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Health of adults aged 22 to 35 years conceived by assisted reproductive technology

      Objective

      To determine the health outcomes for adults aged 22–35 years old who were conceived via assisted reproduction technology (ART) compared with adults of the same age conceived without use of ART.

      Design

      Cohort study.

      Setting

      Not applicable.

      Patient(s)

      Adult men and women aged 22–35 years who were conceived with and without use of ART.

      Intervention(s)

      Questionnaire and clinical review.

      Main Outcome Measure(s)

      Vascular structure (carotid artery intima-media thickness, pulse wave velocity), vascular function (blood pressure), metabolic markers (fasting blood glucose, insulin, and standard lipid profiles), anthropometric measurements, and respiratory function (spirometry).

      Result(s)

      The mean age of the 193 ART and 86 non-ART participants was 27.0 and 26.9 years, respectively. There were no substantial intragroup differences in demographics or vascular intermediate phenotypes, metabolic parameters, or anthropometric measures, before or after adjusting for perinatal factors and a quality of life measure with four domains. Diastolic blood pressure was lower in the ART men than the non-ART men (adjusted mean difference −4.4 mm Hg, 95% CI, −8.7 to −0.1). The ART group reported a higher prevalence of ever having asthma, (40.8% vs. 28.6%; odds ratio 1.7; 95% CI, 1.0–3.0), but expiratory flow rates were similar.

      Conclusion(s)

      This study of the health of 193 adults conceived via ART, the largest to date globally, found no evidence of increased vascular or cardiometabolic risk, or growth or respiratory problems in the ART group compared with a non-ART group from the same source population. Follow-up observation for reproductive and later-onset adverse health effects remains important.
      Estado de salud de los adultos entre 22 y 35 años concebidos tras técnicas de reproducción asistida

      Objetivo

      Determinar los parámetros de salud de adultos entre 22-35 años que fueron concebidos por técnicas de reproducción asistida (TRA).

      Diseño

      Estudio de cohortes.

      Entorno

      No aplica.

      Paciente(s)

      Hombres y mujeres adultos entre 22-35 años que fueron concebidos con y sin el uso de TRA.

      Intervención (es)

      Cuestionario y revisión clínica.

      Principales medidas evaluadas

      Estructura vascular (grosor de la capa íntima-media de la arteria carótida, velocidad de la onda del pulso), función vascular (presión arterial), marcadores metabólicos (glucemia en ayunas, insulina y perfiles lipídicos estándar), mediciones antropométricas y función respiratoria (espirometría).

      Resultado(s)

      La edad media de los participantes de los 193 TRA y de los 86-no TRA, fue de 27.o y 26.9 respectivamente. No hubo diferencias sustanciales intragrupo en los fenotipos demográficos o vasculares intermedios, parámetros metabólicos o medidas antropométricas, antes o después del ajuste por factores perinatales, ni en la medición de la calidad de vida con cuatro dominios. La presión arterial diastólica fue menor en los hombres de TRA que en los hombres no TRA (diferencia de medias ajustada de -4.4 mm Hg, IC del 95%, -8.7 a -0.1). El grupo de TRA reportó una mayor prevalencia de tener asma en alguna ocasión (40.8% vs. 28.6%; cálculo de probabilidades 1.7; IC 95%, 1.0-3.0), pero las tasas de flujo espiratorio fueron similares.

      Conclusión(es)

      Este estudio sobre la salud de 193 adultos concebido tras TRA, el más extenso hasta la fecha a nivel global, no encontró evidencia de un aumento del riesgo vascular o cardiometabólico, ni problemas de crecimiento o respiratorios en el grupo de TRA comparado con el grupo de no TRA en la misma población de origen. El seguimiento observacional de los efectos adversos para la salud de aparición tardía y efectos reproductivos siguen siendo importantes parámetros para considerar.

