Human beings have been producing more twins, triplets, and
quadruplets than ever before, due to the expansion of medically
assisted conception. This book analyzes the anticipatory regimes of
making ...multiple babies. With archival documents, participant
observation, in-depth interviews, and registry data, this book
traces the global and local governance of the assisted reproductive
technologies (ARTs) used to tackle multiple pregnancy since the
1970s, highlighting the early promotion of single embryo transfer
in Belgium and Japan and the making of the world's most lenient
guidelines in Taiwan.
To create a tool that accurately predicts live birth chances after a positive pregnancy test after elective single embryo transfer (ET).
Retrospective cohort.
CHUM hospital and Ovo clinic in ...Montreal, Canada.
Patients with a positive pregnancy test result who underwent their first single ET after in vitro fertilization (IVF) at the CHUM hospital and Ovo clinic in Montreal, Canada, from 2012 to 2016 were selected. A total of 1,995 patients were included in this study.
The data from both centers were combined and divided into training (70%, n = 1,398) and validation (30%, n = 597) sets. The predictive model was developed using backward selection method for the following variables: age of patient at egg retrieval; log β-human chorionic gonadotropin (β-hCG) (β-hCG) 1; log β-hCG 2; and IVF treatment type. Moreover, the classification tree, random forest, and neural network models were generated.
The measured outcomes were live birth (live fetus ≥24 weeks of gestation) and nonviable pregnancies. The performance of all models was evaluated by area under the receiver operating characteristic curve (AUC).
Advancing age was negatively correlated with live birth. The odds ratio (OR) of age of patient at the time of egg retrieval was 0.95 (95% confidence interval CI, 0.91–0.99). The log β-hCG 1 and log β-hCG 2 were positively correlated with live birth in the univariate analysis (OR, 4.15 95% CI, 3.19–5.39, and OR, 3.84 95% CI, 2.99–4.93, respectively). The β-hCG 1 level needed for a successful pregnancy was lower in frozen ET and modified natural IVF than in simulated IVF (OR, 0.55 95% CI, 0.34–0.91, and OR, 0.49 95% CI, 0.26–0.95, respectively). The best performance in terms of the AUC was the updated logistic model: POPI-Plus. The AUC values were 0.76 (95% CI, 0.73–0.79) and 0.78 (95% CI, 0.74–0.82) for the training and validation data, respectively. The other models (classification tree, random forest, and neural network) also performed adequately, with an AUC of ≥0.7, but remained below POPI-Plus. An open-access calculator was generated and can be found on the website of the University of Montreal on the following link: https://deptobsgyn.umontreal.ca/departement/divisions/medecine-et-biologie-de-la-reproduction/the-popi-plus-tool/.
The POPI-Plus tool offers individualized counseling for patients after an initial positive β-hCG test result. Future studies will assess its impact on patient anxiety while awaiting viability ultrasound and perform prospective validation on new patients.
La herramienta POPI-Plus: modelo de predicción de resultado del embarazo en la fecundación in vitro de un amplio estudio retrospectivo de cohorte
Crear una herramienta que prediga con precisión las posibilidades de nacidos vivos tras una prueba de embarazo positiva después de la transferencia electiva de un solo embrión (TE).
Cohorte retrospectivo.
Hospital CHUM y clínica Ovo en Montreal, Canadá.
Las pacientes con un resultado positivo en la prueba de embarazo que se sometieron a su primera TE única después de la fertilización in vitro (FIV) en el CHUM hospital y la clínica Ovo en Montreal, Canadá, de 2012 a 2016 fueron seleccionadas. Se incluyeron un total de 1.995 pacientes en este estudio.
Los datos de ambos centros se combinaron y se dividieron en pruebas (70%, n ¼ 1.398) y validación (30%, n ¼ 597). El modelo predictivo se desarrolló utilizando el método de selección hacia atrás para las siguientes variables: edad de la paciente en el momento de la extracción de los óvulos;, log b-gonadotropina coriónica humana (b-hCG) (b-hCG) 1; log b-hCG 2; y tipo de tratamiento de FIV. Además, se generaron los modelos de árbol de clasificación modelos de bosque aleatorio y de red neuronal.
