rates of gestational diabetes, gestational hypertension, uterine bleeding, placental complications, prenatal hospitalizations, and primary C-sections among the subfertile and IVF groups
Uterine bleeding (adjusted relative risk ratios, 1.92 for subfertile and 2.58 for IVF) and placental complications (adjusted relative risk ratios, 2.07 for subfertile and 1.83 for IVF) were the highest risks
Subfertile women had increased risk for very preterm birth (< 32 weeks) and neonatal and infant death (adjusted relative risk ratios, 1.36, 1.89, and 1.87, respectively)
In the IVF group, women were at increased risk for very preterm birth, preterm birth (<37 weeks), and birth defects (adjusted relative risk ratios, 1.28, 1.07, and 1.26, respectively)
The risk of adverse maternal and infant outcomes was increased among subfertile and IVF twins
Especially increased risk of bleeding and placental complications is a consistent finding among studies
These data are in keeping with guidelines promoting single embryo transfer and cautious use of ovulation induction to limit multiple gestation with ART
ASRM guidance: ART and recommended number of embryos to transfer
ASRM and SART have released updated guidance on assisted reproductive technologies (ART) and the number of embryos to transfer to prevent twin and higher order multiple births. The guideline promotes elective single-embryo transfer (eSET). The rationale for this guidance is based on evidence that demonstrates:
Multiple gestations lead to higher maternal and newborn complication rates, including twins
Approximately 50% of multiple gestations from ART are occurring women < 35 years of age and 23% of of women < 38 years of age
When financial barriers are removed, IVF is associated with fewer embryos transferred, thereby implicating economic factors in the transfer of multiple embryos
eSET in women < 38 years of age resulted in decreased rates of multiple gestations but no impact on live-birth rates
Preimplantation genetic screening (PGS) may also be helpful
In women < 42 years of age, transferring a tested (euploid) blastocyst resulted in the same pregnancy rate as the transfer of 2 untested blastocysts
In the case of favorable prognosis which, aside from younger age, may include the following features (1) one or more high-quality embryos will be available for cryopreservation; (2) euploid embryos; (3) previous live birth after IVF; (4) frozen embryos – availability of high quality day-5 or day-6 blastocysts for transfer, recommendations are as follows:
Any age: euploid embryo
Transfer 1 embryo
< 35 years:
Transfer 1, regardless of embryo stage
35 – 37 years:
strong consideration for 1 embryo
38 – 40 years:
3 cleavage-stage embryos
euploid embryo: 1 blastocyst
4 cleavage stage embryos
euploid embryo: 1 blastocyst
≥ 43 years
Risks associated with multiple gestations increase with age
Consider transferring additional embryos depending on clinical circumstances such as
This study by Nyfløt et al. (BJOG, 2016) aimed to determine if a relationship exists between assisted reproductive technology (ART) and postpartum hemorrhage.
1,064 cases of severe postpartum hemorrhage and 2,059 controls were included in the study. Women who had conceived using ART had a significantly increased risk of severe postpartum hemorrhage. Anticoagulant medication and mode of delivery had confounding effects. Risks were seen in both singleton and multiple births, with an even higher risk for multiples. This evidence supports the argument for being prepared for hemorrhage at delivery and the value of single embryo transfer during ART to avoid twins and higher order births.
Vasa previa is defined as fetal vessels that run through the fetal membranes, over or near the endocervical os (2 cm or less) and are unprotected by placenta or umbilical cord.
Deliver by cesarean section before the onset of labor and before rupture of membranes
Scheduled delivery 34w0d to 37w0d
Deliver by cesarean section in the case of PPROM and viability
Antenatal corticosteroids 28 to 32 weeks gestation
SMFM guidance states to consider hospitalization at 30 to 34 weeks
Benefit is unproven and there have been good outcomes reported with outpatient management
When considering hospitalization, individualize based on the following
History of preterm birth
Logistics in getting to hospital with transfusion capabilities
Patients with normal cervical lengths are the best candidates for possible outpatient management
Repeat ultrasound in the third trimester is suggested if vasa previa is suspected in the second trimester, as approximately 20% of apparent vasa previa will resolve by the late third trimester
Vasa previa occurs in 1/2500 to 1/5000 pregnancies and is associated with an increased risk of preterm birth and the associated complications of prematurity. There is a 97% survival rate when diagnosed by prenatal ultrasound and a 44% survival rate when the diagnosis is made intrapartum.