      Key Words

      Discuss: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/users/16110-fertility-and-sterility/posts/44794-27154
      In vitro fertilization (IVF) was developed in the late 1970s, and the first child was born as a result of this assisted reproductive technology (ART) in England in 1978 (
      • Steptoe P.C.
      • Edwards R.G.
      Birth after the reimplantation of a human embryo.
      ). Not long after, the third IVF-conceived baby in the world was born in the state of Victoria, Australia (
      • Lopata A.
      • Johnston I.W.
      • Hoult I.J.
      • Speirs A.I.
      Pregnancy following intrauterine implantation of an embryo obtained by in vitro fertilization of a preovulatory egg.
      ). In the 1980s the gamete intrafallopian transfer (GIFT) technique was developed and used in some cases of unexplained infertility (
      • Asch R.H.
      • Ellsworth L.R.
      • Balmaceda J.P.
      • Wong P.C.
      Pregnancy after translaparoscopic gamete intrafallopian transfer.
      ). The use of ART worldwide has continued to expand, with almost 2% of births in the United States and over 4% of those in Victoria, Australia, being conceived this way (
      Victorian Assisted Reproductive Technologies Authority
      Annual Report 2017.
      ,
      American Society for Reproductive Medicine, More than 71 thousand babies born from assisted reproductive technology cycles done in 2016.
      ). Given the large uptake globally, studies of the potential long-term health outcomes of ART are of paramount importance.
      An increased risk of a range of high-burden noncommunicable diseases resulting from use of ART could be related to the inherent developmental plasticity of the early embryo. That is, ART could be an environmental influence around the time of conception that affects perinatal outcomes, developmental trajectories, and risks of later pathophysiologic processes (
      • Roseboom T.J.
      Developmental plasticity and its relevance to assisted human reproduction.
      ). The hypothesis that ART may be such an environmental influence was highlighted in an article that summarized the potential adverse effects on long-term health that are likely attributable to perturbation of early gametes or embryos, inducing long-acting epigenetic variation in the periconceptional period (
      • Fleming T.P.
      • Watkins A.J.
      • Velazquez M.A.
      • Mathers J.C.
      • Prentice A.M.
      • Stephenson J.
      • et al.
      Origins of lifetime health around the time of conception: causes and consequences.
      ). With this in mind, researchers have specifically looked for an association of ART with vascular and cardiometabolic changes, the outcomes associated with adverse perinatal outcomes and epigenetic variation. To date, these studies have mostly been of young children; several systematic reviews of these studies concluded that more follow up is essential to confirm the long-term safety of ART (
      • Guo X.Y.
      • Liu X.M.
      • Jin L.
      • Wang T.T.
      • Ullah K.
      • Sheng J.Z.
      • et al.
      Cardiovascular and metabolic profiles of offspring conceived by assisted reproductive technologies: a systematic review and meta-analysis.
      ,
      • Hart R.
      • Norman R.J.
      The longer-term health outcomes for children born as a result of IVF treatment: part I–general health outcomes.
      ,
      • Vrooman L.A.
      • Bartolomei M.S.
      Can assisted reproductive technologies cause adult-onset disease? Evidence from human and mouse.
      ).
      A few studies have involved adolescents or adults. Arterial hypertension was reported in a single center study of 16- and 17-year-olds conceived by IVF or intracytoplasmic sperm injection (ICSI) (
      • Meister T.A.
      • Rimoldi S.F.
      • Soria R.
      • von Arx R.
      • Messerli F.H.
      • Sartori C.
      • et al.
      Association of assisted reproductive technologies with arterial hypertension during adolescence.
      ). Male-specific changes in body fat distribution (
      • Belva F.
      • De Schepper J.
      • Roelants M.
      • Tournaye H.
      • Bonduelle M.
      • Provyn S.
      Body fat content, fat distribution and adipocytokine production and their correlation with fertility markers in young adult men and women conceived by intracytoplasmic sperm injection (ICSI).
      ) and high-density lipoprotein (HDL) cholesterol concentrations (
      • Belva F.
      • Bonduelle M.
      • Provyn S.
      • Painter R.C.
      • Tournaye H.
      • Roelants M.
      • et al.
      Metabolic syndrome and its components in young adults conceived by ICSI.
      ) were reported in 18- to 22-year-olds conceived by ICSI. Indeed, the results to date have been described as “provocative,” requiring replication (
      • Fleming T.P.
      • Watkins A.J.
      • Velazquez M.A.
      • Mathers J.C.
      • Prentice A.M.
      • Stephenson J.
      • et al.
      Origins of lifetime health around the time of conception: causes and consequences.
      ).
      In 2010–2012, through initial contact with their mothers, we established a cohort of singleton ART-conceived young adults, with an average age of 21.4 years. We conducted separate telephone interviews with these young adults and their mothers and recruited a matched non-ART group from the same source population (state of Victoria, Australia) who were conceived without the use of ART, with an average age of 22.5 years (
      • Halliday J.
      • Wilson C.
      • Hammarberg K.
      • Doyle L.W.
      • Bruinsma F.
      • McLachlan R.
      • et al.
      Comparing indicators of health and development of singleton young adults conceived with and without assisted reproductive technology.
      ). The ART-conceived adults had an increased rate of hospital admissions, atopic respiratory conditions, and metabolic/endocrine/nutritional disease (ICD-10 coding category) as compared with the non-ART-conceived adults. Our present study further assessed the vascular, cardiometabolic, anthropometric, and respiratory health of the original study cohort, now aged 22–35, to investigate whether ART conception was associated with clinically measurable changes in these health parameters (
      • Fleming T.P.
      • Watkins A.J.
      • Velazquez M.A.
      • Mathers J.C.
      • Prentice A.M.
      • Stephenson J.
      • et al.
      Origins of lifetime health around the time of conception: causes and consequences.
      ).

      Materials and methods

      The protocol and details of measurements were published previously (
      • Lewis S.
      • Kennedy J.
      • Burgner D.
      • McLachlan R.
      • Ranganathan S.
      • Hammarberg K.
      • et al.
      Clinical review of 24–35 year olds conceived with and without in vitro fertilization: study protocol.
      ). There were 540 ART-conceived and 532 non-ART-conceived singleton adults in the 2010–2012 study who consented to be recontacted (
      • Halliday J.
      • Wilson C.
      • Hammarberg K.
      • Doyle L.W.
      • Bruinsma F.
      • McLachlan R.
      • et al.
      Comparing indicators of health and development of singleton young adults conceived with and without assisted reproductive technology.
      ,
      • Wilson C.
      • Hammarberg K.
      • Bruinsma F.
      • Berg T.
      • Amor D.
      • Sanson A.
      • et al.
      Health and development of ART conceived young adults: a study protocol for the follow-up of a cohort.
      ). The study was approved by the Royal Children's Hospital Human Research Ethics Committee (Project 33163).

       Recruitment of ART and Non-ART Populations

      Recruitment was by letter (postal mailing), with a follow-up letter after 3 weeks and a phone call after a further 3 weeks. Additional attempts at contacting the participants included the use of social media and phone calls to their mothers. The potential participants who were located and agreed to take part were sent detailed participant information and a consent form. When a signed consent form was returned, a member of the research team arranged a time for the clinical review and sent an online questionnaire to be completed at a time other than during the clinical assessment period. The 8% of women who reported that they were pregnant or breastfeeding were excluded from the study.
      Of the 531 ART-conceived adults for whom an address was found, 42% did not respond, 21% declined to participate, and 36% participated. A higher proportion of the non-ART group than the ART group did not respond to any of the three communication attempts (60%). Overall, women were more likely to participate than men (59% of ART and 67% of non-ART were female). The final study sample comprised 193 ART (147 IVF, 43 GIFT, 3 unknown) and 86 non-ART participants.

