Alessandro Ghidini, MD

Assisted reproductive technology (ART) now accounts for 1.6% of all infants and 18.3% of all multiple-birth infants in the United States.

 Although most of these pregnancies are uncomplicated, IVF is associated with several adverse maternal and perinatal outcomes. This Consult discusses the management of pregnancies achieved with in vitro fertilization and provides recommendations based on the available evidence.

What genetic conditions should be discussed for patients considering or who have undergone IVF?

The IVF procedure itself does not appear to lead to a higher prevalence of chromosomal anomalies when compared with naturally occurring pregnancy.

 However, a significantly increased rate of de-novo chromosomal abnormalities has been reported in ICSI pregnancies compared with a reference group of naturally occurring pregnancies or the general population.

Other factors may play a role in the increased risk of chromosomal anomalies in IVF pregnancies, including advanced maternal age, polycystic ovary syndrome,

 and severe male and female factor infertility. Imprinting syndromes, including Beckwith-Wiedemann syndrome (BWS),

Angelman/Prader Willi syndrome (PWS), and Russell-Silver syndrome,

are thought to occur more frequently in the offspring of subfertile parents,

although the absolute risk remains small. 

Patients with reduced ovarian reserve and primary ovarian insufficiency have an increased risk of being full mutation or premutation carriers of fragile X.These patients typically undergo 

 gene testing before undergoing IVF. Preimplantation genetic testing should be offered for monogenic disorders with the transfer of only embryos carrying the normal X chromosome.

We suggest genetic counseling be offered to all patients undergoing or who have undergone IVF with or without ICSI (GRADE 2C)

What are the different types of preimplantation genetic testing?

The types of preimplantation genetic testing (PFT) are as follows:

PGT for aneuploidy (PGT-A): Its value as a screening test for IVF patients has been debated.

 It does not replace the recommendation for prenatal screening or diagnosis.

Preimplantation genetic testing for monogenic disorders (PGT-M): It is used most commonly in couples with previous offspring affected by single-gene disorders (such as cystic fibrosis) or who have undergone carrier screening with both partners testing positive for a mutation associated with a genetic disease.

Preimplantation genetic testing for structural [chromosomal] rearrangements (PGT-SR):This testing is usually performed when one partner is known to be a carrier of a balanced translocation or a deletion or duplication.

For both PGT-M and PGT-SR, it is recommended that a confirmatory diagnostic test be offered during the pregnancy.

Many patients, however, do not wish to pursue invasive testing after PGT.

Regardless of whether PGT has been performed, we recommend that all patients who have achieved pregnancy with IVF be offered the options of prenatal genetic screening and diagnostic testing via chorionic villus sampling or amniocentesis (GRADE 1C).

If euploid embryos are unavailable, aneuploid mosaic embryos are sometimes transferred.

 Prenatal diagnostic testing should be offered to patients with pregnancies that occur from transferring an embryo with a mosaic trisomy or monosomy. Consultation with a genetic counselor or geneticist can be offered to discuss diagnostic testing for these patients. Screening with cell-free DNA (cfDNA) has limited clinical utility in this setting.

What is the accuracy of first-trimester genetic screening tests in IVF pregnancies?

The accuracy of first-trimester genetic screening tests for aneuploidies may be affected by IVF, with a potential increased risk of false-positive results for aneuploidies in patients who undergo first trimester combined screening.

Lower fetal fraction (FF) has been reported with cfDNA in IVF pregnancies,

 leading to higher rates of failed cfDNA results compared with naturally occurring pregnancies. However, IVF does not appear to be a risk factor for failed results on repeat cfDNA testing (second draw).

We recommend that the accuracy of first-trimester screening tests, including cfDNA for aneuploidy, be discussed with patients undergoing or who have undergone IVF (GRADE 1A).

Does multifetal pregnancy reduction reduce the risks associated with multiple gestations?

Given the increase in maternal and perinatal morbidity and mortality associated with twins and higher-order multifetal pregnancies,27 efforts should be made to limit multifetal pregnancies during ART. However, even when a single embryo is transferred, the risk of monozygotic twins is increased. 

When multifetal pregnancies do occur, we recommend counseling be offered regarding the option of multifetal pregnancy reduction (GRADE 1C).