Velamentous cord insertion (Type 1 vasa previa)
Succinturate or bilobed placenta connecting vessels (Type 2 vasa previa)
Placenta previa or low lying placenta in the second trimester
IVF (1/250 risk of Type 1 vasa previa)
In cases of low lying placenta, bilobed placenta, succinturate placenta or velamentous cord insertion, a targeted ultrasound for vasa previa should be performed
Screening possible at 2nd trimester fetal anatomy ultrasound
If detected on 2nd trimester ultrasound, 20% will resolve
Document cord insertion site if possible
Diagnosis is made by ultrasound, ideally with transvaginal and color flow Doppler
Ultrasound findings include a linear tubular echolucent body overlying the endocervical os with color flow doppler demonstrating flow through the structure and pulsed doppler showing fetal vascular wave forms
Risk of perinatal loss due to fetal exsanguination – watch for sinusoidal pattern on FHT tracing
Plan for delivery at a center that can perform neonatal transfusion if required
Note: Center should have negative blood available for neonate in case rapid transfusion is necessary
This study by Yeung et al. (JAMA Pediatrics, 2016) aimed to assess if there exists a link between type of infertility treatment and children’s development. The authors’ noted a lack of data from the U.S.
Prospective Cohort Study
1,422 mothers underwent infertility treatments including assisted reproductive technology (ART), ovulation induction, or intrauterine insemination. Parents completed the Ages and Stages Questionnaires at 4, 8, 12, 18, 24, 30, and 36 months of age in order to test their children’s development. The authors found no difference in children’s development at 3 years of age, regardless of infertility treatment or type.
When LMP and Ultrasound Dates Don’t Match: When to Redate?
Historically, dating pregnancies and calculating due dates were left to weekly pregnancy calendars. However, ultrasound dating, in particular first trimester sonography, has greatly improved our ability to calculate the estimated due date (EDD). There will be times that dating based on LMP does not match the ultrasound date.
ACOG recommends redating as follows:
First trimester: based on CRL measurement
8w6d or less: redate if discrepancy is > 5d
9w0d – 13w6d: redate if discrepancy is > 7d
Second trimester: based on BPD, HC, AC and FL
14w0d – 15w6d: redate if discrepancy is > 7d
16w0d – 21w6d: redate if discrepancy is > 10d
22w0d – 27w6d: redate if discrepancy is > 14d
Third trimester: based on BPD, HC, AC and FL
28w0d and beyond: redate if discrepancy is > 21d
Use caution when redating in the 3rd trimester as discrepancy may reflect growth restriction
Management should not be based on ultrasound alone but rather comprehensive clinical assessment
Clinical determination of EDD, 280 days after the last menstrual period (LMP) still plays a role but may not always be accurate due to variability in length of an individual woman’s cycle length or timing of ovulation. Accurate dating is vital to pregnancy management, as certain interventions and management decisions may be based on such information including timing of delivery in the case of pregnancy complications.
First trimester ultrasound is the most accurate time frame for pregnancy dating and can increase the accuracy of the EDD even if LMP is known
Consider a pregnancy without a dating ultrasound prior to 22 0/7 weeks ‘suboptimally dated’ (refer to Related ObG Topics below)
Mean sac diameter is not recommended for dating
In the setting of assisted reproductive technology (ART), the ART derived gestational age should be used for EDD using the age of the embryo and the transfer date
The age of the embryo is subtracted from the number of days between ovulation to delivery (280-14 = 266). For example, if the embryo is 3 days at transfer, the due date is 263 days from the date of transfer.
If the CRL is greater than 84 mm, biometric parameters should be used to date the pregnancy
Once the EDD has been established using the LMP and/or first accurate ultrasound measurement, it should be recorded in the medical record and discussed with the patient
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