       Questionnaire

      The questionnaire included demographic questions and questions relating to potentially confounding or modifying variables, such as education level achieved, working hours, relationship status, financial situation, smoking, frequency of exercise, and alcohol consumption. Participants were provided with a detailed pictorial drinks guide (
      • Muggli E.
      • O’Leary C.
      • Donath S.
      • Orsini F.
      • Forster D.
      • Anderson P.J.
      • et al.
      “Did you ever drink more?” A detailed description of pregnant women’s drinking patterns.
      ) and were asked to record the number and frequency of up to three different alcoholic drink types, which were converted into average number of standard drinks per week. The Australian World Health Organization Quality of Life–Brief assessment (WHOQoL-BREF) was used to assess perceived health and quality of life (
      Development of the World Health Organization WHOQOL-BREF quality of life assessment. The WHOQOL Group.
      ). This 26-item validated instrument addresses four domains of quality of life: physical health, psychological health, social relationships, and environment. A number of health conditions were listed, and participants were asked to indicate any that applied to them. The self-reported health conditions were subsequently grouped into 20 categories. Data were also collected on whether a health professional had been consulted for the reported health condition and about current medication use.

       Clinical Assessments

      The participants attended a 2- to 3-hour appointment at the Murdoch Children's Research Institute at the Royal Children's Hospital in Melbourne where the clinical assessors were blinded to the ART or non-ART status of the participant. The risk factor measures included [1] subclinical ultrasound markers of atherosclerosis: carotid artery intima-media thickness, and pulse wave velocity (PWV); vascular function: resting blood pressure—brachial and central aortic, systolic and diastolic; [2] metabolic markers: fasting blood sample for glucose, lipids, and insulin, bioimpedance (percent body fat), growth measures of height, weight, and waist circumference; [3] respiratory function: spirometry. Details of the biophysical assessments and laboratory analyses were described previously elsewhere (
      • Lewis S.
      • Kennedy J.
      • Burgner D.
      • McLachlan R.
      • Ranganathan S.
      • Hammarberg K.
      • et al.
      Clinical review of 24–35 year olds conceived with and without in vitro fertilization: study protocol.
      ).

       Statistical Analysis

      For each of the characteristics and for all outcome measures, unadjusted group differences were investigated using chi-square tests for categorical outcomes, and two-sample t-tests for continuous outcomes. Univariable and multivariable analyses were performed using linear regression, and the outcomes were stratified by sex.
      Covariates were selected on the basis of their potential influence on the outcomes of interest and showed statistically significant differences between the ART and non-ART groups. For cardiometabolic and anthropometric outcomes they were birthweight and parity (data collected in the original study) and all four current quality of life domains, with the addition of current height for the pulse-wave velocity measurements. Mode of delivery (data also collected in the original study) was also included for respiratory outcomes. A sample size of 149 ART and 75 non-ART would be able to detect a difference from 116 to 120 ±10 mm Hg (systolic blood pressure) with 80% power and alpha 0.05.
      Multiple imputation was performed on the full eligible sample using chained equations and 20 replications. Estimation included the baseline variables of age at interview, birth weight, body mass index (BMI), parity, delivery type, gender, quality of life (WHOQoL); and the current variables of age, BMI, WHOQoL, and all outcomes. A univariate linear regression imputation method was performed for continuous measures and a univariate logistic regression imputation method for binary measures.
      Study data were collected and managed using REDCap electronic data capture tools hosted at Murdoch Children's Research Institute (
      • Harris P.A.
      • Taylor R.
      • Thielke R.
      • Payne J.
      • Gonzalez N.
      • Conde J.G.
      Research electronic data capture (REDCap)—a metadata-driven methodology and workflow process for providing translational research informatics support.
      ). Analyses were all done with Stata, version 15.1 (StataCorp LLC). Two-tailed P<.05 was considered statistically significant.

      Results

       Characteristics of the Study Population

      Table 1 shows that there were no marked differences in most characteristics between the ART and non-ART groups except for some perinatal factors (birth weight, gestation, cesarean delivery) and the mother's parity. Quality of life (WHOQoL) scores were more favorable in the ART group, particularly in the social relationship and environment domains, the former representing personal relationships, sexual activity, and social support and the latter representing a better financial situation, home environment, perceived safety, and access to health care and transport.
      Table 1Participant characteristics, ART group compared with non-ART group, using questionnaire data.
      CharacteristicART (n = 193)Non-ART (n = 86)P value
      Current age (y), mean (SD)27.5 (2.8)27.6 (2.6).76
      Sex (female), %58.367.9.14
      Completed education level.78
       Secondary school9.07.1
       Certificate, diploma or trade26.223.8
       University degree64.969.1
      Financial status, %.26
       Living comfortably41.140.5
      Doing alright43.234.5
      Just getting by14.221.4
      Finding it quite/very difficult1.63.6
      Working status, %.37
       Working81.879.8
       Studying6.34.8
       Looking for work1.13.6
       Parental leave17.910.7
       Working and studying2.60
       Other0.51.2
      Working hours (per wk), mean (SD)36.2 (13.5)34.8 (12.5).43
      Relationship status, %.20
       Not seeing or dating anyone20.429.8
       Dating one or more person6.811.9
       In a committed relationship20.417.9
       Living with a partner50.339.3
       Not specified2.11.9
      Sexual orientation, %.69
       Heterosexual93.193.7
       Gay/lesbian2.13.8
       Bisexual4.32.5
       Undecided0.50.0
      Frequency of vigorous exercise, %.21
       Never/few times a year21.916.1
       Less than weekly19.113.6
       At least once a week59.070.6
      Smoking (current, yes)6.38.3.54
      Alcohol consumption (standard drinks/wk), %.19
       013.818.1
       <222.230.1
       2–427.022.9
       5–915.918.1
       ≥1021.210.8
      WHOQoL-BREF domain, mean (±SD)
       Physical81.2 (14.5)77.0 (15.9).04
       Psychological70.0 (14.9)65.4 (18.7).03
       Social76.8 (18.8)69.6 (19.2)<.01
       Environment81.1 (12.3)75.8 (13.4)<.01
      Data collected in the original questionnaire
      • Belva F.
      • De Schepper J.
      • Roelants M.
      • Tournaye H.
      • Bonduelle M.
      • Provyn S.
      Body fat content, fat distribution and adipocytokine production and their correlation with fertility markers in young adult men and women conceived by intracytoplasmic sperm injection (ICSI).
      Gestation (wk), mean (SD)38.3 (3.0)39.6 (1.9)<.01
      Birthweight (g), mean (SD)3,040 (697)3,532 (542)<.01
      Mode of delivery (vaginal), %66.887.2<.01
      Parity (child 1), %75.330.2<.01
      Note: ART = assisted reproduction technology; SD = standard deviation; WHOQoL-BREF = Australian World Health Organization Quality of Life–Brief assessment.

