This Consult discusses the management of pregnancies achieved with in vitro fertilization and provides recommendations based on the available evidence.
Assisted reproductive technology (ART) now accounts for 1.6% of all infants and 18.3% of all multiple-birth infants in the United States.1 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.
The IVF procedure itself does not appear to lead to a higher prevalence of chromosomal anomalies when compared with naturally occurring pregnancy.2,3 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.4,5
Other factors may play a role in the increased risk of chromosomal anomalies in IVF pregnancies, including advanced maternal age, polycystic ovary syndrome,6,7 and severe male and female factor infertility. Imprinting syndromes, including Beckwith-Wiedemann syndrome (BWS),8-11 Angelman/Prader Willi syndrome (PWS), and Russell-Silver syndrome,12,13are thought to occur more frequently in the offspring of subfertile parents,14 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 FMR1 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.15,16
The types of preimplantation genetic testing (PFT) are as follows:
For both PGT-M and PGT-SR, it is recommended that a confirmatory diagnostic test be offered during the pregnancy.21 Many patients, however, do not wish to pursue invasive testing after PGT.
If euploid embryos are unavailable, aneuploid mosaic embryos are sometimes transferred.22 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.23
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.24
Lower fetal fraction (FF) has been reported with cfDNA in IVF pregnancies,25 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).26
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.
Multifetal pregnancy reduction has been shown to significantly reduce the risks of preterm birth, neonatal morbidity, and maternal complications.28,29
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.30-32 It is also difficult to distinguish the risk associated with IVF alone versus IVF with ICSI.
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.35,36
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.
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.38,39 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.
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.40
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.41 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.
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.
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.41,44-46
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.
IVF and underlying infertility are associated with adverse perinatal outcomes, including hypertensive disorders of pregnancy.47 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.48
Pregnancies achieved with IVF have a two to three-fold increased risk of stillbirth even after controlling for maternal age, parity, and multifetal gestations.40,49-51
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.53
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.
References
1.Sunderam S, Kissin DM, Crawford SB, et al. Assisted Reproductive Technology Surveillance - United States, 2014. MMWR Surveill Summ 2017;66(6):1-24. (In eng). DOI: 10.15585/mmwr.ss6606a1.
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.
17.Katagiri Y, Tamaki Y. Genetic counseling prior to assisted reproductive technology. Reprod Med Biol 2021;20(2):133-143. (In eng). DOI: 10.1002/rmb2.12361.
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.
19.Sciorio R, Dattilo M. PGT-A preimplantation genetic testing for aneuploidies and embryo selection in routine ART cycles: Time to step back? Clin Genet 2020;98(2):107-115. (In eng). DOI: 10.1111/cge.13732.
20.Carson SA, Kallen AN. Diagnosis and Management of Infertility: A Review. Jama 2021;326(1):65-76. (In eng). DOI: 10.1001/jama.2021.4788.
21.Preimplantation Genetic Testing: ACOG Committee Opinion, Number 799. Obstet Gynecol 2020;135(3):e133-e137. (In eng). DOI: 10.1097/aog.0000000000003714.
22.Greco E, Minasi MG, Fiorentino F. Healthy Babies after Intrauterine Transfer of Mosaic Aneuploid Blastocysts. N Engl J Med 2015;373(21):2089-90. (In eng). DOI: 10.1056/NEJMc1500421.
23.Clinical management of mosaic results from preimplantation genetic testing for aneuploidy (PGT-A) of blastocysts: a committee opinion. Fertil Steril 2020;114(2):246-254. (In eng). DOI: 10.1016/j.fertnstert.2020.05.014.
24.Gjerris AC, Tabor A, Loft A, Christiansen M, Pinborg A. First trimester prenatal screening among women pregnant after IVF/ICSI. Hum Reprod Update 2012;18(4):350-9. (In eng). DOI: 10.1093/humupd/dms010.
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.
29.Hviid KVR, Malchau SS, Pinborg A, Nielsen HS. Determinants of monozygotic twinning in ART: a systematic review and a meta-analysis. Hum Reprod Update 2018;24(4):468-483. (In eng). DOI: 10.1093/humupd/dmy006.