Los resultados medidos fueron nacidos vivos (feto vivo > o igual a 24 semanas de gestación) y embarazos no viables.
El rendimiento de todos los modelos se evaluó mediante el área bajo la curva receiver operating characteristic (AUC).
El aumento de la edad se correlacionó negativamente con los nacidos vivos. La odds ratio (OR) de la edad de la paciente en el momento de la extracción de óvulos fue de 0,95 (intervalo de confianza IC del 95%, 0,91-0,99). El log b-hCG 1 y el log b-hCG 2 se correlacionaron positivamente con los nacidos vivos en el análisis univariante ((OR, 4,15 IC 95%, 3,19-5,39, y OR, 3,84 IC 95%, 2,99-4,93, respectivamente). El nivel de b-hCG 1 necesario para un embarazo fue menor en la TE congelado y la FIV natural modificada que en la FIV simulada (OR, 0,55 IC 95%, 0,34-0,91, y OR, 0,49 IC 95%,0,26-0,95, respectivamente). El mejor rendimiento en términos de AUC fue el modelo logístico actualizado: POPI-Plus. Los valores de AUC fueron 0,76 (IC 95%, 0,73-0,79) y 0,78 (IC 95%, 0,74-0,82) para los datos de entrenamiento y validación, respectivamente. Los demás modelos (árbol de clasificación bosque aleatorio y red neuronal) también funcionaron adecuadamente, con un AUC de R0,7, pero se mantuvieron por debajo de POPI-Plus. Se generó una calculadora
que puede consultarse en el sitio web de la Universidad de Montreal, en el siguiente enlace: https://deptobsgyn.umontreal.ca/departement/divisions/medecine-et-biologie-de-la-reproduction/the-popi-plus-tool/.
La herramienta POPI-Plus ofrece asesoramiento individualizado a las pacientes tras un resultado positivo inicial de la prueba de b-hCG. Estudios futuros evaluarán su impacto en la ansiedad de las pacientes mientras esperan la ecografía de viabilidad y realizarán una validación prospectiva en nuevas pacientes.
Abstract
Globally, IVF patients are routinely offered and charged for a selection of adjunct treatments and tests or ‘add-ons’ that they are told may improve their chance of a live birth, despite ...there being no clinical evidence supporting the efficacy of the add-on. Any new IVF technology claiming to improve live birth rates (LBR) should, in most cases, first be tested in an appropriate animal model, then in clinical trials, to ensure safety, and finally in a randomized controlled trial (RCT) to provide high-quality evidence that the procedure is safe and effective. Only then should the technique be considered as ‘routine’ and only when applied to the similar patient population as those studied in the RCT. Even then, further pediatric and long-term follow-up studies will need to be undertaken to examine the long-term safety of the procedure. Alarmingly, there are currently numerous examples where adjunct treatments are used in the absence of evidence-based medicine and often at an additional fee. In some cases, when RCTs have shown the technique to be ineffective, it is eventually withdrawn from the clinic. In this paper, we discuss some of the adjunct treatments currently being offered globally in IVF laboratories, including embryo glue and adherence compounds, sperm DNA fragmentation, time-lapse imaging, preimplantation genetic screening, mitochondria DNA load measurement and assisted hatching. We examine the evidence for their safety and efficacy in increasing LBRs. We conclude that robust studies are needed to confirm the safety and efficacy of any adjunct treatment or test before they are offered routinely to IVF patients.
To investigate the impact of body mass index (BMI) on the success rate and prenatal outcomes of fresh embryo transfer in women undergoing their first in vitro fertilization/intracytoplasmic sperm ...injection (IVF/ICSI) treatment.
It is a post-hoc analysis of a prospective observational cohort study. 2569 Chinese women were grouped in quintiles of BMI and according to the official Chinese classification of body weight. IVF/ICSI and pregnancy outcomes were compared between groups.