       Participation Bias

      Data collected in the original telephone interviews with mothers and young adults (
      • Belva F.
      • De Schepper J.
      • Roelants M.
      • Tournaye H.
      • Bonduelle M.
      • Provyn S.
      Body fat content, fat distribution and adipocytokine production and their correlation with fertility markers in young adult men and women conceived by intracytoplasmic sperm injection (ICSI).
      ) were used to compare participants with nonparticipants, stratified by sex (Table 2). These included a range of maternally reported health outcomes up to 18 years of age, perinatal factors, young adult reported BMI, sexual development, psychosocial measures, and education scores (Australian Tertiary Admission Rank [ATAR], which is a percentile score relative to their peers upon completion of secondary education and impacts their tertiary admission).
      Table 2Potential sources of participation bias.
      OutcomeARTNon-ART
      ParticipantsNonparticipantsP valueParticipantsNonparticipantsP value
      Menn = 82n = 162n = 28n = 215
      Age at interview in original study (y) mean (SD)21.1 (2.8)21.6 (2.6).2221.6 (2.2)22.2 (2.9).33
      Working (>37 h/wk), %52.459.3.3132.145.2.19
      Chronic health problems
       Allergies29.324.8.521.414.9.39
       Anxiety/behavior problems14.620.4.2632.115.8.05
      ATAR score, mean (SD)77.9 (16.4)69.4 (20.3).0070.2 (18.2)74.5 (14.1).01
      Psychological domain of WHOQoL-BREF, mean (SD)77.8 (14.0)76.2 (13.4).3874.0 (12.4)77.3 (14.0).23
      Environment domain of WHOQoL-BREF, mean (SD)82.9 (12.0)83.1 (11.0).9281.8 (9.5)79.9 (12.0).40
      Hospitalizations (yes), %
       Hospital ever58.074.7.0053.653.0.96
       First year of life9.921.0.0410.715.4.50
       Preschool24.736.4.0725.024.7.97
       Primary school34.629.0.3814.318.6.58
       Secondary school21.025.5.4421.423.8.78
      Financial status (of parents) when young adult in secondary school, %.45.04
       Living comfortably56.846.357.130.2
       Doing alright27.235.225.037.2
       Just getting by12.413.014.324.7
       Finding it quite/very difficult3.75.63.47.9
      Womenn = 111n = 192n = 58n = 248
      Age at interview in original study (y), mean (SD)21.0 (2.5)21.6 (2.5).0422.3 (2.5)22.3 (2.8).95
      Working (>37 h/wk), %25.235.4.0622.422.2.97
      Chronic health problems, %
       Allergies34.225.5.1031.027.0.26
       Anxiety/behavior problems18.928.1.0731.421.6.50
      ATAR score, mean (SD)74.7 (16.7)75.8 (17.9).6480.2 (18.1)72.3 (17.9)<.01
      Psychological domain of WHOQoL-BREF, mean (SD)78.8 (12.6)75.1 (13.8).0276.1 (15.1)73.8 (14.6).30
      Environment domain of WHOQoL-BREF, mean (SD)84.6 (11.6)83.5 (10.3).3983.8 (10.2)80.8 (12.0).08
      Hospitalizations (yes), %
       Hospital ever55.156.8.7850.050.01.0
       First year of life6.411.5.145.28.9.33
       Preschool21.123.4.6417.524.4.26
       Primary school27.521.9.2719.019.4.95
       Secondary school22.929.6.2020.719.4.82
      Financial status (of parents) when young adult in secondary school, %.05.42
       Living comfortably49.552.149.238.1
       Doing alright38.526.026.336.4
       Just getting by11.018.217.518.6
       Finding it quite/very difficult0.93.77.06.9
      Note: Participant and nonparticipant data derived from young adult and maternal interviews in the original study
      • Belva F.
      • De Schepper J.
      • Roelants M.
      • Tournaye H.
      • Bonduelle M.
      • Provyn S.
      Body fat content, fat distribution and adipocytokine production and their correlation with fertility markers in young adult men and women conceived by intracytoplasmic sperm injection (ICSI).
      . ATAR = Australian Tertiary Admission Rank; SD = standard deviation; WHOQoL-BREF = Australian World Health Organization Quality of Life–Brief assessment.
      Compared with nonparticipating ART men, the participating ART men had higher ATAR scores and a lower exposure to hospitals in their early years. The participating ART women were slightly younger when initially interviewed, and they had higher scores in the psychological health domain of the WHOQoL-BREF scale. Compared with the nonparticipating non-ART men, the participating non-ART men had more self-reported anxiety/behavior problems and lower ATAR scores, and the participating non-ART women had higher ATAR scores, but no other intragroup differences were found.

