Perinatal outcomes of pregnancies resulting from assisted reproduction technology in SARS-CoV-2-infected women: a prospective observational study.

OBJECTIVE: To evaluate the perinatal and maternal outcomes of pregnancies in women infected with SARS-CoV-2, comparing spontaneous and in vitro fertilization (IVF) pregnancies (with either own or donor oocytes). DESIGN: Multicenter, prospective, observational study. SETTING: 78 centers participating in the Spanish COVID19 Registry. PATIENT(S): 1,347 pregnant women with SARS-CoV-2 positive results registered consecutively between February 26 and November 5, 2020. INTERVENTION(S): The patients' information was collected from their medical records, and multivariable regression analyses were performed, controlling for maternal age and the clinical presentation of the infection. MAIN OUTCOME MEASURE(S): Obstetrics and neonatal outcomes, pregnancy comorbidities, intensive care unit admission, mechanical ventilation need, and medical conditions. RESULT(S): The IVF group included 74 (5.5%) women whereas the spontaneous pregnancy group included 1,275 (94.5%) women. The operative delivery rate was high in all patients, especially in the IVF group, where cesarean section became the most frequent method of delivery (55.4%, compared with 26.1% of the spontaneous pregnancy group). The reason for cesarean section was induction failure in 56.1% of the IVF patients. IVF women had more gestational hypertensive disorders (16.2% vs. 4.5% among spontaneous pregnancy women, adjusted odds ratio [aOR] 5.31, 95% confidence interval [CI] 2.45-10.93) irrespective of oocyte origin. The higher rate of intensive care unit admittance observed in the IVF group (8.1% vs. 2.4% in the spontaneous pregnancy group) was attributed to preeclampsia (aOR 11.82, 95% CI 5.25-25.87), not to the type of conception. CONCLUSION(S): A high rate of operative delivery was observed in pregnant women infected with SARS-CoV-2, especially in those with IVF pregnancies; method of conception did not affect fetal or maternal outcomes, except for preeclampsia. CLINICAL TRIAL REGISTRATION NUMBER: NCT04558996.

Mortality from infancy to adolescence in singleton children conceived from assisted reproductive techniques versus naturally conceived singletons in Sweden.

OBJECTIVE: To assess infant (<1 year) and childhood (1-18 years) mortality in singletons conceived through assisted reproductive techniques (ART) versus naturally conceived singletons. DESIGN: Nationwide prospective study. SETTING: Sweden. PATIENT(S): All singleton liveborn infants born from 1983 to 2012 in Sweden identified using the Medical Birth Register (N = 2,847,108), of whom 43,506 were conceived through ART treatments including in vitro fertilization with and without intracytoplasmic sperm injection. INTERVENTION(S): None. MAIN OUTCOME MEASURES(S): Infant (<1 year) and childhood (1-18 years) mortality. RESULT(S): Data on ART treatment and covariates were retrieved from population-based registers using the unique personal identity number assigned to all permanent residents in Sweden. Cox proportional hazards models estimated the hazard ratios (HRs) with 95% confidence intervals (CIs) as measures of association between ART treatments and death. The analyses were adjusted for maternal characteristics, infertility, child sex, and birth cohort and were restricted to individuals with complete information on covariates for fully adjusted analysis. Compared with naturally conceived singletons, higher infant mortality risks were seen in infants conceived through ART (adjusted HR 1.45; 95% CI, 1.19-1.77), especially after transfer of cryopreserved embryos (adjusted HR 2.30; 95% CI, 1.46-3.64). Early neonatal mortality risk (deaths during the first week) was increased in children born after transfer of blastocysts (HR 2.40; 95% CI, 1.05-5.48). No increased mortality risk was observed between the ages of 1 and 18 years. CONCLUSION(S): Singletons conceived through ART had an increased risk of infant mortality from birth up to 1 year of life, predominantly in the early neonatal period and in pregnancies after transfer of frozen and thawed embryos.

Influence of subfertility and assisted reproductive technology treatment on mortality of women after delivery.

