Children born after assisted fertilization have an increased rate of major congenital anomalies

doi:10.1016/j.fertnstert.2005.03.085

Fertility and Sterility

Volume 84, Issue 5, November 2005, Pages 1300-1307

Presented at the Conference of Health Technology Assessment International, May 30–June 2, 2004, Krakow, Poland.

https://doi.org/10.1016/j.fertnstert.2005.03.085 Get rights and content

Objective

To study the occurrence of major congenital anomalies (CAs) among children born after IVF (IVF, microinjections, and frozen embryo transfers) and after ovulation inductions with or without insemination (other assisted reproductive technologies [ART]).

Design

Setting

Data regarding CAs were obtained from the Register of Congenital Malformations.

Patient(s)

Children from IVF (n = 4,559), children from other ART (n = 4,467), and controls (n = 27,078, a random sample of naturally conceived children) from the Medical Birth Register.

Intervention(s)

In vitro fertilization and other ART treatment in ordinary practice.

Main Outcome Measure(s)

Rate of major CAs. Children from IVF and other ART were compared with control children, both overall and by plurality, controlling for confounding factors by logistic regression.

Result(s)

For IVF children, the adjusted odds ratio (OR) was 1.3 (95% confidence interval [CI], 1.1–1.6). Stratifying by gender and plurality showed that the risk was only increased for boys, and the risk was decreased for multiple IVF girls (OR = 0.5, 95% CI 0.2–0.9). The crude OR of major CA for other ART children was 1.3 (95% CI 1.1–1.5), but adjusted differences by gender and plurality were statistically insignificant.

Conclusion(s)

In vitro fertilization was associated with an increased risk for major CAs among singleton boys and a decreased risk among multiple girls. The risk after other ART was only slightly increased.

Section snippets

Materials and methods

The study is based on children born to women having received IVF (IVF, ICSI, and FET) and other ART between 1996 and 1998 in Finland. The women were identified with a predesigned algorithm from the reimbursement files of the Social Insurance Institution (15) and linked to the Finnish Medical Birth Register (MBR); the time difference between the beginning of the last treatment cycle and the birth of the child was used to estimate which infants resulted from IVF or other ART (16).

The MBR includes

Results

In vitro fertilization and other ART mothers differed from control mothers, and IVF mothers from other ART mothers in regard to most characteristics (Table 1). Multiplicity was much higher in the IVF than in the other ART group, but the number of triplets was the same (16 vs. 17).

Among IVF and other ART children, 51% of reported major CAs had been accepted by the RCM, whereas among control children the proportion was 46%. In total, 195 IVF children (4.3%), 166 other ART children (3.7%), and 787

Discussion

We found increased total rates of major CAs for IVF and other ART singletons. Singleton boys from IVF in particular had more major urogenital and musculoskeletal CAs, and other ART singleton girls had more major heart anomalies. Among multiples, the total risk for a major CA was not increased, and for multiple IVF girls the risk had even decreased.

Can our results be trusted? Our data include most infants born as a result of IVF and other ART in Finland during the study period. The

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Congenital malformations in 4224 children conceived after IVF
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Incidence of congenital malformations in children born after ICSI
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Congenital malformations in infants born after IVFa population-based study
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The risk of major birth defects after intracytoplasmic sperm injection and in vitro fertilization
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Neonatal outcome and congenital malformations in children born after in vitro fertilization

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Pregnancy course and outcome after intracytoplasmic sperm injectiona controlled, prospective cohort study

Fertil Steril

(2004)

Cited by (162)