Multifetal pregnancy reduction has been shown to significantly reduce the risks of preterm birth, neonatal morbidity, and maternal complications.

Are congenital anomalies increased in IVF pregnancies?

Meta-analyses demonstrate associations between IVF/ICSI and congenital malformations, although it remains unclear if this association is due to infertility, factors associated with the procedure, or both.

It is also difficult to distinguish the risk associated with IVF alone versus IVF with ICSI. 

 we recommend a detailed obstetrical ultrasound examination (CPT 76811) be performed for pregnancies achieved with IVF and ICSI (GRADE 1B).

Several studies report higher rates of total congenital heart disease (CHD) in the IVF/ICSI population compared with naturally occurring pregnancies, while other studies report that the incidence of CHD in IVF pregnancies without other risk factors is not significantly different from baseline population rates 34The cost-effectiveness of routine screening for CHD in pregnancies following IVF has also been questioned.

We suggest fetal echocardiography be offered to patients with pregnancies achieved with IVF and ICSI (GRADE 2C).

Are placental anomalies increased in IVF pregnancies?

IVF pregnancies are associated with higher risks for abnormal placental shape (bilobed placenta, accessory placental lobes), placenta previa, marginal or velamentous cord insertion, and placenta accreta spectrum compared with naturally occurring pregnancies. 

All of the above manifestations of placental implantation disorders appear related and can occur together. 

, we recommend a careful examination of the placental location, placental shape, and cord insertion site be performed at the time of the detailed fetal anatomy ultrasound, including evaluation for vasa previa (GRADE 1B).

Targeted screening via transvaginal sonogram should be considered in all IVF pregnancies with velamentous cord insertion, succenturiate or bilobed placentas, or resolved placenta previa to rule out vasa previa.

 Due to the ongoing risk of vasa previa in the setting of resolved placenta previa, reassessment for vasa previa is warranted when reassessing placental location at 32 weeks of gestation.

Is the prevalence of spontaneous preterm birth higher in IVF pregnancies?

A meta-analysis of singleton pregnancies demonstrated that IVF is associated with higher odds of preterm delivery, low birthweight, and very low birthweight compared with naturally occurring pregnancies.

Preterm birth has been recognized for several decades as the primary independent cause of increased rates of several adverse neonatal outcomes, including neonatal encephalopathy and perinatal mortality, in IVF pregnancies. 

Such risks are more than doubled in the presence of IVF twin gestations. Subfertility is also a major risk factor for prematurity.

 Although there may be an increased risk for spontaneous preterm birth with IVF pregnancies, the utility of serial cervical length measurement to screen for preterm birth risk is unknown when the sole indication is IVF.

Although visualization of the cervix at the 18 0/7 to 22 6/7 weeks of gestation anatomy assessment with either a transabdominal or endovaginal approach is recommended, we do not recommend serial cervical length assessment as a routine practice for IVF pregnancies (GRADE 1C).

In addition, progesterone supplementation initiated for IVF cycles is not indicated after 12 weeks of gestation if it was solely initiated for IVF purposes without any other indication. Discontinuation of progesterone supplementation initiated for the sole purpose of IVF is recommended by 12 weeks.

Is the prevalence of fetal growth restriction higher in IVF pregnancies?

An increased risk of small for gestational age (SGA) infants is documented for singleton IVF pregnancies. Meta-analyses have described a higher risk of SGA babies in IVF/ICSI pregnancies from fresh cycles compared with frozen cycles.

The optimal gestational ages for fetal growth scans and their frequency in the presence of additional risk factors (eg, placental implantation anomalies or maternal age >40 years) are presently unknown. 

We suggest an assessment of fetal growth in the third trimester for IVF pregnancies; however, serial growth ultrasounds are not recommended for the sole indication of IVF (GRADE 2B).

In pregnancies achieved with IVF, does low-dose aspirin prophylaxis reduce the risk of fetal and placental complications?

IVF and underlying infertility are associated with adverse perinatal outcomes, including hypertensive disorders of pregnancy.

 The United States Preventative Services Task Force states IVF is a moderate risk factor for preeclampsia and recommends low-dose aspirin if an additional moderate risk factor is found.