OBJECTIVE: To compare incidence, risk factors, and etiology of women's deaths in fertile, subfertile, and undergoing assisted reproductive technology (ART) in the years after delivery. DESIGN: Retrospective cohort. SETTING: University hospital. PATIENT(S): Women who had delivered in Massachusetts. INTERVENTION(S): This study used data from the Society for Assisted Reproductive Technology Clinic Outcome Reporting System linked to vital records, hospital stays, and the Massachusetts death file. Mortality of patients delivered from 2004-2013 was evaluated through 2015. The exposure groups, determined on the basis of the last delivery, were ART-treated (linked to Society for Assisted Reproductive Technology Clinic Outcome Reporting System), subfertile (no ART but with indicators of subfertility including birth certificate checkbox for fertility treatment, prior hospitalization for infertility [International Classification of Disease codes 9 628 or V23], and/or prior delivery with checkbox or ART), or fertile (neither ART nor subfertile). Numbers (per 100,000 women-years) and causes of death were obtained from the Massachusetts death file. MAIN OUTCOME MEASURE(S): Mortality of women after delivery in each of the three fertility groups and the most common etiology of death in each. RESULT(S): We included 483,547 women: 16,429 ART, 11,696 subfertile, and 455,422 fertile among whom there were 1,280 deaths with 21.1, 25.5, and 44.7 deaths, respectively, per 100,000 women-years. External causes (violence, accidents, and poisonings) were the most common reasons for death in the fertile group. Deaths occurred on average 46 months after delivery. When external causes of death were removed, there were 19.1, 17.0, and 25.6 deaths per 100,000 women-years and leading causes of death in all groups were cancer and circulatory problems. CONCLUSION(S): The study presents reassuring data that death rates within 5 years of delivery in ART-treated and subfertile women do not differ from those in fertile women.

The way to move beyond the numbers: the lesson learnt from the Italian Obstetric Surveillance System.

OBJECTIVE: To describe the Italian Obstetric Surveillance System (ItOSS) investigating maternal death through incident case reporting and confidential enquiries. METHODS: All maternal deaths occurred in any public and private health facility in 8 Italian regions covering 73% of national births have been notified to the ItOSS. Every incident case is confidentially reviewed to assess quality of care and establish the cause and avoidability of the death. FINDINGS: A total of 106 maternal deaths among 1 455 545 live births have been notified to the surveillance system in 2013-17. Haemorrhage, sepsis and hypertensive disorders of pregnancy are the leading causes of direct maternal deaths due to obstetric causes. CONCLUSIONS: A maternal mortality surveillance system, including incidence reporting and confidential enquiries along with a retrospective analysis of administrative data sources, emerged as the best option for case ascertainment and for preventing avoidable maternal deaths.

Relationship between reproductive medicine for women with severe complications and maternal death in Japan.

AIM: To investigate the influence of reproductive medicine in maternal death cases in Japan. METHODS: This retrospective study investigated the incidence of maternal deaths related to reproductive medicine in Japan from 2013 to 2015, and the relationship between fertility treatment and maternal death. RESULTS: Fifteen out of 134 women (11.2%) involved in this study who underwent treatment for infertility died. Four experienced pregnancy with severe maternal complications (26.6%). The complications were active systemic lupus erythematosus, exacerbated depression, uncontrolled arrhythmia and uncontrolled type 2 diabetes mellitus. At least three of these four died due to these complications. CONCLUSION: The maternal death rate of women who have undergone fertility treatment is similar to the birth rate due to assisted reproductive technology in Japan. Some maternal death cases involve severe uncontrolled complications. Therefore, medical histories should be evaluated before fertility treatment.

Mortality in Women Treated With Assisted Reproductive Technology-Addressing the Healthy Patient Effect.

In previous studies, investigators have reported reduced mortality among women undergoing assisted reproductive technology (ART) treatment, possibly related to selection of healthy women into ART treatment. Our aim in this study was to explore the impact of relevant selection factors on the association between ART treatment and mortality and to explore effect modification by parity. Women treated with ART in fertility clinics in Denmark during 1994-2009 (n = 42,897) were age-matched with untreated women from the background population (n = 204,514) and followed until December 31, 2010. With adjustment for relevant confounders, the risk of death was lower among ART-treated women during the first 2 years after ART treatment (hazard ratio (HR) = 0.68, 95% confidence interval (CI): 0.63, 0.74), but there was no apparent difference after 10 years (HR = 0.92, 95% CI: 0.79, 1.07). Having children prior to ART treatment was associated with markedly reduced mortality (HR = 0.45, 95% CI: 0.38, 0.53), possibly due to better health among fertile women. While the frequencies of previous medical and psychiatric diagnoses among ART-treated and untreated women were similar, differences in disease severity could explain the reduced mortality among ART-treated women, as poor prognosis would make initiation of ART treatment unlikely. The survival advantage among ART-treated women is likely a selection phenomenon rather than a biological phenomenon.

Validation of birth outcomes from the Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS): population-based analysis from the Massachusetts Outcome Study of Assisted Reproductive Technology (MOSART).

