Abstract
STUDY QUESTION
Is the health of singletons born after frozen embryo transfer (FET) comparable to that of singletons born after fresh embryo transfer (ET) until early adulthood?
SUMMARY ANSWER
The health of singletons born after FET does not differ from that of singletons born after fresh ET.
WHAT IS KNOWN ALREADY
The differences in perinatal outcomes of children born after FET and fresh ET are well known. FET is associated with an increased risk of large-for-gestational-age but diminished risks of preterm birth (PTB), small-for-gestational-age and decreased perinatal mortality compared to fresh ET. However, knowledge on the long-term health after FET is scarce.
STUDY DESIGN, SIZE, DURATION
This retrospective register-based cohort study compares singletons born after FET (n = 1825) between the years 1995 and 2006 to those born after fresh ET (n = 2933) and natural conception (NC, n = 31 136) with a mean follow-up time of 18–20 years.
PARTICIPANTS/MATERIALS, SETTING, METHODS
Singletons born after FET were compared to those born after fresh ET and NC regarding the frequencies of diagnoses in the main ICD-10 chapters (International Statistical Classification of Diseases and Related Health Problems, 10th revision), the number of outpatient visits and hospital admissions, and mortality. Adjustments were made for PTB, maternal age, parity, socioeconomic status based on mother’s occupation and offspring sex. The study combines data from the Finnish Medical Birth Register, the Finnish Care Register for Health Care (CRHC) and the Cause-of-Death Register at Statistics Finland. The Student’s T-test was used for continuous variables, and the Chi-square test was used for categorical variables. Cox regression was used to estimate crude and adjusted hazard ratios (HRs and aHRs, respectively). A general linear model was used to compare the means of outpatient visits, hospital admissions and lengths of hospital stays per person.
MAIN RESULTS AND THE ROLE OF CHANCE
No significant differences between the FET and fresh ET groups were found in the frequency of diagnoses in any of the ICD-10 chapters or in the parameters describing the need for hospital care. However, compared to the NC group, higher proportions in the FET group had outpatient visits in the hospital (93.5% vs 92.2%, aHR 1.23, 95% CI 1.17, 1.30) or hospital admissions (48% vs 46.5%, aHR 1.28, 95% CI 1.19, 1.37). Compared to the NC group, the FET group had elevated adjusted risks of diagnoses of infectious and parasitic diseases (aHR 1.24; 95% CI 1.11, 1.38), neoplasms (aHR 1.68; 95% CI 1.48, 1.91), diseases of the eye and adnexa, the ear or mastoid process (aHR 1.11; 95% CI 1.01, 1.21), the respiratory system (aHR 1.15; 95% CI 1.06, 1.23), the digestive system (aHR 1.17; 95% CI 1.05, 1.32), the skin or subcutaneous tissue (aHR 1.28; 95% CI 1.14, 1.43) and the genitourinary system (aHR 1.27; 95% CI 1.11, 1.45), as well as congenital malformations or chromosomal abnormalities (aHR 1.31; 95% CI 1.14, 1.50) and symptoms, signs or abnormal clinical or laboratory findings (aHR 1.25, 95% CI 1.16, 1.34).
LIMITATIONS, REASONS FOR CAUTION
Only hospital-based inpatient and outpatient care is covered by the CRHC register, excluding milder cases diagnosed elsewhere. We were not able to study the effect of ART treatments and subfertility separately in our setting. In addition, although our cohort is reasonably sized, even larger cohorts would be needed to reliably study rare outcomes, such as cancer.
WIDER IMPLICATIONS OF THE FINDINGS
For many ICD-10 chapters, we present the first published data on the long-term outcome of singletons born after FET. The results on FET versus fresh ET are reassuring, whereas the results on FET versus NC warrant further investigation.
STUDY FUNDING/COMPETING INTEREST(S)
Finnish government research funding was obtained for this study. Funding was also obtained from the Finnish Medical Society Duodecim, the Päivikki and Sakari Sohlberg Foundation, Orion Research Foundation, Finnish Society of Obstetrics and Gynaecology (research grants to A.M.T.) and Finnish government research funding. The funding sources were not involved in the planning or execution of the study. The authors have no competing interests to declare.
TRIAL REGISTRATION NUMBER
N/A.
Keywords: frozen embryo transfer, FET, ART, long-term health, outcome
Introduction
The health of children born after assisted reproduction is of major interest since already up to 6% of children born in European countries are the result of ARTs (Wyns et al., 2020). Frozen embryo transfers (FETs) are on a steep rise and comprise 32.6% of all ART treatment cycles in Europe. Delivery rates are higher for FET cycles per thawing than for fresh embryo transfer (ET) cycles per oocyte aspiration (Wyns et al., 2021). In Finland, nearly 50% of ART children are born after FET (THL, 2019).
Large cohort studies and meta-analyses have described the perinatal results. Singletons born after FET have a higher mean birthweight and a higher risk of large-for-gestational-age (LGA) compared to children born after fresh ET (Pelkonen et al., 2010; Maheshwari et al., 2018; Sha et al., 2018; Terho et al., 2021). In turn, the risks of preterm birth (PTB) and small-for-gestational-age (SGA) (Maheshwari et al., 2018; Sha et al., 2018) as well as perinatal mortality (Sha et al., 2018) are decreased for FET children compared to fresh ET children. Compared to children born from natural conception (NC), FET singletons have increased risks of LGA and PTB (Elias et al., 2020).
Long-term health data on children born after FET are scarce. Most studies have presented results on ART, fertility treatments or IVF compared to NC, and the possible effects of FET remain unclear (Wainstock et al., 2019; Wijs et al., 2021; Pettersson et al., 2022). In addition, previous studies have concentrated on outcomes of selected separate diagnoses, such as cancer (Spector et al., 2019; Zhang et al., 2020). Our previous study (Pelkonen et al., 2015) described widely the health results until the age of three and found the health of singleton children to be similar between FET and fresh ET groups, with ART children having slightly increased risks of hospital admission compared to NC children. The aim of this study is to provide a long-term follow-up until the age of 18 on singletons born after FET, based on Finnish high-quality population-based register data.