A systematic review of genome-wide analyses of methylation changes associated with assisted reproductive technologies in various tissues
2024, Fertility and Sterility
Because analytic technologies improve, increasing amounts of data on methylation differences between assisted reproductive technology (ART) and unassisted conceptions are available. However, various studies use different tissue types and different populations in their analyses, making data comparison and integration difficult.
To compare and integrate data on genome-wide analyses of methylation differences due to ART, allowing exposure of overarching themes.
All studies undertaking genome-wide analysis of human methylation differences due to ART or infertility in any tissue type across the lifespan were assessed for inclusion.
Seventeen studies were identified that met the inclusion criteria. One study assessed trophectoderm biopsies, 2 first-trimester placenta, 1 first-trimester fetal tissue, 2 term placenta, 7 cord blood, 3 newborn dried blood spots, 1 childhood buccal smears, 1 childhood peripheral blood, and 2 adult peripheral blood. Eleven studies compared tissues from in vitro fertilization (IVF) conceptions with those of unassisted conceptions, 4 compared intracytoplasmic sperm injection with unassisted conceptions, 4 compared non-IVF fertility treatment (NIFT) with unassisted conceptions, 4 compared NIFT with IVF, and 5 compared an infertile population (conceiving via various methods) with an unassisted presumably fertile population. In studies assessing placental tissue, 1 gene with potential methylation changes due to IVF when compared with unassisted conceptions was identified by 2 studies. In blood, 11 potential genes with methylation changes due to IVF compared with unassisted conceptions were identified by 2 studies, 1 of which was identified by 3 studies. Three potentially affected genes were identified by 2 studies involving blood between intracytoplasmic sperm injection and unassisted populations. There were no overlapping genes identified in any tissue type between NIFT and unassisted populations, between NIFT and IVF, or the infertility combined population when compared with the unassisted fertile population.
Comparing studies is challenging due to differing variables between analyses. However, even in similar tissue types and populations, overlapping methylation changes are limited, suggesting that differences due to ART are minimal.
Information from this systematic review is significant for providers and patients who provide and use ART to understand methylation risks that may be associated with the technology.
Revisión sistemática de los análisis de genoma completo de los cambios de metilación asociados con las tecnologías de reproducción asistida en varios tejidos.
A medida que las tecnologías analíticas mejoran, cada vez hay más datos disponibles sobre las diferencias de metilación entre las tecnologías de reproducción asistida (ART) y la concepción sin asistencia. Sin embargo, varios estudios utilizan diferentes tipos de tejido y diferentes poblaciones en sus análisis, lo que dificulta la comparación e integración de datos.
Comparar e integrar datos sobre análisis de genoma completo de las diferencias de metilación debidas al ART, permitiendo la exposición de temas generales.
todos los estudios que realizan análisis de las diferencias de metilación humanas en genoma completo debido al ART o la infertilidad en cualquier tipo de tejido a lo largo de la vida fueron evaluados para su inclusión.
Se identificaron diecisiete estudios que cumplieron con los criterios de inclusión. Un estudio evaluó biopsias de trofectodermo, dos la placenta en el primer trimestre, uno el tejido fetal del primer trimestre, dos la placenta a término, siete la sangre del cordón umbilical, tres gotas de sangre seca de recién nacido, uno frotis bucal infantil, otro frotis de sangre periférica infantil y dos sangre periférica de adulto. Once estudios compararon tejidos procedentes de fecundación in vitro (IVF) con los de concepciones no asistidas, cuatro compararon la inyección intracitoplasmática de espermatozoides con concepciones no asistidas, cuatro compararon el tratamiento de fertilidad sin FIV (NIFT) con concepciones sin asistencia, cuatro compararon NIFT con FIV y cinco compararon una población infértil (concepción mediante varios métodos) con una población presumiblemente fértil sin asistencia. En estudios que evalúan el tejido placentario, un gen con posibles cambios de metilación debido al IVF cuando fueron comparados con las concepciones sin asistencia fue identificado en dos estudios. En sangre, once genes con cambios potenciales de metilación debido al IVF comparado con la concepción sin asistencia fue identificada por dos estudios, uno de los cuales fue identificado por tres estudios. Tres genes potencialmente afectados fueron identificados mediante dos estudios basados en sangre entre poblaciones con inyección intracitoplasmática de espermatozoides y no asistidas. No había genes solapantes identificados en ningún tipo de tejido entre NIFT y poblaciones no asistidas, entre NIFT y IVF, o la población de infertilidad cuando se compararon con la población fértil no asistida.
