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.
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