Materials and methods
Study population
The population of the present study includes preterm and term live-born singletons born after FET (n = 1825) and fresh ET (n = 2933) between the years 1995 and 2006 in Oulu and Helsinki city areas in Finland. A 10% sample of NC controls (n = 31 136) from the same birth years, matched for area of residence, was obtained from the Finnish Medical Birth Register (FMBR). This study is a continuation of previous studies by our study group covering the perinatal health (Pelkonen et al., 2010), major congenital anomalies (Pelkonen et al., 2014) and somatic health of children born after FET and fresh ET until the age of 3 (Pelkonen et al., 2015). This register-based cohort study combines data from the FMBR, as well as the Finnish Care Register for Health Care (CRHC) and the Cause-of-Death Register at Statistics Finland.
The Finnish Institute for Health and Welfare (THL) is responsible for the FMBR and the CRHC registers. The FMBR includes data on live births and on stillbirths of fetuses with a birth weight of at least 500 g or gestational age of at least 22 weeks, as well as data on the mothers. Data sources of the FMBR include maternity hospitals and neonatal units, the Finnish Central Population Register kept by the Digital and population data services agency and Statistics Finland. The CRHC covers hospital and other inpatient care, and outpatient visits in public hospitals for the purpose of statistics, research and planning. Care providers submit the mandatory care notifications on a yearly basis. The care notifications include data on the personal identity number of the patient, reason for seeking care, admission and discharge, diagnoses, procedures and interventions (THL, 2021).
The Cause of Death Register is maintained by Statistics Finland, and it produces yearly statistics on causes of death and mortality based on death certificates complemented with data on deaths from the Population Information System of the Digital and population data services agency (Official Statistics of Finland (OSF): Causes of death, 2022).
Data linkage between registers is possible using the unique personal identity numbers assigned to each Finnish citizen immediately at birth or upon immigration. The personal identity numbers are extensively used throughout the society: in healthcare, social welfare system, school system, banking etc. All data were pseudonymized after the register linkage and before analyses.
Study permission and ethical approval
Study permission was granted by Findata, the Social and Health Data Permit Authority. Separate ethical approval was not needed since the study was based on register data and no registered person was contacted.
Outcomes and statistical methods
The frequencies of diagnoses in the main ICD-10 chapters (International Statistical Classification of Diseases and Related Health Problems, 10th revision) were compared between the study groups, with the first occurring diagnosis in each chapter counted per person, not taking repeated events into account. Crude hazard ratios (HRs) and adjusted hazard ratios (aHRs) were calculated for each main ICD-10 diagnosis chapter for FET versus fresh ET, FET versus NC and fresh ET versus NC. Adjustments were made for PTB, maternal age, parity, socioeconomic status (SES) based on mother’s occupation and offspring sex.
In addition, the proportion of persons with outpatient visits and hospital admissions in each study group were compared. Outpatient visits in the hospital, hospital admissions and the lengths of hospital stay (days) per person were compared between the FET, fresh ET and NC groups. Mortality rates for each study group were calculated.
Background characteristics were described as mean and SD for continuous variables and as count and percentage for categorical variables. The Student’s T-test was used for continuous variables, and the Chi-square test was used for categorical variables. Cox regression was used to estimate HRs and aHRs. The follow-up started at birth and ended in the first appearance of the selected outcome, death or end of follow-up, 31 December 2020. A general linear model was used to compare the means of outpatient visits, hospital admissions and lengths of hospital stays per person.
All statistical analyses were performed using SAS statistical software, version 9.4 (SAS Institute).
Results
Background characteristics
The background characteristics for the study groups are presented in Table I. Mothers in the FET group were older (mean 34.3 years) compared to those of the fresh ET group (33.9 years) and were less often primiparous (34.8%) compared to those of the fresh ET group (52.3%). The number of PTBs in the FET group was lower (6.4%) compared to the fresh ET group (8.5%), and the percentage of LGA was significantly higher for FET (3.9%) compared to fresh ET (2.1%). The mean follow-up time was shorter for FET (18.8 years) compared to fresh ET (19.5 years) and NC (20.5 years).
Table I.
Background characteristics of the study population.
| Variable | FET | Fresh ET | NC | P | P | P |
|---|---|---|---|---|---|---|
| n = 1825 | n = 2933 | n = 31 136 | FET vs fresh ET | FET vs NC | fresh ET vs NC | |
| Maternal age, y, mean (SD) | 34.3 (4.0) | 33.9 (4.3) | 30.0 (5.4) | 0.009 | <0.001 | <0.001 |
| Missing, n (%) | 2 (0.1) | 0 (0) | 71 (0.2) | |||
| Primiparous, n (%) | 635 (34.8) | 1535 (52.3) | 9893 (31.8) | <0.001 | 0.007 | <0.001 |
| Missing (%) | 2 (0.1) | 1 (0.0) | 105 (0.3) | |||
| Smoking, n (%) | 130 (7.1) | 194 (6.6) | 4707 (15.1) | 0.498 | <0.001 | <0.001 |
| Missing, n (%) | 24 (1.3) | 43 (1.5) | 774 (2.5) | |||
| Maternal SES | 0.629 | <0.001 | <0.001 | |||
| Upper white collar worker, n (%) | 581 (31.8) | 912 (31.1) | 6460 (20.7) | |||
| Lower white collar worker, n (%) | 798 (43.7) | 1254 (42.8) | 11 873 (38.1) | |||
| Blue collar worker, n (%) | 166 (9.1) | 286 (9.8) | 3971 (12.8) | |||
| Other or missing, n (%) | 280 (15.3) | 481 (16.4) | 8832 (28.4) | |||
| ICSI, n (%) | 536 (29.4) | 965 (32.9) | NA | 0.011 | NA | NA |
| Preterm births, n (%) | 117 (6.4) | 250 (8.5) | 1341 (4.3) | 0.008 | <0.001 | <0.001 |
| Extremely preterm, <28 GW, n (%) | 5 (0.3) | 14 (0.5) | 73 (0.2) | 0.279 | 0.736 | 0.013 |
| Caesarean sections, n (%) | 518 (28.4) | 818 (27.9) | 5151 (16.5) | 0.712 | <0.001 | <0.001 |
| Missing, n (%) | 0 (0) | 0 (0) | 5 (0.0) | |||
| Offspring male sex, n (%) | 926 (50.7) | 1500 (51.1) | 15 945 (51.2) | 0.787 | 0.696 | 0.943 |
| Birth weight, g, mean (SD) | 3554 (579) | 3423 (594) | 3544 (544) | <0.001 | 0.437 | <0.001 |
| SGA, n (%) | 55 (3.0) | 126 (4.3) | 992 (3.2) | 0.025 | 0.683 | 0.001 |
| LGA, n (%) | 72 (3.9) | 62 (2.1) | 909 (2.9) | <0.001 | 0.012 | 0.012 |
| NICU, n (%) | 49 (2.7) | 77 (2.6) | 525 (1.7) | 0.901 | 0.002 | <0.001 |
| Birth year | <0.001 | <0.001 | <0.001 | |||
| 1994–1997 | 241 (13.2) | 567 (19.3) | 9937 (31.9) | |||
| 1998–2000 | 421 (23.1) | 820 (28.0) | 6895 (22.1) | |||
| 2001–2003 | 533 (29.2) | 773 (26.4) | 6944 (22.3) | |||
| 2004–2006 | 630 (34.5) | 773 (26.4) | 7289 (23.4) | |||
| Missing, n (%) | 0 (0) | 0 (0) | 71 (0.2)a | |||
| Follow-up time, y, mean (SD)b | 18.8 (3.3) | 19.5 (3.6) | 20.5 (4.0) | <0.001 | <0.001 | <0.001 |
Independent samples T-test and Chi-square test.