       Self-Reported Health Problems

      Current self-reported physical health and lifetime health problems were mostly comparable between the ART and non-ART groups (Table 3). Anxiety, allergies/skin atopy, and depression had a prevalence of >20% in both groups, and anxiety was higher in the non-ART group. Self-reported asthma, lung, or breathing problems at any age were higher in the ART group than the non-ART group, but the rates of current asthma were similar. Additional data on health professional consultation and current medications were examined as possible indicators of severity of the conditions, and the details are shown at the bottom of Table 3. For instance, 47 (60%) of 78 ART and 16 (67%) of 24 non-ART participants had seen a health professional for asthma; 6 (8%) of 78 ART and 17 (71%) of 24 non-ART participants were currently taking asthma medication.
      Table 3Participant self-reported health from the questionnaire.
      Health itemART (n = 193)Non-ART (n = 86)P value
      Excellent physical health in general29.522.0.20
      Medical advice for fertility concerns10.55.6.23
       Known cause for infertility55.660.0.90
      Pregnancy attempted15.711.9.41
      Anxiety
      ART 44/69 (64%) and non-ART 25/41 (61%) have seen a health professional; ART 12/69 (17%) and non-ART 9/41 (22%) currently take medication.
      36.148.8.05
      Allergies/skin atopy
      ART 35/52 (67%) and non-ART 22/29 (76%) have seen a health professional; ART 11/52 (21%) and non-ART 11/29 (38%) currently take medication.
      27.035.4.18
      Orthopedic/bone issues8.36.0.49
      Rheumatic disease2.60.0
      Depression/bipolar disorder
      ART 37/45 (82%) and non-ART 19/22 (86%) have seen a health professional; ART 8/45 (18%) and non-ART 7/22 (32%) currently take medication.
      23.626.2.64
      Other psychiatric/behavioral1.61.0.80
      Diabetes1.61.2.81
      Thyroid1.00.0
      Epilepsy1.00.0
      Other neurologic2.10.0
      Sleep disturbance10.515.7.23
      Gynecologic7.33.5.24
      Gastrointestinal3.61.2.28
      Cancer/tumor2.10.0
      Cardiac1.02.3.42
      Asthma, lung or breathing problems
      ART 47/78 (60%) and non-ART 16/24 (67%) have seen a health professional; ART 6/78 (8%) and non-ART 17/24 (71%) currently taking medication.
      40.828.6.05
      Age (y) when asthma ceased.13
       Never had asthma59.271.4
       <106.30.0
       10–124.22.4
       13–195.82.4
       20–261.12.4
       Age unspecified0.50.0
       Ongoing22.921.4
      Note: Values presented as percent unless specified otherwise.
      a ART 44/69 (64%) and non-ART 25/41 (61%) have seen a health professional; ART 12/69 (17%) and non-ART 9/41 (22%) currently take medication.
      b ART 35/52 (67%) and non-ART 22/29 (76%) have seen a health professional; ART 11/52 (21%) and non-ART 11/29 (38%) currently take medication.
      c ART 37/45 (82%) and non-ART 19/22 (86%) have seen a health professional; ART 8/45 (18%) and non-ART 7/22 (32%) currently take medication.
      d ART 47/78 (60%) and non-ART 16/24 (67%) have seen a health professional; ART 6/78 (8%) and non-ART 17/24 (71%) currently taking medication.