Comparar estudios es un desafío debido a las diferentes variables entre los análisis. Sin embargo, incluso en tipos de tejido y poblaciones similares, los cambios de metilación solapantes son limitados, lo que sugiere que las diferencias debidas al ART son mínimas.
La información de esta revisión sistemática es importante para que los proveedores y pacientes que proveen y utilizan ART comprendan que los riesgos de metilación pueden estar asociados con la tecnología.
Infertility and treatments used have minimal effects on first-trimester placental DNA methylation and gene expression
2023, Fertility and Sterility
To determine whether deoxyribonucleic acid (DNA) methylation alterations exist in the first-trimester human placenta between conceptions using fertility treatments and those that do not and, if so, whether they are the result of underlying infertility or fertility treatments. We also assessed whether significant alterations led to changes in gene expression.
We compared DNA methylation of the first-trimester placenta from singleton pregnancies that resulted in live births from unassisted, in vitro fertilization (IVF), and non–IVF fertility treatment (NIFT) conceptions using the Infinium MethylationEPIC BeadChip array. Significant CpG sites were compared with corresponding ribonucleic acid sequencing analysis in similar cohorts to determine whether methylation alterations lead to differences in gene expression.
Academic medical center.
A total of 138 singleton pregnancies undergoing chorionic villus sampling resulting in a live birth were recruited for methylation analysis (56 unassisted, 38 NIFT, and 44 IVF conceptions). Ribonucleic acid-sequencing data consisted of 141 subjects (74 unassisted, 33 NIFT, and 34 IVF conceptions) of which 116 overlapped with the methylation cohort.
In vitro fertilization–conceived pregnancy or pregnancy conceived via NIFT, such as ovulation induction and intrauterine insemination.
Significant methylation changes at CpG sites after adjustment for multiple comparisons. The secondary outcome was gene expression changes of significant CpG sites.
Of the 741,145 probes analyzed in the placenta, few were significant at Bonferroni <0.05: 185 CpG sites (0.025%) significant in pregnancies conceived with the fertility treatments (NIFT + IVF) vs. unassisted conceptions; 28 in NIFT vs. unassisted; 195 in IVF vs. unassisted; and only 13 (0.0018%) in IVF vs. NIFT conceptions. Of all significant CpG sites combined, 10% (35) were located in genes with suggestive gene expression changes, but none were significant after adjustment for multiple comparisons (ribonucleic acid sequencing false discovery rate <0.05). None of the 13 differentially methylated probes in the IVF vs. NIFT placenta were located in genes with suggestive IVF vs. NIFT gene expression differences.
Underlying infertility is the most significant contributor to the minimal differences in first-trimester placental methylation, and not the specific fertility treatment used, such as IVF.
La infertilidad y los tratamientos utilizados tienen efectos mínimos en la expresión génica y la metilación del ADN placentario del primer trimestre.
Determinar si existen alteraciones en la metilación del ácido desoxirribonucleico (ADN) en la placenta humana del primer trimestre entre las concepciones que utilizan tratamientos de fertilidad y las que no lo hacen y, de ser así, si son el resultado de una infertilidad subyacente o de los tratamientos de fertilidad. También evaluamos si alteraciones significativas llevaron a cambios en la expresión génica.
Comparamos la metilación del ADN de la placenta del primer trimestre de embarazos únicos que resultaron en nacidos vivos de embarazos sin tratamientos, con fertilización in vitro (FIV) y con tratamiento de fertilidad sin FIV (NIFT) usando el test Infinium MethylationEPIC BeadChip . Los sitios CpG significativos se compararon con el análisis de secuenciación de ácido ribonucleico correspondiente en cohortes similares para determinar si las alteraciones de la metilación conducen a diferencias en la expresión génica.
Centro médico académico.
Se reclutaron un total de 138 embarazos únicos que resultaron en nacido vivo a los que se les realizó una muestra de vellosidades coriónicas para análisis de metilación (56 espontáneos, 38 NIFT y 44 embarazos de FIV). Los datos de secuenciación de ácido ribonucleico consistieron en 141 sujetos (74 embarazos espontáneos, 33 NIFT y 34 FIV) de las cuales 116 se superpusieron con la cohorte de metilación.
Embarazo concebido por fertilización in vitro o embarazo concebido mediante NIFT, como inducción de la ovulación e inseminación intrauterina.
Cambios de metilación significativos en los sitios CpG después del ajuste para comparaciones múltiples. El resultado secundario fue cambios en la expresión génica de sitios CpG significativos.