FET, frozen embryo transfer; ET, embryo transfer; NC, natural conception; y, year; SES, socioeconomic status; NA, not applicable; GW, gestational week; SGA, small-for-gestational-age; LGA, large-for-gestational-age; NICU, treatment in neonatal intensive care unit.
Incomplete personal ID code.
Follow-up from birth until 31 December 2020 or death.
Bold indicates statistical significance at P < 0.05.
Diagnoses (ICD-10 chapters)
Table II presents the results on the frequency of diagnoses in the main ICD-10 chapters. No significant differences were found between the FET and fresh ET groups. However, the FET group had modestly elevated adjusted risks for diagnoses in several ICD-10 chapters compared to the NC group: A + B (infectious and parasitic diseases, aHR 1.24; 95% CI 1.11, 1.38), C + D00–D48 (neoplasms, aHR 1.68; 95% CI 1.48, 1.91), H (diseases of the eye and adnexa and the ear and mastoid process, aHR 1.11; 95% CI 1.01, 1.21), J (diseases of the respiratory system, aHR 1.15; 95% CI 1.06, 1.23), K (diseases of the digestive system, aHR 1.17; 95% CI 1.05, 1.32), L (diseases of the skin and subcutaneous tissue, aHR 1.28; 95% CI 1.14, 1.43), N (diseases of the genitourinary system, aHR 1.27; 95% CI 1.11, 1.45), Q (congenital malformations and chromosomal abnormalities, aHR 1.31; 95% CI 1.14, 1.50) and R (symptoms, signs and abnormal clinical and laboratory findings, aHR 1.25, 95% CI 1.16, 1.34). Adjustments were made for PTB, maternal age, parity, SES and offspring sex (Table II).
Table II.
Frequency of main ICD-10 chapters in hospital visits and admissions.a
| ICD-10 chapter | FET | Fresh ET | NC | P FET vs fresh ET | P FET vs NC | P Fresh ET vs NC | FET vs Fresh ET (1.0) |
FET vs NC (1.0) |
Fresh ET vs NC (1.0) |
|||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| HR | aHRb | HR | aHRb | HR | aHRb | |||||||
| n = 1825 | n = 2933 | n = 31 136 | (95% CI) | (95% CI) | (95% CI) | (95% CI) | (95% CI) | (95% CI) | ||||
| A + B, Infectious and parasitic diseases, n (%) | 382 (20.9) | 627 (21.4) | 5971 (19.2) | 0.714 | 0.065 | 0.004 | 1.00 (0.88, 1.13) | 1.01 (0.89, 1.14) | 1.18 (1.06, 1.31) | 1.24 (1.11, 1.38) | 1.17 (1.08, 1.27) | 1.22 (1.12, 1.33) |
| C + D00–D48, Neoplasms, n (%) | 278 (15.2) | 447 (15.2) | 4597 (14.8) | 0.994 | 0.584 | 0.488 | 1.17 (1.01, 1.36) | 1.16 (1.00, 1.35) | 1.76 (1.55, 1.99) | 1.68 (1.48, 1.91) | 1.51 (1.37, 1.67) | 1.44 (1.30, 1.60) |
| D50–D89, Diseases of the blood and immune system, n (%) | 141 (7.7) | 241 (8.2) | 2337 (7.5) | 0.545 | 0.729 | 0.164 | 0.96 (0.77, 1.20) | 0.95 (0.76, 1.18) | 1.23 (1.02, 1.47) | 1.20 (1.00, 1.45) | 1.27 (1.11, 1.46) | 1.24 (1.07, 1.44) |
| E, Endocrine, nutritional and metabolic diseases, n (%) | 134 (7.3) | 206 (7.0) | 1988 (6.4) | 0.678 | 0.105 | 0.178 | 1.06 (0.85, 1.32) | 1.07 (0.86, 1.33) | 1.22 (1.03, 1.46) | 1.17 (0.97, 1.40) | 1.14 (0.99, 1.32) | 1.08 (0.93, 1.26) |
| F, Mental and behavioral disorders, n (%) | 394 (21.6) | 663 (22.6) | 7769 (25.0) | 0.412 | 0.001 | 0.005 | 1.00 (0.88, 1.13) | 0.99 (0.88, 1.13) | 0.95 (0.86, 1.05) | 0.99 (0.90, 1.10) | 0.95 (0.88, 1.03) | 0.98 (0.90, 1.06) |
| G, Diseases of the nervous system, n (%) | 110 (6.0) | 192 (6.5) | 2183 (7.0) | 0.475 | 0.108 | 0.344 | 0.98 (0.78, 1.25) | 0.97 (0.77, 1.23) | 1.00 (0.82, 1.21) | 1.01 (0.88, 1.30) | 1.02 (0.88, 1.18) | 1.07 (0.92, 1.25) |
| H, Diseases of the eye and adnexa and the ear and mastoid process, n (%) | 551 (30.2) | 924 (31.5) | 9549 (30.7) | 0.341 | 0.668 | 0.349 | 0.98 (0.88, 1.09) | 0.97 (0.88, 1.08) | 1.01 (0.93, 1.10) | 1.11 (1.01, 1.21) | 1.04 (0.97, 1.11) | 1.14 (1.07, 1.23) |
| I, Diseases of the circulatory system, n (%) | 49 (2.7) | 81 (2.8) | 955 (3.1) | 0.875 | 0.356 | 0.357 | 1.07 (0.75, 1.53) | 1.08 (0.76, 1.55) | 1.08 (0.81, 1.43) | 1.07 (0.80, 1.44) | 1.01 (0.80, 1.26) | 1.00 (0.79, 1.27) |
| J, Diseases of the respiratory system, n (%) | 770 (42.2) | 1266 (43.2) | 12 819 (41.2) | 0.510 | 0.398 | 0.036 | 1.00 (0.92, 1.10) | 1.02 (0.93, 1.11) | 1.09 (1.01, 1.17) | 1.15 (1.06, 1.23) | 1.08 (1.02, 1.15) | 1.13 (1.07, 1.21) |