30.Chen L, Yang T, Zheng Z, Yu H, Wang H, Qin J. Birth prevalence of congenital malformations in singleton pregnancies resulting from in vitro fertilization/intracytoplasmic sperm injection worldwide: a systematic review and meta-analysis. Arch Gynecol Obstet 2018;297(5):1115-1130. (In eng). DOI: 10.1007/s00404-018-4712-x.
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.
33.AIUM Practice Parameter for the Performance of Detailed Second- and Third-Trimester Diagnostic Obstetric Ultrasound Examinations. J Ultrasound Med 2019;38(12):3093-3100. (In eng). DOI: 10.1002/jum.15163.
34.Giorgione V, Parazzini F, Fesslova V, et al. Congenital heart defects in IVF/ICSI pregnancy: systematic review and meta-analysis. Ultrasound Obstet Gynecol 2018;51(1):33-42. (In eng). DOI: 10.1002/uog.18932.
35.Bjorkman KR, Bjorkman SH, Ferdman DJ, Sfakianaki AK, Copel JA, Bahtiyar MO. Utility of routine screening fetal echocardiogram in pregnancies conceived by in vitro fertilization. Fertility and Sterility 2021. DOI: https://doi.org/10.1016/j.fertnstert.2021.04.035.
36.Chung EH, Lim SL, Havrilesky LJ, Steiner AZ, Dotters-Katz SK. Cost-effectiveness of prenatal screening methods for congenital heart defects in pregnancies conceived by in-vitro fertilization. Ultrasound Obstet Gynecol 2021;57(6):979-986. (In eng). DOI: 10.1002/uog.22048.
37.AIUM Practice Parameter for the Performance of Fetal Echocardiography. J Ultrasound Med 2020;39(1):E5-e16. (In eng). DOI: 10.1002/jum.15188.
38.Sinkey RG, Odibo AO, Dashe JS. #37: Diagnosis and management of vasa previa. Am J Obstet Gynecol 2015;213(5):615-9. (In eng). DOI: 10.1016/j.ajog.2015.08.031.
39.Sullivan EA, Javid N, Duncombe G, et al. Vasa Previa Diagnosis, Clinical Practice, and Outcomes in Australia. Obstet Gynecol 2017;130(3):591-598. (In eng). DOI: 10.1097/aog.0000000000002198.
40.Jackson RA, Gibson KA, Wu YW, Croughan MS. Perinatal outcomes in singletons following in vitro fertilization: a meta-analysis. Obstet Gynecol 2004;103(3):551-63. (In eng). DOI: 10.1097/01.Aog.0000114989.84822.51.
41.Pinborg A, Wennerholm UB, Romundstad LB, et al. Why do singletons conceived after assisted reproduction technology have adverse perinatal outcome? Systematic review and meta-analysis. Hum Reprod Update 2013;19(2):87-104. (In eng). DOI: 10.1093/humupd/dms044.
42.Prediction and Prevention of Spontaneous Preterm Birth: ACOG Practice Bulletin, Number 234. Obstet Gynecol 2021;138(2):e65-e90. (In eng). DOI: 10.1097/aog.0000000000004479.
43.McIntosh J, Feltovich H, Berghella V, Manuck T. The role of routine cervical length screening in selected high- and low-risk women for preterm birth prevention. Am J Obstet Gynecol 2016;215(3):B2-7. (In eng). DOI: 10.1016/j.ajog.2016.04.027.
44.Maheshwari A, Pandey S, Shetty A, Hamilton M, Bhattacharya S. Obstetric and perinatal outcomes in singleton pregnancies resulting from the transfer of frozen thawed versus fresh embryos generated through in vitro fertilization treatment: a systematic review and meta-analysis. Fertil Steril 2012;98(2):368-77.e1-9. (In eng). DOI: 10.1016/j.fertnstert.2012.05.019.
45.Sha T, Yin X, Cheng W, Massey IY. Pregnancy-related complications and perinatal outcomes resulting from transfer of cryopreserved versus fresh embryos in vitro fertilization: a meta-analysis. Fertil Steril 2018;109(2):330-342.e9. (In eng). DOI: 10.1016/j.fertnstert.2017.10.019.