De las 741.145 sondas analizadas en la placenta, pocas fueron significativas en Bonferroni <0,05: 185 sitios CpG (0,025 %) fueron significativos en embarazos concebidos con los tratamientos de fertilidad (NIFT y FIV) comparadas con embarazos espontáneos; 28 en NIFT comparadas con espontáneos; 195 en FIV comparado con espontáneo; y solo 13 (0,0018%) en concepciones con FIV comparado con NIFT. De todos los sitios CpG significativos combinados, el 10% (35) se ubicaron en genes con cambios sugestivos en la expresión génica, pero ninguno fue significativo luego del ajuste para comparaciones múltiples (índice menor 0.05 de descubrimiento de falsas secuencias de ácido ribonucleico). Ninguna de las 13 sondas diferencialmente metiladas en la placenta de FIV vs NIFT fueron localizadas en genes con diferencia sugestiva de expresión génica por FIV comparado con NIFT.
La infertilidad subyacente es el contribuidor más significativo a las diferencias mínimas en la metilación de la placenta del primer trimestre, y no el tratamiento específico usado, como FIV.
Assisted reproductive technologies and the risk of congenital urogenital tract malformations: A systematic review and meta-analysis
2021, Journal of Pediatric Urology
A systematic review was conducted to evaluate the relationship between ART and the risk of urogenital tract malformations, especially hypospadias and cryptorchidism. Thirty-three papers were selected. Meta-analysis showed that ART was correlated with an increased risk of urogenital tract malformation in offspring (odds ratio (OR) = 1.61, 95% confidence interval (CI): 1.41–1.85), hypospadias (OR = 1.87, 95% CI: 1.47–2.40) and cryptorchidism (OR = 1.83, 95% CI: 1.54–2.18). Among offspring conceived by ART, multiple pregnancies appeared to result in a higher risk of urogenital tract malformation than singleton pregnancies (OR = 1.42, 95% CI: 0.99–2.04; P = 0.058). No significant difference in the risk of urogenital tract malformation was found between in vitro fertilization and intracytoplasmic sperm injection technologies. A sensitivity analysis showed that the above conclusions were relatively consistent. Conclusion: ART is correlated with an increased risk of urogenital tract malformations in offspring, especially hypospadias and cryptorchidism. Among ART offspring, multiple pregnancies may lead to a higher risk of urogenital tract malformations than singleton pregnancies, but more studies are needed for confirmation.
Speech and language development of children born following assisted reproductive technologies
2020, International Journal of Pediatric Otorhinolaryngology
Studies which targeted communication skills of children born following assisted reproductive technologies have reported contradictory results. Concerning the increasing rates of children born in these technologies and the importance of some factors as risk factors like birth weight, gestational age, and the number of children per birth in these procedures, studying speech and language skills is critical. So, the current study aimed to investigate the speech and language capabilities of Persian speaking children born following these procedures.
A descriptive and cross-sectional study was carried out in Babol city in 2016–2017 to investigate the receptive and expressive language and speech of Persian speaking children born in assisted reproductive technologies in the age range of 6–72 months. Parents of 78 children completed the Newsha Developmental Scale to assess language and speech skills. Then, the language and speech performance of the participants were compared in terms of gestational age, birth weight, number of children per birth, and sex in the current research and they are categorized as normal or having delay in language and speech development.
The participants had statistically significant difference for the receptive language in terms of gestational age (χ² (1) = 5.76, p = 0.01) and birth weight (χ² (1) = 8.22, p = 0.004) but in terms of the number of children per birth (χ² (1) = 7.11, p = 0.009) and sex (χ² (1) = 0.037, p = 0.84) did not have statistically significant difference. The children did not show significant difference for the expressive language in terms of gestational age (χ² (1) = 1.09, p = 0.29), birth weight (χ² (1) = 0.34, p = 0.55), the number of children per birth (χ² (1) = 1.58, p = 0.2), and sex (χ2 (1) = 0.037, p = 0.84). The participants of the present study did not have statistically significant difference in speech in terms of gestational age (χ² (1) = 2.82, p = 0.09), the number of children per birth (χ² (1) = 3.57, p = 0.06), and sex (χ2 (1) = 0.06, p = 0.79). They had significant difference in speech only in terms of birth weight (χ² (1) = 4.13, p = 0.04).
Based on the results of the administration of the Newsha Developmental Scale as a screening tool, it seems that some factors like sex and number of children per birth do not affect speech and language performance of children born following ART. Another factor including gestational age and birth weight had effects on some domains. It is essential to design longitudinal studies to follow the speech and language performance of this population.
Associations between embryo grading and congenital malformations in IVF/ICSI pregnancies
2019, Reproductive BioMedicine Online
Does the quality of transferred embryos have an impact on the rate of congenital malformations in IVF/intracytoplasmic sperm injection (ICSI)-conceived babies?
