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Are Offspring of IVF/ICSI Pregnancies at Higher Risk for Congenital Heart Defects?


  • There have been studies that suggest an increased risk for cardiac defects in IVF/ICSI pregnancies
  • There are no meta-analyses that specifically look at the incidence of CHD in the IVF/ICSI  
  • Giorgione et al. (Ultrasound in Obstetrics & Gynecology, 2018) examined whether there was a higher risk of congenital heart defects (CHD) in offspring conceived through IVF/ICSI 


  • Systematic review and meta-analysis 
  • Literature search of studies comparing neonatal incidence of CHD in pregnancies conceived after IVF/ICSI and those conceived spontaneously  
  • For the meta-analysis, the authors selected cohort studies to estimate the pooled odds ratio (OR) with 95% CI   


  • Data was pooled from 8 cohort studies for meta-analysis 
    • 25,856 children were conceived using IVF/ICSI techniques and 287,995 children conceived spontaneously  
    • Both singleton and multiple gestations were included  
  • 1.30% of patients in the IVF/ICSI group and 0.68% in the spontaneous conception group had CHD events  
  • The risk of CHD was significantly increased in the IVF/ICSI group  
    • Pooled OR, 1.45; 95% CI, 1.20–1.76 (P = 0.0001)  
  • In the subgroup of singleton pregnancies, a significant difference was also evident 
    • Pooled OR, 1.29; 95% CI, 1.03–1.60; P = 0.02 
  • CHD subtypes
    • VSD was more frequent in IVF/ICSI
    • TOF (tetralogy of Fallot) and TGA (transposition of great arteries) were more common in pregnancies conceived spontaneously


  • The risk of CHD in IVF/ICSI pregnancies is significantly increased by approximately 50% 
  • CHD subtypes
    • VSD was more frequent in IVF/ICSI
    • TOF and TGA were more common in pregnancies conceived spontaneously  
  • These results held in subgroup analyses even after adjusting for confounding factors, including maternal age  
  • The authors cite results of this paper as evidence to support fetal echocardiography in IVF/ICSI pregnancies 

Learn More – Primary Sources:

Congenital heart defects in IVF/ICSI pregnancy: systematic review and meta-analysis 


Does ART increase the risk for imprinting disorders such as BWS?


  • 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)
    • Russell-Silver syndrome
    • Angelman syndrome
  • 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

Learn More – Primary Sources:

Assisted Reproductive Techniques and Risk of Beckwith-Wiedemann Syndrome

GeneReviews: Beckwith-Wiedemann Syndrome

GeneReviews: RussellSilver Syndrome

GeneReviews: Angelman Syndrome



Does Maternal Subfertility Impact Outcomes in Twin Pregnancies?


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

Learn More – Primary Sources:

Adverse pregnancy, birth, and infant outcomes in twins: effects of maternal fertility status and infant gender combinations; the Massachusetts Outcomes Study of Assisted Reproductive Technology


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
    • 2 blastocysts
    • euploid embryo: 1 blastocyst
  • 41-42 years:
    • 4 cleavage stage embryos
    • 3 blastocysts
    • euploid embryo: 1 blastocyst
  • ≥ 43 years
    • Insufficient data
    • Risks associated with multiple gestations increase with age

Consider transferring additional embryos depending on clinical circumstances such as

  • Good prognosis but multiple cycle failures
  • Co-existing medical conditions
  • Doesn’t meet criteria for good prognosis
  • Counsel based on risks/benefits

Learn More – Primary Sources:

ASRM & SART: Guidance on the limits to the number of embryos to transfer – a committee opinion

Does ART Increase Risk of Postpartum Hemorrhage?


This study by Nyfløt et al. (BJOG, 2016) aimed to determine if a relationship exists between assisted reproductive technology (ART) and postpartum hemorrhage.


Case-Control Study


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.

Learn More – Primary Sources:

Assisted reproductive technology and severe postpartum haemorrhage: a case–control study

BJOG Mini Commentary: Assisted reproductive technologies: an additional risk factor for severe postpartum haemorrhage

Vasa Previa: Diagnosis and Management

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
      • Symptoms
      • 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.


  • Risk factors:
    • 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
    • Multiple gestation
    • 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

Learn More – Primary Sources:

SMFM: Diagnosis and management of vasa previa

ACOG/SMFM Committee Opinion 831: Medically Indicated Late-Preterm and Early-Term Deliveries

Society for Maternal-Fetal Medicine (SMFM) Consult Series #44: management of bleeding in the late preterm period

Abnormal Placentation: Placenta Previa, Vasa Previa, and Placenta Accreta

Locate a Maternal Fetal Medicine Specialist:

Maternal-Fetal Medicine Specialist Locator-SMFM

Infertility Treatment and Childhood Development


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.

Learn More – Primary Sources:

Examining Infertility Treatment and Early Childhood Development in the Upstate KIDS Study