46.Wennerholm UB, Henningsen AK, Romundstad LB, et al. Perinatal outcomes of children born after frozen-thawed embryo transfer: a Nordic cohort study from the CoNARTaS group. Hum Reprod 2013;28(9):2545-53. (In eng). DOI: 10.1093/humrep/det272.
47.Tandberg A, Klungsoyr K, Romundstad LB, Skjaerven R. Pre-eclampsia and assisted reproductive technologies: consequences of advanced maternal age, interbirth intervals, new partner and smoking habits. BJOG 2015;122(7):915-22. DOI: 10.1111/1471-0528.13051.
48.Davidson KW, Barry MJ, Mangione CM, et al. Aspirin Use to Prevent Preeclampsia and Related Morbidity and Mortality: US Preventive Services Task Force Recommendation Statement. Jama 2021;326(12):1186-1191. (In eng). DOI: 10.1001/jama.2021.14781.
49.Bay B, Boie S, Kesmodel US. Risk of stillbirth in low-risk singleton term pregnancies following fertility treatment: a national cohort study. BJOG 2019;126(2):253-260. (In eng). DOI: 10.1111/1471-0528.15509.
50.Marino JL, Moore VM, Willson KJ, et al. Perinatal outcomes by mode of assisted conception and sub-fertility in an Australian data linkage cohort. PLoS One 2014;9(1):e80398. (In eng). DOI: 10.1371/journal.pone.0080398.
51.Wisborg K, Ingerslev HJ, Henriksen TB. IVF and stillbirth: a prospective follow-up study. Hum Reprod 2010;25(5):1312-6. (In eng). DOI: 10.1093/humrep/deq023.
52.Indications for Outpatient Antenatal Fetal Surveillance: ACOG Committee Opinion, Number 828. Obstet Gynecol 2021;137(6):e177-e197. (In eng). DOI: 10.1097/aog.0000000000004407.
53.Saccone G, Della Corte L, Maruotti GM, et al. Induction of labor at full-term in pregnant women with uncomplicated singleton pregnancy: A systematic review and meta-analysis of randomized trials. Acta Obstet Gynecol Scand 2019;98(8):958-966. (In eng). DOI: 10.1111/aogs.13561.
54.Lagrew DC, Kane Low L, Brennan R, et al. National Partnership for Maternal Safety: Consensus Bundle on Safe Reduction of Primary Cesarean Births-Supporting Intended Vaginal Births. J Obstet Gynecol Neonatal Nurs 2018;47(2):214-226. (In eng). DOI: 10.1016/j.jogn.2018.01.008.
Chemoattractants in fetal membranes enhance leukocyte migration near term pregnancy
November 22nd 2024A recent study highlights the release of chemoattractants from human fetal membranes at term, driving leukocyte activation and migration, with implications for labor and postpartum recovery.
Read More
S4E1: New RNA platform can predict pregnancy complications
February 11th 2022In this episode of Pap Talk, Contemporary OB/GYN® sat down with Maneesh Jain, CEO of Mirvie, and Michal Elovitz, MD, chief medical advisor at Mirvie, a new RNA platform that is able to predict pregnancy complications by revealing the biology of each pregnancy. They discussed recently published data regarding the platform's ability to predict preeclampsia and preterm birth.
Listen
Reproductive genetic carrier screening: A tool for reproductive decision-making
November 22nd 2024A new study highlights the efficacy of couple-based reproductive genetic carrier screening in improving reproductive decisions and outcomes, emphasizing its growing availability and acceptance among diverse populations.
Read More
Contemporary OB/GYN Senior Editor Angie DeRosa gets insight on the current state of COVID-19 from Christina Han, MD, division director of maternal-fetal medicine at the University of California, Los Angeles, and member of its COVID-19 task force. Han is an active member of the Society for Maternal-Fetal Medicine and discusses the issues on behalf of SMFM.
Listen
Early preterm birth risk linked to low PlGF levels during pregnancy screening
November 20th 2024New research highlights that low levels of placental growth factor during mid-pregnancy screening can effectively predict early preterm birth, offering a potential tool to enhance maternal and infant health outcomes.
Read More
Improved maternal cardiac arrest management reported from Obstetric Life Support training
November 19th 2024A study found that Obstetric Life Support education significantly improves health care providers' readiness and outcomes in maternal cardiac arrest management, advocating for broader implementation.
Read More