       Clinical Assessments

      The results of the multivariable analysis of the clinical findings, stratified by sex, are shown in Table 4.
      Table 4Clinical measures: comparing differences between ART and non-ART individuals, unadjusted and adjusted regression analysis results.
      Clinical measureSexARTNon-ARTMean difference
      nMean (SD)nMean (SD)UnadjustedAdjusted
      All adjusted for birthweight, parity, and quality of life domains; respiratory measures also adjusted for mode of delivery.
      β (95% CI)P valueβ (95% CI)P value
      Anthropometry
       Height
      Female99165.5 (6.5)55166.6 (7.5)−1.1 (−3.3, 1.2).351.6 (−1.1, 4.3).24
      Male74180.0 (6.4)26182.3 (6.8)−2.3 (−5.2, 0.7).13−0.2 (−3.7, 3.4).92
       Weight
      Female9969.0 (14.5)5570.5 (14.4)−1.5 (−6.3, 3.3).52.8 (−3.2, 8.8).36
      Male7483.7 (15.8)2686.0 (15.5)−2.3 (−9.4, 4.8).5−1.8 (−10.9, 7.3).70
       BMI
      Female9925.1 (4.9)5525.5 (5.4)−0.3 (−2.0, 1.4).710.4 (−1.7, 2.5).69
      Male7425.9 (5.3)2625.8 (3.8)0.1 (−2.1, 2.4).91−0.4 (−3.3, 2.5).78
       % Body fat
      Female9131.8 (8.1)4930.4 (9.7)1.5 (−1.6, 4.5).343.3 (−0.2, 6.8).06
      Male7020.5 (8.6)2518.0 (8.2)2.5 (−1.4, 6.4).210.4 (−4.5, 5.4).86
      Cardiovascular
       Carotid intermedia thickness (mm)
      Mean average far wall
      Female970.5 (0.1)510.5 (0.1)−0.0 (−0.0, 0.0).240.0 (−0.0, 0.0).69
      Male680.5 (0.1)230.5 (0.1)0.0 (−0.0, 0.0).970.0 (−0.0, 0.0).39
      Mean maximum far wall
      Female970.6 (0.1)510.6 (0.1)−0.0 (−0.0, 0.0).330.0 (−0.0, 0.0).91
      Male680.6 (0.1)230.6 (0.1)0.0 (−0.0, 0.0).880.0 (−0.0, 0.0).94
       Pulse wave velocity (ms−1)
      Adjusted as in note a, with the addition of current height.
      Female915.6 (0.7)505.9 (1.5)−0.3 (0.6, 0.1).16−0.1 (−0.5, 0.4).68
      Male706.1 (0.7)256.2 (0.5)−0.1 (−0.5, 0.2).37−0.1 (−0.4, 0.3).79
       Blood pressure (mm Hg)
      Brachial: systolic
      Female100119.8 (10.8)55119.3 (11.0)0.5 (−3.1, 4.1).770.8 (−3.7, 5.3).73
      Male73125.8 (11.0)26126.4 (7.8)−0.6 (−5.2, 4.1).81−3.8 (−9.9, 2.4).23
      Brachial: diastolic
      Female10072.6 (8.5)5572.5 (7.9)0.1 (−2.6, 2.9).92−0.1 (−3.6, 3.4).96
      Male7372.5 (7.6)2674.5 (6.9)−2.0 (−5.4, 1.3).23−4.4 (−8.7, −0.0).05
      Central aortic: systolic
      Female92104.6 (9.9)51105.4 (10.1)−0.8 (−4.2, 2.7).650.0 (−4.2, 4.2)1.00
      Male70108.9 (9.8)25110.4 (6.4)−1.4 (−5.6, 2.8).50−3.9 (−9.3, 1.5).15
      Central aortic: diastolic
      Female9272.6 (8.6)5173.0 (7.9)−0.4 (−3.3, 2.5).77−0.4 (−4.0, 3.2).83
      Male7073.0 (7.8)2575.7 (6.2)−2.8 (−6.2, 0.7).11−4.4 (−8.7, −0.1).04
      Fasting blood pathology
       Fasting glucose (mmol/L)
      Female944.6 (0.4)494.6 (0.4)−0.0 (−0.1, 0.1).910.0 (−0.1, 0.2).74
      Male704.9 (0.4)264.8 (0.4)0.1 (−0.1, 0.3).250.2 (−0.1, 0.4).18
       Cholesterol (mmol/L)
      Female984.8 (0.9)524.6 (0.9)0.2 (−0.1, 0.5).270.3 (−0.1, 0.7).17
      Male724.6 (0.9)264.5 (0.8)0.1 (−0.4, 0.5).80−0.2 (−0.7, 0.3).38
       Triglyceride (mmol/L)
      Female981.0 (0.6)521.0 (0.4)0.0 (−0.1, 0.2).63−0.0 (−0.2, 0.2).76
      Male721.0 (0.5)261.0 (0.5)−0.0 (−0.3, 0.2).80−0.1 (−0.4, 0.3).75
       HDLC (mmol/L)
      Female981.8 (0.5)521.8 (0.6)0.0 (−0.2, 0.2).780.1 (−0.2, 0.3).64
      Male721.4 (0.3)261.4 (0.3)0.0 (−0.1, 0.2).600.0 (−0.2, 0.2).83
       LDLC (mmol/L)
      Female982.5 (0.7)522.4 (0.7)0.1 (−0.1, 0.4).370.2 (−0.1, 0.5).17
      Male722.7 (0.8)262.7 (0.7)0.0 (−0.3, 0.4).91−0.2 (−0.7, 0.2).30
       Fasting insulin (mU/L)
      Female968.7 (5.8)528.8 (5.9)−0.1 (−2.1, 1.9).900.2 (−2.0, 2.4).88
      Male708.3 (5.5)257.7 (4.8)0.6 (−1.8, 3.1).610.4 (−2.8, 3.5).82
      Respiratory
       FEV1, z scores
      Female94−0.2 (0.9)53−0.1 (0.9)−0.1 (−0.4, 0.2).39−0.1 (−0.5, 0.3).65
      Male71−0.3 (0.8)26−0.2 (1.0)−0.2 (−0.6, 0.3).45−0.1 (−0.7, 0.4).68
       FVC, z scores
      Female940.1 (1.0)530.2 (0.9)−0.1 (−0.4, 0.2).57−0.1 (−0.5, 0.3).66
      Male710.1 (0.9)260.1 (1.0)−0.1 (−0.5, 0.4).77−0.3 (−0.8, 0.3).36
      Note: ART = assisted reproduction technology; BMI = body mass index; CI = confidence interval; FEV = forced expiratory volume; FVC = forced vital capacity; HDLC = high-density lipoprotein cholesterol; LDLC = low-density lipoprotein cholesterol; SD = standard deviation.
      a All adjusted for birthweight, parity, and quality of life domains; respiratory measures also adjusted for mode of delivery.
      b Adjusted as in note a, with the addition of current height.

       Anthropometric measurements

      Height, weight, and BMI were similar for the ART and non-ART groups, before and after accounting for perinatal and quality of life differences.

       Cardiovascular structure and function

      The detailed clinical measurements of vascular structure (carotid artery intima-media thickness and pulse wave velocity) demonstrated no differences between the study groups in the univariable or multivariable analyses (see Table 4). In regards to vascular function, systolic blood pressure did not differ between study groups; the diastolic blood pressure (both brachial and central aortic) was lower in the ART men than the non-ART men. All fasting blood measures of vascular and metabolic function were similar between the study groups (see Table 4).