| K, Diseases of the digestive system, n (%) | 321 (17.6) | 547 (18.6) | 5583 (17.9) | 0.357 | 0.711 | 0.332 | 0.97 (0.84, 1.11) | 0.97 (0.85, 1.12) | 1.10 (0.98, 1.23) | 1.17 (1.05, 1.32) | 1.13 (1.03, 1.23) | 1.19 (1.09, 1.31) |
| L, Diseases of the skin and subcutaneous tissue, n (%) | 343 (18.8) | 520 (17.7) | 5141 (16.5) | 0.354 | 0.011 | 0.090 | 1.11 (0.96, 1.27) | 1.10 (0.96, 1.27) | 1.24 (1.12, 1.39) | 1.28 (1.14, 1.43) | 1.13 (1.03, 1.24) | 1.15 (1.05, 1.27) |
| M, Diseases of the musculoskeletal system and connective tissue, n (%) | 246 (13.5) | 463 (15.8) | 4706 (15.1) | 0.030 | 0.057 | 0.332 | 0.89 (0.76, 1.04) | 0.89 (0.76, 1.04) | 1.04 (0.91, 1.18) | 1.02 (0.99, 1.04) | 1.15 (1.05, 1.27) | 1.24 (1.12, 1.37) |
| N, Diseases of the genitourinary system, n (%) | 246 (13.5) | 409 (13.9) | 4196 (13.5) | 0.651 | 0.057 | 0.478 | 1.03 (0.88, 1.21) | 1.05 (0.89, 1.23) | 1.18 (1.04, 1.35) | 1.27 (1.11, 1.45) | 1.14 (1.03, 1.26) | 1.23 (1.10, 1.37) |
| Q, Congenital malformations and chromosomal abnormalities, n (%) | 247 (13.5) | 400 (13.6) | 3159 (10.1) | 0.919 | <0.001 | <0.001 | 1.00 (0.86, 1.17) | 0.99 (0.84, 1.16) | 1.40 (1.23, 1.59) | 1.31 (1.14, 1.50) | 1.39 (1.25, 1.54) | 1.28 (1.15, 1.43) |
| R, Symptoms, signs and abnormal clinical and laboratory findings, n (%) | 795 (43.6) | 1236 (42.1) | 12 710 (40.8) | 0.335 | 0.021 | 0.164 | 1.08 (0.99, 1.19) | 1.09 (1.00, 1.20) | 1.21 (1.12, 1.30) | 1.25 (1.16, 1.34) | 1.11 (1.04, 1.17) | 1.14 (1.07, 1.21) |
Chi-square test and Cox regression.
Only the first diagnosis per person is included in the analyses, repeated events are not taken into account.
ICD-10, International Classification of diseases, 10th revision; FET, frozen embryo transfer; ET, embryo transfer; NC, natural conception; HR, hazard ratio; aHR, adjusted hazard ratio.
Any overnight visit is considered hospital stay.
Adjusted for preterm birth, maternal age, parity, socioeconomic status and offspring sex (Cox regression takes follow-up time into account).
Bold indicates statistical significance.
Hospital visits and admissions
More than 90% of persons in each study group had outpatient hospital visits, and almost 50% had hospital admissions. There were no significant differences between the FET and fresh ET groups in the number of outpatient hospital visits or hospital admissions. However, when compared to the NC group (92.2%), the proportion of persons with outpatient visits in the hospital was higher in the FET group (93.5%; P < 0.001; aHR 1.23, 95% CI 1.17, 1.30). For hospital admissions, an aHR of 1.28 (95% CI 1.19, 1.37) was found for FET versus NC. Adjustments were made for PTB, maternal age, parity, SES and offspring sex (Table III).
Table III.
Outpatient hospital visits and hospital admissions.a
| Variable | FET | Fresh ET | NC | P FET vs fresh ET | P FET vs NC | P fresh ET vs NC | FET vs fresh ET (1.0) |
FET vs NC (1.0) |
Fresh ET vs NC (1.0) |
|||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| HR | aHRb | HR | aHRb | HR | aHRb | |||||||
| n = 1825 | n = 2933 | n = 31 136 | (95% CI) | (95% CI) | (95% CI) | (95% CI) | (95% CI) | (95% CI) | ||||
| Persons with outpatient visits, n (%) | 1706 (93.5) | 2732 (93.1) | 29 717 (92.2) | 0.656 | <0.001 | <0.001 | 1.04 (0.98, 1.11) | 1.05 (0.99, 1.12) | 1.21 (1.15, 1.27) | 1.23 (1.17, 1.30) | 1.16 (1.12, 1.21) | 1.17 (1.12, 1.22) |
| Persons with hospital admissions, n (%) | 876 (48.0) | 1401 (47.8) | 14 473 (46.5) | 0.876 | 0.207 | 0.183 | 1.04 (0.95, 1.13) | 1.07 (0.98, 1.16) | 1.16 (1.08, 1.24) | 1.28 (1.19, 1.37) | 1.11 (1.05, 1.17) | 1.21 (1.14, 1.28) |
Independent samples T-test and Cox regression.
FET, frozen embryo transfer; ET, embryo transfer; NC, natural conception; HR, crude hazard ratio; aHR, adjusted hazard ratio.
Any overnight stay is considered a hospital admission.
Adjusted for preterm birth, maternal age, parity, socioeconomic status and offspring sex. Cox regression takes follow-up time into consideration.
Bold indicates statistical significance.