Retrospective cohort study involving 6637 pregnancies of ≥20 weeks’ gestation from women undergoing embryo transfer with a single Day 5 embryo at a private multisite IVF clinic between 2005 and 2015. Embryos were classified as good quality (n = 5537) or poor quality (n = 1100) based on an internal grading system of morphological parameters; malformation rates were compared.
In pregnancies proceeding to delivery (≥20 weeks’ gestation), poor quality embryos were associated with increased odds of at least one anomaly (adjusted odds ratio [OR] 1.33, 95% confidence interval [CI] 1.03–1.71), major anomalies (adjusted OR 1.42, 95% CI 1.05–1.91), musculoskeletal anomalies (adjusted OR 2.09, 95% CI 1.35–3.22), particularly talipes (adjusted OR 2.88, 95% CI 1.33–6.25), and the International Classification of Diseases (ICD) classification ‘Other congenital malformations’ (adjusted OR 2.34, 95% CI 1.13–4.34). Furthermore, for pregnancies ≥9 weeks’ gestation, poor embryos had more than double the odds of chromosomal anomalies than good embryos (adjusted OR 2.33, 95% CI 1.30–4.18, P = 0.005).
This is the first study to compare the rates of individual congenital malformations for good and poor quality embryos. It provides insight into potential risks of transferring poor quality embryos. In pregnancies ≥20 weeks’ gestation, poor quality Day 5 embryos are associated with major malformations, at least one anomaly, musculoskeletal anomalies, talipes and the ICD classification ‘Other congenital malformations’. In pregnancies ≥9 weeks’ gestation, poor quality Day 5 embryos are associated with chromosomal anomalies.
Differential gene expression during placentation in pregnancies conceived with different fertility treatments compared with spontaneous pregnancies
2019, Fertility and Sterility
To identify differences in the transcriptomic profiles during placentation from pregnancies conceived spontaneously vs. those with infertility using non-in vitro fertilization (IVF) fertility treatment (NIFT) or IVF.
Cohort study.
Academic medical center.
Women undergoing chorionic villus sampling at gestational age 11–13 weeks (n = 141), with pregnancies that were conceived spontaneously (n = 74), with NIFT (n = 33), or with IVF (n = 34), resulting in the delivery of viable offspring.
Collection of chorionic villus samples from women who conceived spontaneously, with NIFT, or with IVF for gene expression analysis using RNA sequencing.
Baseline maternal, paternal, and fetal demographics, maternal medical conditions, pregnancy complications, and outcomes. Differential gene expression of first-trimester placenta.
There were few differences in the transcriptome of first-trimester placenta from NIFT, IVF, and spontaneous pregnancies. There was one protein-coding differentially expressed gene (DEG) between the spontaneous and infertility groups, CACNA1I, one protein-coding DEG between the spontaneous and IVF groups, CACNA1I, and five protein-coding DEGs between the NIFT and IVF groups, SLC18A2, CCL21, FXYD2, PAEP, and DNER.
This is the first and largest study looking at transcriptomic profiles of first-trimester placenta demonstrating similar transcriptomic profiles in pregnancies conceived using NIFT or IVF and spontaneous conceptions. Gene expression differences found to be highest in the NIFT group suggest that the underlying infertility, in addition to treatment-related factors, may contribute to the observed gene expression profiles.
Expresión génica diferencial durante la placentación de embarazos concebidos con diferentes tratamientos de fertilidad en comparación con embarazos espontáneos
identificar las diferencias en los perfiles transcriptómicos durante la placentación de embarazos concebidos espontáneamente frente a aquellos con infertilidad que utilizan el tratamiento de fertilidad (FIV) sin fertilización in vitro (NIFT) o FIV.
Estudio de cohorte.
Centro médico académico.
mujeres sometidas a muestreo de vellosidades coriónicas en edad gestacional de 11–13 semanas (n = 141), con embarazos que fueron concebidos espontáneamente (n = 74), con NIFT (n = 33), o con FIV (n = 34), resultantes en partos con descendencias viables.
colección de muestras de vellosidades coriónicas de mujeres que concibieron espontáneamente, con NIFT o con FIV para el análisis de la expresión génica mediante secuenciación de ARN.
datos demográficos maternos, paternos y fetales de referencia, estado médico materno, complicaciones del embarazo y resultados. Expresión génica diferencial de la placenta del primer trimestre.
Hubo pocas diferencias en el transcriptoma de la placenta del primer trimestre de NIFT, IVF y embarazos espontáneos. Hubo expresión diferencial de un gen codificador de proteínas (DEG) entre los grupos espontáneos y de infertilidad, CACNA1I, un codificador DEG de proteínas entre los grupos espontáneos y de FIV, CACNA1I, y cinco codificadores DEG de proteínas entre los grupos NIFT e IVF, SLC18A2, CCL21, FXYD2, PAEP y DNER.
Este es el primer estudio y el más grande que analiza los perfiles transcriptómicos de la placenta del primer trimestre y que demuestra perfiles transcriptómicos similares en embarazos concebidos con NIFT o FIV y concepciones espontáneas.