We do not recommend low-dose aspirin in patients with an IVF pregnancy as the sole indication for preeclampsia prophylaxis; however, if one or more additional risk factors are present, low-dose aspirin is recommended (GRADE 1B).

Is the prevalence of stillbirth increased in IVF pregnancies?

Pregnancies achieved with IVF have a two to three-fold increased risk of stillbirth even after controlling for maternal age, parity, and multifetal gestations.

Given the increased risk of stillbirth, we suggest weekly antenatal fetal surveillance beginning by 36 0/7 weeks of gestation

for pregnancies achieved with IVF (GRADE 2C).

In pregnancies achieved with IVF, does delivery at 39 weeks reduce the risk of adverse perinatal outcomes?

It is currently unknown whether elective delivery at 39 weeks reduces the risks of maternal morbidity and improves perinatal outcomes in IVF pregnancies compared with expectant management. 

A systematic review revealed that in asymptomatic uncomplicated singleton gestations, induction of labor between 39 0/7 and 40 6/7 weeks does not increase the risk of cesarean delivery compared with expectant management but does not reduce the rates of adverse perinatal outcomes, including perinatal death, low Apgar score at 5 minutes, or need for NICU admission.

In the absence of studies focused specifically on timing of deliveryIVF pregnancies, we recommend shared decision-making between patients and healthcare providers when considering induction of labor at 39 weeks of gestation (GRADE 1C).

IVF is associated with an increased risk of adverse maternal and perinatal outcomes. However, evidence is limited regarding whether specific screening, diagnostic, or preventative interventions during pregnancy obviate or reduce such risks. Specific technical characteristics of IVF and the presence of underlying infertilityaffect the risks of adverse clinical outcomes. Therefore, individualization of care may be ideal for optimizing outcomes.

Summary of Recommendations

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2.Conway DA, Patel SS, Liem J, et al. The risk of cytogenetic abnormalities in the late first trimester of pregnancies conceived through assisted reproduction. Fertil Steril 2011;95(2):503-6. (In eng). DOI: 10.1016/j.fertnstert.2010.09.019.

3.Shevell T, Malone FD, Vidaver J, et al. Assisted reproductive technology and pregnancy outcome. Obstet Gynecol 2005;106(5 Pt 1):1039-45. (In eng). DOI: 10.1097/01.AOG.0000183593.24583.7c.

4.Aboulghar H, Aboulghar M, Mansour R, Serour G, Amin Y, Al-Inany H. A prospective controlled study of karyotyping for 430 consecutive babies conceived through intracytoplasmic sperm injection. Fertil Steril 2001;76(2):249-53. (In eng). DOI: 10.1016/s0015-0282(01)01927-6.

5.Bonduelle M, Van Assche E, Joris H, et al. Prenatal testing in ICSI pregnancies: incidence of chromosomal anomalies in 1586 karyotypes and relation to sperm parameters. Hum Reprod 2002;17(10):2600-14. (In eng). DOI: 10.1093/humrep/17.10.2600.

6.Hong KH, Franasiak JM, Werner MM, et al. Embryonic aneuploidy rates are equivalent in natural cycles and gonadotropin-stimulated cycles. Fertil Steril 2019;112(4):670-676. (In eng). DOI: 10.1016/j.fertnstert.2019.05.039.

7.Li Y, Wang L, Xu J, et al. Higher chromosomal aberration rate in miscarried conceptus from polycystic ovary syndrome women undergoing assisted reproductive treatment. Fertil Steril 2019;111(5):936-943.e2. (In eng). DOI: 10.1016/j.fertnstert.2019.01.026.

8.DeBaun MR, Niemitz EL, Feinberg AP. Association of in vitro fertilization with Beckwith-Wiedemann syndrome and epigenetic alterations of LIT1 and H19. Am J Hum Genet 2003;72(1):156-60. (In eng). DOI: 10.1086/346031.

9.Gicquel C, Gaston V, Mandelbaum J, Siffroi JP, Flahault A, Le Bouc Y. In vitro fertilization may increase the risk of Beckwith-Wiedemann syndrome related to the abnormal imprinting of the KCN1OT gene. Am J Hum Genet 2003;72(5):1338-41. (In eng). DOI: 10.1086/374824.