BMI was not associated with IVF/ICSI pregnancy outcomes including hCG positive rate, clinical pregnancy rate, implantation rate, ectopic pregnancy rate, ongoing pregnancy rate, early miscarriage rate, and live birth rate. However, it was negatively related to some pregnancy complications such as gestational diabetes mellitus (GDM) and hypertension. Additionally, the proportion of Cesarean-section was increased with BMI. As for prenatal outcomes, the current results showed no statistical difference in the number of male and female newborn, the proportion of low live birth weight (<2500 g), macrosomia (≥4000 g) (both in all live birth and full-term live birth), and premature delivery (<37 weeks).
The current study showed that BMI was not associated with embryo transfer outcomes after fresh embryo transfer in women undergoing their first IVF/ICSI treatment, whereas BMI was associated with GDM and gestational hypertension.
Initial observational studies and a systematic review published 5 years ago have suggested that obstetric and perinatal outcomes are better in offspring conceived following frozen rather than fresh ...embryo transfers, with reduced risks of preterm birth, small for gestational age, low birth weight and pre-eclampsia. More recent primary studies are beginning to challenge some of these findings. We therefore conducted an updated systematic review and cumulative meta-analysis to examine if these results have remained consistent over time.
The aim of this study was to perform a systematic review and cumulative meta-analysis (trend with time) of obstetric and perinatal complications in singleton pregnancies following the transfer of frozen thawed and fresh embryos generated through in-vitro fertilisation.
Data Sources from Medline, EMBASE, Cochrane Central Register of Clinical Trials DARE and CINAHL (1984-2016) were searched using appropriate key words. Observational and randomised studies comparing obstetric and perinatal outcomes in singleton pregnancies conceived through IVF using either fresh or frozen thawed embryos. Two independent reviewers extracted data in 2 × 2 tables and assessed the methodological quality of the relevant studies using CASP scoring. Both aggregated as well as cumulative meta-analysis was done using STATA.
Twenty-six studies met the inclusion criteria. Singleton babies conceived from frozen thawed embryos were at lower relative risk (RR) of preterm delivery (0.90; 95% CI 0.84-0.97) low birth weight (0.72; 95% CI 0.67-0.77) and small for gestational age (0.61; 95% CI 0.56-0.67) compared to those conceived from fresh embryo transfers, but faced an increased risk (RR) of hypertensive disorders of pregnancy (1.29; 95% CI 1.07-1.56) large for gestational age (1.54; 95% CI 1.48-1.61) and high birth weight (1.85; 95% CI 1.46-2.33). There was no difference in the risk of congenital anomalies and perinatal mortality between the two groups. The direction and magnitude of effect for these outcomes have remained virtually unchanged over time while the degree of precision has improved with the addition of data from newer studies.
The results of this cumulative meta-analysis confirm that the decreased risks of small for gestational age, low birth weight and preterm delivery and increased risks of large for gestational age and high birth weight associated with pregnancies conceived from frozen embryos have been consistent in terms of direction and magnitude of effect over several years, with increasing precision around the point estimates. Replication in a number of different populations has provided external validity for the results, for outcomes of birth weight and preterm delivery. Meanwhile, caution should be exercised about embarking on a policy of electively freezing all embryos in IVF as there are increased risks for large for gestational age babies and hypertensive disorders of pregnancy. Therefore, elective freezing should ideally be undertaken in specific cases such as ovarian hyperstimulation syndrome, fertility preservation or in the context of randomised trials.