       Respiratory function

      There were no differences in spirometry z-scores for forced expiratory volume and forced vital capacity between ART and non-ART groups, either before or after adjustment for confounders (see Table 4).

       Multiple Imputation

      Unadjusted and adjusted multiply imputed regression analysis results are presented in Supplemental Table 1 (available online). The sensitivity analysis of the multiply imputed data demonstrated similar results to Table 4, with overlapping confidence intervals.

      Discussion

      We found no differences in multiple clinical phenotypes between ART and non-ART conceived adults aged 22 to 35 years. The intermediate vascular phenotypes in our study are validated, reproducible, and predictive of cardiovascular disease events in later adulthood (
      • Lorenz M.W.
      • Markus H.S.
      • Bots M.L.
      • Rosvall M.
      • Sitzer M.
      Prediction of clinical cardiovascular events with carotid intima-media thickness: a systematic review and meta-analysis.
      ,
      • Zhong Q.
      • Hu M.J.
      • Cui Y.J.
      • Liang L.
      • Zhou M.M.
      • Yang Y.W.
      • et al.
      Carotid-femoral pulse wave velocity in the prediction of cardiovascular events and mortality: an updated systematic review and meta-analysis.
      ). The lack of differences in these phenotypes is of considerable clinical importance to providers and users of ART and contributes to the limited current knowledge regarding potential long-term health effects of ART.
      A recent meta-analysis summarizing 10 statistically heterogeneous studies, some of which were very small and mostly related to children 12 years and younger, found only four studies with positive effect estimates on vascular risk, and a pooled effect size indicating a minimal elevation of blood pressure among the ART groups (
      • Guo X.Y.
      • Liu X.M.
      • Jin L.
      • Wang T.T.
      • Ullah K.
      • Sheng J.Z.
      • et al.
      Cardiovascular and metabolic profiles of offspring conceived by assisted reproductive technologies: a systematic review and meta-analysis.
      ). Another systematic and one narrative review of cardiovascular disease risk associated with ART reported marginally increased blood pressure in some observational studies of children and adolescents (
      • Hart R.
      • Norman R.J.
      The longer-term health outcomes for children born as a result of IVF treatment: part I–general health outcomes.
      ,
      • Vrooman L.A.
      • Bartolomei M.S.
      Can assisted reproductive technologies cause adult-onset disease? Evidence from human and mouse.
      ). A recent hospital-based study of 16- and 17-year-olds, not included in these reviews, reported an increase in ART-conceived individuals' 24-hour ambulatory blood pressure (
      • Meister T.A.
      • Rimoldi S.F.
      • Soria R.
      • von Arx R.
      • Messerli F.H.
      • Sartori C.
      • et al.
      Association of assisted reproductive technologies with arterial hypertension during adolescence.
      ). However, this was a small study, and the analyses were not adjusted for age and sex. In contrast, we found no increases in blood pressure and in fact found a marginally lower diastolic blood pressure in ART men, noting that this subgroup association, if replicated, is unlikely to be clinically important. Therefore, our findings add weight to the body of evidence that ART conception is not associated with altered blood pressure.
      The meta-analysis described previously (
      • Guo X.Y.
      • Liu X.M.
      • Jin L.
      • Wang T.T.
      • Ullah K.
      • Sheng J.Z.
      • et al.
      Cardiovascular and metabolic profiles of offspring conceived by assisted reproductive technologies: a systematic review and meta-analysis.
      ) found differences in the metabolic profiles of ART and non-ART offspring, with studies reporting a “more favorable” lipid profile and a higher fasting insulin level in the ART group, but no group differences in fasting glucose level were reported (
      • Guo X.Y.
      • Liu X.M.
      • Jin L.
      • Wang T.T.
      • Ullah K.
      • Sheng J.Z.
      • et al.
      Cardiovascular and metabolic profiles of offspring conceived by assisted reproductive technologies: a systematic review and meta-analysis.
      ). No consistent ART-associated effects on cardiometabolic measures (e.g., anthropometry, glucose homeostasis variables, and lipid profiles) have been found in other studies (
      • Lorenz M.W.
      • Markus H.S.
      • Bots M.L.
      • Rosvall M.
      • Sitzer M.
      Prediction of clinical cardiovascular events with carotid intima-media thickness: a systematic review and meta-analysis.
      ,
      • Zhong Q.
      • Hu M.J.
      • Cui Y.J.
      • Liang L.
      • Zhou M.M.
      • Yang Y.W.
      • et al.
      Carotid-femoral pulse wave velocity in the prediction of cardiovascular events and mortality: an updated systematic review and meta-analysis.
      ). Additional reassurance can now be provided that the metabolic profile in adults conceived by ART does not appear to differ substantially from that expected in people of the same age and sex who were conceived without the use of ART.
      Studies including respiratory measures are few, and their findings have been inconsistent: some report increased asthma among ART offspring, but others show no effect of mode of conception (
      • Ericson A.
      • Nygren K.G.
      • Olausson P.O.
      • Kallen B.
      Hospital care utilization of infants born after IVF.
      ,
      • Kuiper D.B.
      • Seggers J.
      • Schendelaar P.
      • Haadsma M.L.
      • Roseboom T.J.
      • Heineman M.J.
      • et al.
      Asthma and asthma medication use among 4-year-old offspring of subfertile couples--association with IVF?.
      ,
      • Cetinkaya F.
      • Gelen S.A.
      • Kervancioglu E.
      • Oral E.
      Prevalence of asthma and other allergic diseases in children born after in vitro fertilisation.
      ). Many of these studies were inadequately powered and were limited to children and teenagers. We included clinical assessments of respiratory function because we had observed an increased odds ratio for self-reported respiratory atopic conditions in our previous study of this cohort (
      • Halliday J.
      • Wilson C.
      • Hammarberg K.
      • Doyle L.W.
      • Bruinsma F.
      • McLachlan R.
      • et al.
      Comparing indicators of health and development of singleton young adults conceived with and without assisted reproductive technology.