10.Halliday J, Oke K, Breheny S, Algar E, D JA. Beckwith-Wiedemann syndrome and IVF: a case-control study. Am J Hum Genet 2004;75(3):526-8. (In eng). DOI: 10.1086/423902.

11.Vermeiden JP, Bernardus RE. Are imprinting disorders more prevalent after human in vitro fertilization or intracytoplasmic sperm injection? Fertil Steril 2013;99(3):642-51. (In eng). DOI: 10.1016/j.fertnstert.2013.01.125.

12.Hattori H, Hiura H, Kitamura A, et al. Association of four imprinting disorders and ART. Clin Epigenetics 2019;11(1):21. (In eng). DOI: 10.1186/s13148-019-0623-3.

13.Uk A, Collardeau-Frachon S, Scanvion Q, Michon L, Amar E. Assisted Reproductive Technologies and imprinting disorders: Results of a study from a French congenital malformations registry. Eur J Med Genet 2018;61(9):518-523. (In eng). DOI: 10.1016/j.ejmg.2018.05.017.

14.Gosden R, Trasler J, Lucifero D, Faddy M. Rare congenital disorders, imprinted genes, and assisted reproductive technology. Lancet 2003;361(9373):1975-7. (In eng). DOI: 10.1016/s0140-6736(03)13592-1.

15.Haham LM, Avrahami I, Domniz N, et al. Preimplantation genetic diagnosis versus prenatal diagnosis-decision-making among pregnant FMR1 premutation carriers. J Assist Reprod Genet 2018;35(11):2071-2075. (In eng). DOI: 10.1007/s10815-018-1293-3.

16.Pastore LM, Christianson MS, McGuinness B, Vaught KC, Maher JY, Kearns WG. Does theFMR1 gene affect IVF success? Reprod Biomed Online 2019;38(4):560-569. (In eng). DOI: 10.1016/j.rbmo.2018.11.009.

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18.Gleicher N, Albertini DF, Barad DH, et al. The 2019 PGDIS position statement on transfer of mosaic embryos within a context of new information on PGT-A. Reprod Biol Endocrinol 2020;18(1):57. (In eng). DOI: 10.1186/s12958-020-00616-w.

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25.Rizzo G, Aiello E, Pietrolucci ME, Arduini D. Are There Differences in Placental Volume and Uterine Artery Doppler in Pregnancies Resulting From the Transfer of Fresh Versus Frozen-Thawed Embryos Through In Vitro Fertilization. Reprod Sci 2016;23(10):1381-6. (In eng). DOI: 10.1177/1933719116641765.

26.White K, Wang Y, Kunz LH, Schmid M. Factors associated with obtaining results on repeat cell-free DNA testing in samples redrawn due to insufficient fetal fraction. J Matern Fetal Neonatal Med 2019:1-6. (In eng). DOI: 10.1080/14767058.2019.1594190.

27.Qin JB, Sheng XQ, Wang H, et al. Worldwide prevalence of adverse pregnancy outcomes associated with in vitro fertilization/intracytoplasmic sperm injection among multiple births: a systematic review and meta-analysis based on cohort studies. Arch Gynecol Obstet 2017;295(3):577-597. (In eng). DOI: 10.1007/s00404-017-4291-2.

28.Committee Opinion No. 719: Multifetal Pregnancy Reduction. Obstet Gynecol 2017;130(3):e158-e163. (In eng). DOI: 10.1097/aog.0000000000002302.

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31.Hoorsan H, Mirmiran P, Chaichian S, Moradi Y, Hoorsan R, Jesmi F. Congenital Malformations in Infants of Mothers Undergoing Assisted Reproductive Technologies: A Systematic Review and Meta-analysis Study. J Prev Med Public Health 2017;50(6):347-360. (In eng). DOI: 10.3961/jpmph.16.122.

32.Wen J, Jiang J, Ding C, et al. Birth defects in children conceived by in vitro fertilization and intracytoplasmic sperm injection: a meta-analysis. Fertil Steril 2012;97(6):1331-7.e1-4. (In eng). DOI: 10.1016/j.fertnstert.2012.02.053.

Articles

This Consult discusses the management of pregnancies achieved with in vitro fertilization and provides recommendations based on the available evidence. 

Alessandro Ghidini, MD

Articles

SMFM Consult Series #60: Management of pregnancies resulting from IVF