ObjectiveTo compare success rates, associated risks and cost-effectiveness between intrauterine insemination (IUI) and in vitro fertilisation (IVF).DesignRetrospective observational study.SettingThe ...UK from 2012 to 2016.ParticipantsData from Human Fertilisation and Embryology Authority’s freedom of information request for 2012–2016 for IVF/ICSI (intracytoplasmic sperm injection)and IUI as practiced in 319 105 IVF/ICSI and 30 669 IUI cycles. Direct-cost calculations for maternal and neonatal expenditure per live birth (LB) was constructed using the cost of multiple birth model, with inflation-adjusted Bank of England index-linked data. A second direct-cost analysis evaluating the incremental cost-effective ratio (ICER) was modelled using the 2016 national mean (baseline) IVF and IUI success rates.Outcome measuresLB, risks from IVF and IUI, and costs to gain 1 LB.ResultsThis largest comprehensive analysis integrating success, risks and costs at a national level shows IUI is safer and more cost-effective than IVF treatment.IVF LB/cycle success was significantly better than IUI at 26.96% versus 11.49% (p<0.001) but the IUI success is much closer to IVF at 2.35:1, than previously considered. IVF remains a significant source of multiple gestation pregnancy (MGP) compared with IUI (RR (Relative Risk): 1.45 (1.31 to 1.60), p<0.001) as was the rate of twins (RR: 1.58, p<0.001).In 2016, IVF maternal and neonatal cost was £115 082 017 compared with £2 940 196 for IUI and this MGP-related perinatal cost is absorbed by the National Health Services. At baseline tariffs and success rates IUI was £42 558 cheaper than IVF to deliver 1LB with enhanced benefits with small improvements in IUI. Reliable levels of IVF-related MGP, OHSS (ovarian hyperstimulation syndrome), fetal reductions and terminations are revealed.ConclusionIUI success rates are much closer to IVF than previously reported, more cost-effective in delivering 1 LB, and associated with lower risk of complications for maternal and neonatal complications. It is prudent to offer IUI before IVF nationally.
IMPORTANCE: The likelihood of achieving a live birth with repeat in vitro fertilization (IVF) is unclear, yet treatment is commonly limited to 3 or 4 embryo transfers. OBJECTIVE: To determine the ...live-birth rate per initiated ovarian stimulation IVF cycle and with repeated cycles. DESIGN, SETTING, AND PARTICIPANTS: Prospective study of 156 947 UK women who received 257 398 IVF ovarian stimulation cycles between 2003 and 2010 and were followed up until June 2012. EXPOSURES: In vitro fertilization, with a cycle defined as an episode of ovarian stimulation and all subsequent separate fresh and frozen embryo transfers. MAIN OUTCOMES AND MEASURES: Live-birth rate per IVF cycle and the cumulative live-birth rates across all cycles in all women and by age and treatment type. Optimal, prognosis-adjusted, and conservative cumulative live-birth rates were estimated, reflecting 0%, 30%, and 100%, respectively, of women who discontinued due to poor prognosis and having a live-birth rate of 0 had they continued. RESULTS: Among the 156 947 women, the median age at start of treatment was 35 years (interquartile range, 32-38; range, 18-55), and the median duration of infertility for all 257 398 cycles was 4 years (interquartile range, 2-6; range, <1-29). In all women, the live-birth rate for the first cycle was 29.5% (95% CI, 29.3%-29.7%). This remained above 20% up to and including the fourth cycle. The cumulative prognosis-adjusted live-birth rate across all cycles continued to increase up to the ninth cycle, with 65.3% (95% CI, 64.8%-65.8%) of women achieving a live birth by the sixth cycle. In women younger than 40 years using their own oocytes, the live-birth rate for the first cycle was 32.3% (95% CI, 32.0%-32.5%) and remained above 20% up to and including the fourth cycle. Six cycles achieved a cumulative prognosis-adjusted live-birth rate of 68.4% (95% CI, 67.8%-68.9%). For women aged 40 to 42 years, the live-birth rate for the first cycle was 12.3% (95% CI, 11.8%-12.8%), with 6 cycles achieving a cumulative prognosis-adjusted live-birth rate of 31.5% (95% CI, 29.7%-33.3%). For women older than 42 years, all rates within each cycle were less than 4%. No age differential was observed among women using donor oocytes. Rates were lower for women with untreated male partner–related infertility compared with those with any other cause, but treatment with either intracytoplasmic sperm injection or sperm donation removed this difference. CONCLUSIONS AND RELEVANCE: Among women in the United Kingdom undergoing IVF, the cumulative prognosis-adjusted live-birth rate after 6 cycles was 65.3%, with variations by age and treatment type. These findings support the efficacy of extending the number of IVF cycles beyond 3 or 4.
Abstract
BACKGROUND
Women who achieve pregnancy by ART show an increased risk of obstetric and perinatal complications compared with those with spontaneous conception (SC).