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: Supported by the Academy of Finland, the Ministry of Education, and the National Research and Development Centre for Welfare and Health.

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ControversyIs IVF associated with an increased rate of birth defects?Children born after assisted fertilization have an increased rate of major congenital anomalies

Objective

Design

Setting

Patient(s)

Intervention(s)

Main Outcome Measure(s)

Result(s)

Conclusion(s)

Section snippets

Materials and methods

Results

Discussion

Lancet

Am J Obstet Gynecol

Lancet

Obstet Gynecol

J Urol

Hedelmällisyys Suomessa ennen, nyt ja tulevaisuudessa. (Fertility in Finland in the past, present and future.)

Yhteiskuntapolitiikka

Congenital malformations in 4224 children conceived after IVF

Hum Reprod

Incidence of congenital malformations in children born after ICSI

Hum Reprod

Congenital malformations in infants born after IVFa population-based study

Hum Reprod

The risk of major birth defects after intracytoplasmic sperm injection and in vitro fertilization

N Engl J Med

Neonatal outcome and congenital malformations in children born after in vitro fertilization

Hum Reprod

Pregnancy course and outcome after intracytoplasmic sperm injectiona controlled, prospective cohort study

Fertil Steril

Controversy
Is IVF associated with an increased rate of birth defects?
Children born after assisted fertilization have an increased rate of major congenital anomalies