      ). It has been postulated that cesarean delivery and epigenetic variations may be directly linked to, or mediate, the effects of environmental exposures on the development and natural history of asthma and that these are both factors potentially more prevalent in ART pregnancies (
      • Arathimos R.
      • Suderman M.
      • Sharp G.C.
      • Burrows K.
      • Granell R.
      • Tilling K.
      • et al.
      Epigenome-wide association study of asthma and wheeze in childhood and adolescence.
      ,
      • Guibas G.V.
      • Moschonis G.
      • Xepapadaki P.
      • Roumpedaki E.
      • Androutsos O.
      • Manios Y.
      • et al.
      Conception via in vitro fertilization and delivery by caesarean section are associated with paediatric asthma incidence.
      ). In our current study, the greater frequency of self-report by the ART group of ever having had “asthma, lung or breathing problems” was not reflected in differences in expiratory airflow before or after adjusting for perinatal (including mode of delivery) and quality of life confounders. The asthma in the ART group was reported as having resolved by 12 years of age in 25% of cases, and ongoing rates of asthma were almost identical in both groups, with more in the non-ART group currently taking medication.
      A U.S.-based study of respiratory health of young adults (aged 18–24 years) conceived with or without ART found no difference in asthma prevalence (
      • Sicignano N.
      • Beydoun H.A.
      • Russell H.
      • Jones Jr., H.
      • Oehninger S.
      A descriptive study of asthma in young adults conceived by IVF.
      ). In light of our similar finding, it may be that the increased prevalence of asthma reported in ART–ICSI 4-year-olds (
      • Kuiper D.B.
      • Seggers J.
      • Schendelaar P.
      • Haadsma M.L.
      • Roseboom T.J.
      • Heineman M.J.
      • et al.
      Asthma and asthma medication use among 4-year-old offspring of subfertile couples--association with IVF?.
      ), in 5- to 7-year-olds (
      • Carson C.
      • Sacker A.
      • Kelly Y.
      • Redshaw M.
      • Kurinczuk J.J.
      • Quigley M.A.
      Asthma in children born after infertility treatment: findings from the UK Millennium Cohort Study.
      ), and in a record linkage study with a majority aged <16 years (
      • Källén B.
      • Finnström O.
      • Nygren K.G.
      • Otterblad Olausson P.
      Asthma in Swedish children conceived by in vitro fertilisation.
      ) is age-dependent and does not persist into chronic adult asthma. Ours is the largest population-based clinical assessment of respiratory function in ART adults to date, and there are no results approaching statistical significance to suggest we were underpowered to detect clinically meaningful differences.
      The primary limitation of our study was the low participation rate, particularly for the male non-ART group. We speculate that, in general, non-ART individuals may have been less invested in the aims of the study and thus had less to gain from participating compared with the ART-conceived individuals. There were undoubtedly logistic problems for many potential participants to attend the clinical review, with more than 15% who responded living in regional areas, interstate, or internationally. The travel time rather than the length of the appointment (2–3 hours) was found to influence their decision to not participate. The large proportion (42%) who did not respond cannot be explained, but it is similar to the only other published study of adults where 50% did not respond (
      • Sicignano N.
      • Beydoun H.A.
      • Russell H.
      • Jones Jr., H.
      • Oehninger S.
      A descriptive study of asthma in young adults conceived by IVF.
      ). Modest sex-specific associations with ART may have been missed due to the low number of male non-ARTs available for analysis, and there may have been a bias in the non-ART group such that those who were more anxious (as shown in Table 3) were more motivated to participate.
      We are confident, however, that the non-ART group was representative of the source population because in the original study we had compared whatever information we could obtain on participating and nonparticipating young adults from maternal interviews. The non-ART mothers themselves were recruited from the same source population as the ART mothers by using random digit dialing, then identifying and screening households for those with a consenting mother of a young adult aged 18–28 years. Of these mothers, 85% consented to their offspring being contacted, and 84% of the offspring agreed to participate. The only known difference between the nonparticipating, non-ART young adults from the source population and those who participated was a lower education level in their mothers, with important potential confounders such as gestational age, birth weight, and perceived financial situation being similar.
      The ability to examine data from the original questionnaire-based study and compare characteristics of the participants and nonparticipants assures us that our results related to health outcomes do not reflect participation bias. Furthermore, multiple imputation analysis using the entire eligible cohort did not provide any evidence for a bias related to nonparticipation for any of the clinical outcomes.

      Conclusion

      Our detailed study of the health of 192 adults aged 22 to 35 years and conceived by ART is the largest to date globally. The clinical assessments found no evidence of increased vascular or cardiometabolic risk or growth or respiratory problems in the ART group compared with the non-ART group from the Victoria population. This is valuable information for adults conceived by ART and those considering ART in future. It may be that adverse health effects of ART reported in children and adolescents are transient, particularly given the widespread effects of cumulative environmental exposures and lifestyle on adult phenotypes. Our findings, however, require replication in other cohorts. There remains a need for ongoing assessment of reproductive health and other ART-related health effects that may appear later, albeit at an earlier age, or more frequently than in non-ART-conceived adults.

      Acknowledgments

      The authors acknowledge the participants who generously gave their time to the study and the invaluable contribution of Ms. Jane Koleff to the development of the protocol and in the training of all assessors to undertake the clinical assessments.

      Supplementary data

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