No significant differences between the FET and fresh ET groups were found in the mean number of outpatient visits, hospital admissions or days in hospital per person. Compared to the NC group, the FET group was associated with increased hospital admissions per person, 1.34 (95% CI 1.21, 1.48) vs 1.15 (95% CI 1.12, 1.19), difference between means 0.19 (95% CI 0.05, 0.32) (Table IV).
Table IV.
Mean number of outpatient hospital visits, hospital admissionsa and days in hospital per person.
| Variable | FET | Fresh ET | NC | P FET vs fresh ET | P FET vs NC | P fresh ET vs NC | FET vs fresh ET | FET vs NC | Fresh ET vs NC |
|---|---|---|---|---|---|---|---|---|---|
| n = 1825 | n = 2933 | n = 31 136 | |||||||
| Difference between means (95% CI) | Difference between means (95% CI) | Difference between means (95% CI) | |||||||
| CRUDE | |||||||||
| Outpatient visits in hospital per person, mean (95% CI) | 19.9 (18.1, 21.8) | 21.7 (20.2, 23.1) | 20.7 (20.3, 21.2) | 0.116 | 0.345 | 0.226 | −1.7 (−4.0, 0.6) | −0.8 (−2.7, 1.1) | 0.9 (−0.6, 2.4) |
| Hospital admissions per person, mean (95% CI) | 1.16 (1.04, 1.30) | 1.22 (1.12, 1.32) | 1.17 (1.14, 1.20) | 0.542 | 0.955 | 0.376 | −0.05 (−0.22, 0.11) | 0.00 (−0.14, 0.13) | 0.05 (−0.06, 0.16) |
| Days in hospital per person, mean (95% CI) | 6.06 (4.23, 7.90) | 7.87 (6.42, 9.31) | 6.90 (6.45, 7.34) | 0.287 | 0.341 | 0.454 | −1.80 (−4.14, 0.54) | −0.83 (−2.72, 1.06) | 0.97 (−0.55, 2.48) |
| ADJUSTEDb | |||||||||
| Outpatient visits in hospital per person, mean (95% CI) | 21.3 (19.4, 23.2) | 22.2 (20.7, 23.7) | 20.6 (20.2, 21.1) | 0.418 | 0.491 | 0.051 | −0.9 (−3.2, 1.4) | 0.7 (−1.2, 2.6) | 1.6 (0.0, 3.1) |
| Hospital admissions per person, mean (95% CI) | 1.34 (1.21, 1.48) | 1.32 (1.22, 1.43) | 1.15 (1.12, 1.19) | 0.838 | 0.006 | 0.002 | 0.02 (−0.15, 0.18) | 0.19 (0.05, 0.32) | 0.17 (0.06, 0.28) |
| Days in hospital per person, mean (95% CI) | 6.92 (5.04, 8.80) | 7.99 (6.49, 9.50) | 6.85 (6.40, 7.29) | 0.367 | 0.940 | 0.155 | −1.07 (−3.41, 1.26) | 0.08 (−1.87, 2.02) | 1.15 (−0.44, 2.73) |
Independent samples T-test and General linear model.
FET, frozen embryo transfer; ET, embryo transfer; NC, natural conception; HR, crude hazard ratio; aHR, adjusted hazard ratio.
Any overnight stay is considered a hospital admission.
Adjusted for birth year, preterm birth, maternal age, parity, socioeconomic status and offspring sex.
Bold indicates statistical significance.
Mortality
The numbers of deaths were 7 (0.4%) for FET, 26 (0.9%) for fresh ET and 175 (0.6%) for NC (P = 0.042 for FET vs fresh ET, P = 0.317 for FET vs NC and P = 0.028 for fresh ET vs NC; data not shown).
Discussion
This Finnish register-based study shows that the general health of singletons born after FET and fresh ET is comparable up to early adulthood. However, as compared to those born after NC, singletons born after both FET and fresh ET had slightly increased risks of hospital visits and admissions, as well as elevated risks of diagnoses in several main ICD-10 chapters.
Our previous study conducted on the same population compared the health outcomes until the age of 3. Compared to the NC group, ART children (FET and fresh ET) had a slightly increased risk of hospital admission; aOR 1.10, 95% CI 1.02–1.19, adjusted for year of birth, PTB, maternal age, parity and SES. No significant differences between the FET and fresh ET groups were found in the risk of hospital admission or for any of the ICD-10 chapters (Pelkonen et al., 2015). These findings persist in the present study. In contrast with our results, a US study found FET (n = 2101) to be associated with increased odds of infectious disease, and respiratory and neurologic conditions compared to fresh ET (Hwang et al., 2019). The size of the FET cohort was similar to ours. However, the exact length of follow-up was not reported but was short, limited to ‘infancy’, which limits the comparability of the results with ours.
There are a few studies describing the risk of neoplasms and cancer of children born after FET. No increased cancer risk was found for FET (n = 33 899) versus fresh ET in a large US cohort with a mean follow-up of 4–6 years (Spector et al., 2019). In accordance with this, a meta-analysis (Zhang et al., 2020) found no difference in cancer risk between FET and fresh ET (relative risk (RR) 1.28, 95% CI 0.96–1.69). However, they described an increased risk of cancer for FET versus NC (RR 1.37, 95% CI 1.04–1.81) (Zhang et al., 2020). In the present study, borderline significant differences were seen in the incidence of diagnoses of neoplasms (ICD-10 chapters C + D00–D48) between FET, fresh ET and NC. When restricting the analysis to malignant neoplasms (ICD-10 chapter C), no significant differences were seen. The overall incidence of malignant neoplasms was low in all groups: 7 (0.4%), 8 (0.3%) and 118 (0.4%) for FET, fresh ET and NC, respectively (data not shown). Since the incidence of childhood cancer is very low, large cohorts are needed to reach sufficient power to show differences between groups. This, as well as the different adjustments, may explain the conflicting results on cancer risk between different studies.
A recent Swedish study suggested that the risk of type 1 diabetes is increased for FET (n = 11 211) compared to fresh ET and NC (aHR 1.52, 95% CI 1.08, 2.14 and aHR 1.41, 95% CI 1.05, 1.89, respectively). Adjustments were made for maternal age, smoking, parental country of birth, educational level, type I diabetes, IVF/ICSI and year of birth (Norrman et al., 2020). In contrast, a Danish study found no association between ART (n = 8490) and type 1 diabetes, nor between FET (n = 715) and type 1 diabetes (Kettner et al., 2016). In our study, no significant differences were found for endocrine, nutritional and metabolic diseases (ICD-10 chapter E) between the groups.