OBJECTIVE AND RATIONALE
...The purpose of this systematic review and meta-analysis was to synthesize the best available evidence regarding the association between ART and gestational diabetes mellitus (GDM) in women with singleton pregnancies. The research question asked was whether the risk of GDM is higher in women achieving singleton pregnancy by ART compared with those achieving singleton pregnancy spontaneously.
SEARCH METHODS
A literature search, in MEDLINE, Scopus and Cochrane databases, covering the period 1978–2019, was performed aiming to identify studies comparing the risk of GDM in singleton pregnancies after ART versus after SC. Both matched and unmatched studies were considered eligible. Meta-analysis of weighted data was performed using the random effects model. Results were reported as risk ratio (RR) with 95% CI. Heterogeneity was quantified with the I2 index.
OUTCOMES
The study reports on 63 760 women who achieved a singleton pregnancy after ART (GDM was present in 4776) and 1 870 734 women who achieved a singleton pregnancy spontaneously (GDM in 158 526). Women with singleton pregnancy achieved by ART showed a higher risk of GDM compared with those with singleton pregnancy achieved spontaneously (RR 1.53, 95% CI 1.39–1.69; I2 78.6%, n = 37, 1 893 599 women). The direction or the magnitude of the effect observed did not change in subgroup analysis based on whether the study was matched (n = 17) or unmatched (n = 20) (matched: RR 1.42, 95% CI 1.17–1.72; I2 61.5%—unmatched: RR 1.58, 95% CI 1.40–1.78; I2 84.1%) or whether it was prospective (n = 12) or retrospective (n = 25) (prospective studies: RR 1.52, 95% CI 1.27–1.83, I2 62.2%—retrospective studies: RR 1.53, 95% CI 1.36–1.72, I2 82.5%). Regarding the method of fertilization, a higher risk of GDM after ART versus SC was observed after IVF (n = 7), but not after ICSI (n = 6), (IVF: RR 1.95, 95% CI 1.56–2.44, I2 43.1%—ICSI: RR 1.42, 95% CI 0.94–2.15, I2 73.5%). Moreover, regarding the type of embryo transfer (ET), a higher risk of GDM after ART versus SC was observed after fresh (n = 14) but not after frozen (n = 3) ET (fresh ET: RR 1.38, 95% CI 1.03–1.85, I2 75.4%—frozen ET: RR 0.46, 95% CI 0.10–2.19; I2 73.1%). A higher risk of GDM was observed after ART regardless of whether the eligible studies included patients with polycystic ovary syndrome (RR 1.49, 95% CI 1.33–1.66, I2 75.0%) or not (RR 4.12, 95% CI 2.63–6.45, I2 0%), or whether this information was unclear (RR 1.46, 95% CI 1.22–1.75, I2 77.7%).
WIDER IMPLICATIONS
The present systematic review and meta-analysis, by analysing 1 893 599 women, showed a higher risk of GDM in women achieving singleton pregnancy by ART compared with those achieving singleton pregnancy spontaneously. This finding highlights the importance of early detection of GDM in women treated by ART that could lead to timely and effective interventions, prior to ART as well as during early pregnancy.
To evaluate the association between the number of oocytes retrieved and cumulative live birth rates.
Retrospective multicenter analysis using individual patient data.
Tertiary referral hospitals.
In ...total, 14,469 patients were analyzed. The study included the first cycle of patients stimulated for IVF/intracytoplasmic sperm injection (ICSI) from 2009 to 2014. All patients included in the analysis had either delivered a baby or had used all their embryos after their first stimulated cycle. All patients had vitrification as cryopreservation method. All women were followed up for at least 2 years.
Ovarian stimulation with GnRH antagonist protocol for IVF/ICSI.
The primary outcome was the cumulative live birth rate defined as the delivery of at least one live-born infant (>24 weeks of gestation) in the fresh or in the subsequent frozen-thawed cycles in relation to the number of oocytes retrieved. Only the first delivery was considered in the analysis. The secondary outcome was live birth after the fresh IVF/ICSI cycle only.