In the present study, no significant differences between FET, fresh ET and NC were found for ICD-10 chapter F (mental or behavioral disorders). In line with this, a recently published large Nordic cohort study found no significant differences in the risk of neurodevelopmental disorders between FET (n = 18 563) and fresh ET. However, ART was associated with a higher risk of learning and motor functioning disorders (aHR 1.17, 95% CI 1.11, 1.24) compared to NC (Rönö et al., 2022). In addition, a recent population-based prospective study from Sweden found slightly increased risks of mood disorders and antidepressant use up to the median age of 18 when FET (n = 3636) was compared to fresh ET. However, the authors concluded that these differences were likely explained by differences in parental characteristics, such as subfertility (Wang et al., 2022).
It has been reported in previous studies that the risk of asthma is increased for ART children compared to children born from NC (Carson et al., 2013; Magnus et al., 2019), but no data have been published specifically on FET and the risk of asthma. A recent meta-analysis of 14 high-quality studies verified the association of ART with an increased risk of asthma (RR 1.28, 95% CI 1.08, 1.51) (Wijs et al., 2021). In the present study, the risk of respiratory diseases was increased for FET compared to NC. These diagnoses were mainly upper respiratory infections, allergic rhinitis, and asthma (data not shown). No significant differences were found between FET and fresh ET. These results seem to be in line with previous literature and further strengthen the association between asthma and assisted reproduction.
Several studies from an Israeli study group have described outcomes after IVF (n = 2603) in a local population-based cohort concerning separate diagnoses, with unfortunately no data on the use of FET. They have described increased risks of pediatric infections (Wainstock et al., 2019), gastrointestinal (Shachor et al., 2020), eruptive dermatological (Krieger et al., 2018) and ophthalmic (Tsumi et al., 2021) morbidities compared to NC. These findings appear to be in line with our results, where FET, as well as fresh ET, were associated with increased risks of hospital-based infectious diagnoses and diseases of the digestive system compared to NC. Additionally, in our study, increased risks of skin conditions were found for FET versus NC and fresh ET versus NC. Atopy and dermatitis were among the most frequent diagnoses in this chapter for FET (data not shown). However, no significant differences were found between FET and fresh ET.
Major congenital anomalies of the present cohort were described in our earlier study based on the Finnish Register of Congenital Malformations. No significant differences were found between FET and fresh ET, but ART had a higher adjusted odds of a major congenital anomalies compared to NC (Pelkonen et al., 2014). This finding persists in the present study regarding a diagnosis in ICD-10 chapter Q including both minor and major anomalies. Overall mortality was significantly lower for FET compared to NC, as well as NC compared to fresh ET. However, these results should be regarded with caution, as the absolute incidences of death are low.
In line with our previous study (Pelkonen et al., 2015), in the current study, the FET and fresh ET groups had slightly higher percentage of outpatient visits and hospital admissions compared to the NC group. In addition, the FET and fresh ET groups had more diagnoses in ICD-10 chapter R (symptoms, signs, and abnormal clinical and laboratory findings) compared to the NC group. This may be indicative of ART children having more contact with health care, in accordance with a recent Swedish register-based study, which found ART to be a risk factor for more in- and outpatient visits and diagnoses in several ICD-10 chapters including chapter R, compared to NC, until the age of 5 (Pettersson et al., 2022).
It remains partly unclear which mechanisms explain the small health differences between singletons born after ART and NC. Not only ART but also parental subfertility and less invasive fertility treatments, such as ovulation induction, associate with poorer outcome of the offspring concerning asthma and infectious diseases (Harju et al., 2013; Magnus et al., 2019; Wainstock et al., 2019). Patient or embryo selection may be caused by the freeze-thaw process. One possible pathway to explain the differences between FET, fresh ET and NC are epigenetic changes, which may be induced by the laboratory procedures or by the different hormonal milieu of the uterus at the time of implantation. Differences in DNA methylation and gene expression have been shown in placental samples and/or cord blood between FET, fresh ET and NC (Estill et al., 2016; Litzky et al., 2017; Choux et al., 2018; Barberet et al., 2021; Caramaschi et al., 2021). However, a recent study found no differences in whole blood methylation patterns in adolescents born after ART compared to NC, suggesting that these changes might be transient in nature (Penova-Veselinovic et al., 2021).
In the analyses of the present study, we adjusted for PTB, which might conceal some of the positive effects of the diminished PTB and SGA risk of FET offspring. A separate analysis was carried out without adjusting for PTB, adjusting only for maternal age, parity, SES and offspring sex. However, no significant differences between FET and fresh ET were found for the need of hospital care or any of the ICD-10 chapter outcomes (data not shown).
The limitations of our study must be acknowledged. First, the CRHC covers hospital-based inpatient and outpatient care, excluding milder cases diagnosed in primary health care or the private sector. Thus, our results should be interpreted as representing only the more severe morbidity. Second, we were not able to study the effect of ART treatments and subfertility separately in our setting. In addition, although our cohort is reasonably sized, even larger cohorts would be needed to reliably study separate diagnoses included in the main ICD-10 chapters, or rare outcomes, such as cancer. It should be noted that only slow freezing was used in Finland when the children of this cohort were born, therefore these results may not be extrapolated to represent outcomes after vitrification. During our study period, a single embryo was transferred in the majority of ETs, and mainly natural cycles were used in FET, though unfortunately exact data were not available for statistical analysis.
A major strength of the study is the reliable register data. It is mandatory for public hospitals to report their discharge diagnoses, thus the CRHC coverage has been found to be accurate (Sund, 2012). Hospital care in Finland is almost exclusively offered by the public hospitals, especially for children, so these results should give an accurate description of the more severe morbidity in the population. Data linkages are feasible and reliable because of the personal identity numbers used widely in the Finnish society. In addition, we were able to adjust for several confounding factors deemed clinically relevant. However, there may be residual confounding that we were not able to control for. Finally, to our knowledge, our study offers the longest follow-up on the general health outcomes of a large FET cohort to date. For many ICD-10 chapters, we present the first published data on the long-term outcome of singletons born after FET.
In conclusion, this study gives further assurance that the health of singletons born after FET does not significantly alter from those born after fresh ET until early adulthood. Certain increased risks were found for FET compared to NC, which warrant further investigations. Similar results were found for fresh ET compared to NC. However, the magnitudes of the increased risks were small or modest at most. The ART cohort is still quite young for thorough investigation of diseases typically prevalent only in older population, such as cardiovascular disease or some cancers. In the future, large cohorts with sufficient follow-up time are needed to investigate the long-term health of ART offspring into adulthood.
Acknowledgements
We would like to thank the Finnish fertility clinics, hospitals and register keepers for their meticulous work on reporting the data.
Authors’ roles
All authors participated in the original study design. A.M.T. and M.G. analyzed the data, and A.M.T. was responsible for the preparation of the manuscript. All authors contributed to the revisions of the manuscript and approved the final version.
Funding
Finnish government research funding was obtained for this study. The study was also supported by the Finnish Medical Society Duodecim, the Päivikki and Sakari Sohlberg Foundation, Orion Research Foundation and Finnish Society of Obstetrics and Gynaecology (research grants to A.M.T.). The funding sources were not involved in the planning or execution of the study.
Conflict of interest
There are no conflicts of interest to declare.
Contributor Information
A M Terho, Department of Obstetrics and Gynaecology, PEDEGO Research Unit & Medical Research Center Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland.
A Tiitinen, Department of Obstetrics and Gynaecology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
H Martikainen, Department of Obstetrics and Gynaecology, PEDEGO Research Unit & Medical Research Center Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland.
M Gissler, Information Services Department, Finnish Institute for Health and Welfare, Helsinki, Finland; Department of Neurobiology, Care Science and Society, Karolinska Institute, Stockholm, Sweden.
S Pelkonen, Department of Obstetrics and Gynaecology, PEDEGO Research Unit & Medical Research Center Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland.
Data Availability
Under Finnish privacy laws, the study permission and access to register data were granted specifically to the authors. Upon reasonable request, statistical code and data output may be available from the corresponding author.
References
- Barberet J, Romain G, Binquet C, Guilleman M, Bruno C, Ginod P, Chapusot C, Choux C, Fauque P.. Do frozen embryo transfers modify the epigenetic control of imprinted genes and transposable elements in newborns compared with fresh embryo transfers and natural conceptions? Fertil Steril 2021;116:1468–1480. [DOI] [PubMed] [Google Scholar]
- Caramaschi D, Jungius J, Page CM, Novakovic B, Saffery R, Halliday J, Lewis S, Magnus MC, London SJ, Håberg SE. et al. Association of medically assisted reproduction with offspring cord blood DNA methylation across cohorts. Hum Reprod 2021;36:2403–2413. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Carson C, Sacker A, Kelly Y, Redshaw M, Kurinczuk JJ, Quigley MA.. Asthma in children born after infertility treatment: Findings from the UK Millennium Cohort Study. Hum Reprod 2013;28:471–479. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Choux C, Binquet C, Carmignac V, Bruno C, Chapusot C, Barberet J, Lamotte M, Sagot P, Bourc'his D, Fauque P.. The epigenetic control of transposable elements and imprinted genes in newborns is affected by the mode of conception: ART versus spontaneous conception without underlying infertility. Hum Reprod 2018;33:331–340. [DOI] [PubMed] [Google Scholar]
- Elias FTS, Weber-Adrian D, Pudwell J, Carter J, Walker M, Gaudet L, Smith G, Velez MP.. Neonatal outcomes in singleton pregnancies conceived by fresh or frozen embryo transfer compared to spontaneous conceptions: a systematic review and meta-analysis. Arch Gynecol Obstet 2020;302:31–45. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Estill MS, Bolnick JM, Waterland RA, Bolnick AD, Diamond MP, Krawetz SA.. Assisted reproductive technology alters deoxyribonucleic acid methylation profiles in bloodspots of newborn infants. Fertil Steril 2016;106:629–639.e10. [DOI] [PubMed] [Google Scholar]
- Harju M, Keski-Nisula L, Raatikainen K, Pekkanen J, Heinonen S.. Maternal fecundity and asthma among offspring—is the risk programmed preconceptionally? Retrospective observational study. Fertil Steril 2013;99:761–767.e1. [DOI] [PubMed] [Google Scholar]
- Hwang SS, Dukhovny D, Gopal D, Cabral H, Diop H, Coddington CC, Stern JE.. Health outcomes for Massachusetts infants after fresh versus frozen embryo transfer. Fertil Steril 2019;112:900–907. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kettner LO, Matthiesen NB, Ramlau-Hansen CH, Kesmodel US, Bay B, Henriksen TB.. Fertility treatment and childhood type 1 diabetes mellitus: a nationwide cohort study of 565,116 live births. Fertil Steril 2016;106:1751–1756. [DOI] [PubMed] [Google Scholar]
- Krieger Y, Wainstock T, Sheiner E, Harlev A, Landau D, Horev A, Bogdanov-Berezovsky A, Walfisch A.. Long-term pediatric skin eruption-related hospitalizations in offspring conceived via fertility treatment. Int J Dermatol 2018;57:317–323. [DOI] [PubMed] [Google Scholar]
- Litzky JF, Deyssenroth MA, Everson TM, Armstrong DA, Lambertini L, Chen J, Marsit CJ.. Placental imprinting variation associated with assisted reproductive technologies and subfertility. Epigenetics 2017;12:653–661. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Magnus MC, Karlstad Ø, Parr CL, Page CM, Nafstad P, Magnus P, London SJ, Wilcox AJ, Nystad W, Håberg SE.. Maternal history of miscarriages and measures of fertility in relation to childhood asthma. Thorax 2019;74:106–113. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Maheshwari A, Pandey S, Raja EA, Shetty A, Hamilton M, Bhattacharya S.. Is frozen embryo transfer better for mothers and babies? Can cumulative meta-analysis provide a definitive answer? Hum Reprod Update 2018;24:35–58. [DOI] [PubMed] [Google Scholar]
- Norrman E, Petzold M, Clausen TD, Henningsen AK, Opdahl S, Pinborg A, Rosengren A, Bergh C, Wennerholm UB.. Type 1 diabetes in children born after assisted reproductive technology: a register-based national cohort study. Hum Reprod 2020;35:221–231. [DOI] [PubMed] [Google Scholar]
- Official Statistics of Finland (OSF): Causes of death. Cause of Death Register. Helsinki: Statistics Finland, 2022. E-Publication. ISSN=1799-5078. Access Method: http://www.stat.fi/Tiul/Ksyyt/Index_en.Html (7 February 2022, date last accessed).