Cumulative live birth rates steadily increased with the number of oocytes, reaching 70% when ≥25 oocytes were retrieved. Interestingly, no plateau in cumulative live birth rates was observed, but a moderate increase of 5.1% on average was detected beyond 27 oocytes. Regarding the fresh cycle outcome, live birth probability increased up to seven oocytes retrieved and remained relatively unchanged (increase or decrease of ≤5%) between seven and 20 oocytes retrieved. However, a drop in fresh live birth rates was identified thereafter, which could be attributed to the progressive increase in “freeze-all” cycle rate with the number of oocytes retrieved, exceeding 20% in patients with >20 oocytes retrieved.
This is the largest multicenter study evaluating for the first time the impact of ovarian response on cumulative live birth rate. The significant progressive increase of cumulative live birth rate with the number of oocytes in our study suggests that ovarian stimulation may not have a detrimental effect on oocyte/embryo quality in good-prognosis women less than 40 year old. Nevertheless, although very high ovarian response may further increase cumulative live birth rates, ovarian stimulation should be rational and avoid extreme response in terms of oocytes retrieved to preserve patients' convenience and safety and avoid ovarian hyperstimulation syndrome or other iatrogenic complications.
Tasas acumuladas de embarazo según el número de ovocitos recuperados en la primera estimulación ovárica para fecundación in vitro/inyección intracitoplasmática de espermatozoides: análisis multicéntrico internacional incluyendo ≈ 15.000 mujeres.
Evaluar la asociación entre el número de ovocitos recuperados y la tasa acumulada de embarazo.
Análisis retrospectivo multicéntrico utilizando datos individuales de pacientes.
Hospitales terciarios de referencia.
Se analizaron un total de 14,469 pacientes. El estudio incluyó el primer ciclo de pacientes estimuladas para FIV/inyección intracitoplasmática de espermatozoides (ICSI) desde 2009 hasta 2014. Todas las pacientes incluidas en el análisis habían dado a luz a un niño o habían utilizado ya todos sus embriones después del primer ciclo de estimulación. Todas las mujeres fueron seguidas al menos durante 2 años.
Estimulación ovárica para FIV/ICSI con protocolo de antagonistas.
El resultado principal fue la tasa acumulada de recién nacido vivo definida como el nacimiento de al menos un niño vivo (>24 semanas de gestación) en el ciclo en fresco o en los siguientes ciclos de criotransferencia en relación al número de ovocitos recuperados. Sólo se consideró el primer parto para el análisis. El resultado secundario fue el recién nacido únicamente después del primer ciclo de FIV/ICSI en fresco.
La tasa acumulada de embarazo aumentó progresivamente con el número de ovocitos, alcanzando el 70% cuando se obtuvieron ≥25 ovocitos. Llama la atención la no observación de plateau en las tasas acumuladas de nacidos vivos, sino un moderado incremento del 5.1% de promedio observado con más de 27 ovocitos. En relación al resultado del ciclo en fresco, la probabilidad de recién nacido se incrementó hasta los 7 ovocitos y permaneció relativamente estable (aumento o descenso ≤ 5%) entre 7 y 20 ovocitos recuperados. Sin embargo, se observó un descenso en las tasas de nacidos en fresco más allá de los 20 ovocitos recuperados, lo cual podría atribuirse al progresivo incremento de los ciclos con congelación de todos los embriones a medida que aumentó el número de ovocitos recuperados, superando el 20% cuando hubo >20 ovocitos.
Este es el mayor estudio multicéntrico realizado que evalúa por primera vez el impacto de la respuesta ovárica sobre las tasas acumuladas de nacidos vivos. El aumento progresivo significativo de la tasa de nacidos vivos en relación al número de ovocitos obtenidos en nuestro estudio sugiere que la estimulación ovárica puede no tener un efecto perjudicial sobre la calidad de los ovocitos/embriones en mujeres con buen pronóstico menores de 40 años. No obstante, aunque una respuesta ovárica muy alta puede incrementar las tasas acumuladas de nacidos vivos, debería realizarse una estimulación ovárica racional y evitar respuestas extremas en términos de ovocitos recuperados para preservar el bienestar y comodidad de las pacientes y evitar el síndrome de hiperestimulación ovárica u otras complicaciones iatrogénicas.
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