- Pelkonen S, Gissler M, Koivurova S, Lehtinen S, Martikainen H, Hartikainen AL, Tiitinen A.. Physical health of singleton children born after frozen embryo transfer using slow freezing: a 3-year follow-up study. Hum Reprod 2015;30:2411–2418. [DOI] [PubMed] [Google Scholar]
- Pelkonen S, Hartikainen AL, Ritvanen A, Koivunen R, Martikainen H, Gissler M, Tiitinen A.. Major congenital anomalies in children born after frozen embryo transfer: a cohort study 1995-2006. Hum Reprod 2014;29:1552–1557. [DOI] [PubMed] [Google Scholar]
- Pelkonen S, Koivunen R, Gissler M, Nuojua-Huttunen S, Suikkari AM, Hydén-Granskog C, Martikainen H, Tiitinen A, Hartikainen AL.. Perinatal outcome of children born after frozen and fresh embryo transfer: the Finnish cohort study 1995-2006. Human Reproduction 2010;25:914–923. [DOI] [PubMed] [Google Scholar]
- Penova-Veselinovic B, Melton PE, Huang RC, Yovich JL, Burton P, Wijs LA, Hart RJ.. DNA methylation patterns within whole blood of adolescents born from assisted reproductive technology are not different from adolescents born from natural conception. Hum Reprod 2021;36:2035–2049. [DOI] [PubMed] [Google Scholar]
- Pettersson ML, Bladh M, Nedstrand E, Svanberg AS, Lampic C, Sydsjö G.. Maternal advanced age, single parenthood, and ART increase the risk of child morbidity up to five years of age. BMC Pediatr 2022;22:39. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rönö K, Rissanen E, Bergh C, Wennerholm UB, Opdahl S, Romundstad LB, Henningsen AKA, Spangmose AL, Pinborg A, Gissler M. et al. The neurodevelopmental morbidity of children born after assisted reproductive technology: a Nordic register study from the Committee of Nordic Assisted Reproductive Technology and Safety group. Fertil Steril 2022;117:1026–1037. [DOI] [PubMed] [Google Scholar]
- 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;109:330–342.e9. [DOI] [PubMed] [Google Scholar]
- Shachor N, Wainstock T, Sheiner E, Harlev A.. Fertility treatments and gastrointestinal morbidity of the offspring. Early Hum Dev 2020;144:105021. [DOI] [PubMed] [Google Scholar]
- Spector LG, Brown MB, Wantman E, Letterie GS, Toner JP, Doody K, Ginsburg E, Williams M, Koch L, Schymura MJ. et al. Association of in vitro fertilization with childhood cancer in the United States. JAMA Pediatr 2019;173:e190392. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sund R. Quality of the Finnish Hospital Discharge Register: a systematic review. Scand J Public Health 2012;40:505–515. [DOI] [PubMed] [Google Scholar]
- Terho AM, Pelkonen S, Opdahl S, Romundstad LB, Bergh C, Wennerholm UB, Henningsen AA, Pinborg A, Gissler M, Tiitinen A.. High birth weight and large-for-gestational-age in singletons born after frozen compared to fresh embryo transfer, by gestational week: a Nordic register study from the CoNARTaS group. Hum Reprod 2021;36:1083–1092. [DOI] [PubMed] [Google Scholar]
- THL. Hedelmöityshoidot 2017-2018.2019. http://www.thl.fi/fi_FI/web/fi/tilastot/aiheittain/rekisteriselosteet/syntyneet_lapset (20 May 2022, date last accessed).
- THL. Register Descriptions. 2021. https://Thl.Fi/En/Web/Thlfi-En/Statistics-and-Data/Data-and-Services/Register-Descriptions (14 April 2022, date last accessed).
- Tsumi E, Lavy Y, Sheiner E, Barrett C, Harlev A, Hagbi Bal M, Wainstock T.. Assisted reproductive technology and long-term ophthalmic morbidity of the offspring. J Dev Orig Health Dis 2021;12:627–631. [DOI] [PubMed] [Google Scholar]
- Wainstock T, Sheiner E, Yoles I, Sergienko R, Landau D, Harlev A.. Fertility treatments and offspring pediatric infectious morbidities: results of a population-based cohort with a median follow-up of 10 years. Fertil Steril 2019;112:1129–1135. [DOI] [PubMed] [Google Scholar]
- Wang C, Johansson ALV, Rodriguez-Wallberg KA, Landén M, Almqvist C, Hernández-Díaz S, Oberg AS.. Long-term follow-up of psychiatric disorders in children and adolescents conceived by assisted reproductive techniques in Sweden. JAMA Psychiatry 2022;79:133–142. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wijs LA, Fusco MR, Doherty DA, Keelan JA, Hart RJ.. Asthma and allergies in offspring conceived by ART: a systematic review and meta-analysis. Hum Reprod Update 2021;28:132–148. [DOI] [PubMed] [Google Scholar]
- Wyns C, Bergh C, Calhaz-Jorge C, de Geyter C, Kupka MS, Motrenko T, Rugescu I, Smeenk J, Tandler-Schneider A, Vidakovic S. et al. ; European IVF-monitoring Consortium (EIM) for the European Society of Human Reproduction and Embryology (ESHRE). ART in Europe, 2016: results generated from European registries by ESHRE. Hum Reprod Open 2020;2020:hoaa032. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wyns C, de Geyter C, Calhaz-Jorge C, Kupka MS, Motrenko T, Smeenk J, Bergh C, Tandler-Schneider A, Rugescu IA, Vidakovic S. et al. ; European IVF-Monitoring Consortium (EIM) for the European Society of Human Reproduction and Embryology (ESHRE). ART in Europe, 2017: results generated from European registries by ESHRE. Hum Reprod Open 2021;2021:hoab026.34377841 [Google Scholar]
- Zhang Y, Gao R, Chen H, Xu W, Yang Y, Zeng X, Sun X, Zhang S, Hu X, Qin L.. The association between fertility treatments and the incidence of paediatric cancer: a systematic review and meta-analysis. Eur J Cancer 2020;138:133–148. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Under Finnish privacy laws, the study permission and access to register data were granted specifically to the authors. Upon reasonable request, statistical code and data output may be available from the corresponding author.