OBJECTIVE: To assess the validity of outcome data reported to the Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS) compared with data from vital records and the birth defects registry in Massachusetts. DESIGN: Longitudinal cohort. SETTING: Not applicable. PARTICIPANT(S): A total of 342,035 live births and fetal deaths from Massachusetts mothers giving birth in the state from July 1, 2004, to December 31, 2008; 9,092 births and fetal deaths were from mothers who had conceived with the use of assisted reproductive technology (ART) and whose cycle data had been reported to the SART CORS. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): Percentage agreement between maternal race and ethnicity, delivery outcome (live birth or fetal death), plurality (singleton, twin, or triplet+), delivery date, and singleton birth weight reported in the SART CORS versus vital records; sensitivity and specificity for birth defects among singletons as reported in the SART CORS versus the Massachusetts Birth Defects Monitoring Program (BDMP). RESULT(S): There was >95% agreement between the SART CORS and vital records for fields of maternal race/ethnicity, live birth/fetal death, and plurality; birth outcome date was within 1 day with 94.9% agreement and birth weight was within 100 g with 89.6% agreement. In contrast, sensitivity for report of any birth defect was 38.6%, with a range of 18.4%-50.0%, for specific birth defect categories. CONCLUSION(S): Although most SART CORS outcome fields are accurately reported, birth defect variables showed poor sensitivity compared with the gold standard data from the BDMP. We suggest that reporting of birth defects be discontinued.

Pregnancy-related complications and adverse pregnancy outcomes in multiple pregnancies resulting from assisted reproductive technology: a meta-analysis of cohort studies.

OBJECTIVE: To provide an up-to-date comparison of pregnancy-related complications and adverse pregnancy outcomes of multiple pregnancies generated with assisted reproductive technology (ART) vs. spontaneous conception. DESIGN: Meta-analysis. SETTING: University-affiliated teaching hospital. PATIENT(S): Multiple pregnancies conceived by ART or naturally. INTERVENTION(S): Searches through October 2014 were conducted on PubMed, Google Scholar, Cochrane Libraries, China Biology Medicine disc, Chinese Scientific Journals Fulltext Database, China National Knowledge Infrastructure, and Wanfang Data, to identify studies that met prestated inclusion criteria. Either a fixed- or a random-effects model was used to calculate the overall combined risk estimates. Subgroup analysis was performed to explore potential heterogeneity moderators. MAIN OUTCOME MEASURE(S): Pregnancy-related complications and adverse pregnancy outcomes. RESULT(S): Thirty-nine cohort studies involving 146,008 multiple births were included in the meta-analysis. Multiple pregnancies from ART were associated with a higher risk of premature rupture of membranes (relative risk [RR] = 1.20, 95% confidence interval [CI]: 1.05-1.37; I(2) = 15%); pregnancy-induced hypertension (RR = 1.11, 95% CI: 1.04-1.19; I(2) = 6%); gestational diabetes mellitus (RR = 1.78, 95% CI: 1.25-2.55; I(2) = 42%); preterm birth (RR = 1.08, 95% CI: 1.03-1.14; I(2) = 83%); very preterm birth (RR = 1.18, 95% CI: 1.04-1.34; I(2) = 79%); low birth weight (RR = 1.04, 95% CI: 1.01-1.07; I(2) = 47%); very low birth weight (RR = 1.13, 95% CI: 1.01-1.25; I(2) = 62%); and congenital malformation (RR = 1.11, 95% CI: 1.02-1.22; I(2) = 30%). The relevant heterogeneity moderators have been identified by subgroup analysis. Sensitivity analysis yielded similar results. No evidence of publication bias was observed. CONCLUSION(S): Although the role of potential bias and evidence of heterogeneity should be carefully evaluated, the present study suggests that multiple pregnancies generated via ART, vs. spontaneous conception, are associated with higher risks of pregnancy-related complications and adverse pregnancy outcomes. Further research is needed to determine which aspect of ART poses the most risk and how this risk can be minimized.

A perspective on the impact of reproductive technologies on food production in Africa.

Africa for the largest part is still regarded as part of the developing world and has a history of political instability, natural disasters, floods and droughts that all had an effect on the development of livestock production systems and the potential application of biotechnologies. It is expected that the human population in sub Saharan Africa will experience a growth of 1.2 % per year over the next 30 years. There is therefore pressure to increase sustainable productivity of livestock. Reproductive technologies such as Artificial Insemination in Africa were driven primarily by the need to control or prevent venereal diseases like Trichomoniases and Campylobacter fetus in cattle. Reproductive biotechnology had a limited impact in Africa due to several factors including a lack of infrastructure and animal recording systems, clear breeding objectives and continuously changing production systems and markets. Africa has a large variety of genetic resources adapted to the diverse environment and production systems and biotechnology should be applied within this context for an increase in food production.

Assisted reproductive technology and pregnancy-related hypertensive complications: a systematic review.

Hypertensive complications in pregnancy are the leading cause of maternal morbidity, at least in the developed countries. In recent years, infertility issues are managed with ever growing therapeutic options namely assisted reproductive technologies (ART), which improve the ratio of successful induction of pregnancy. It is still debated whether various ART modalities are associated with adverse pregnancy outcomes, including hypertensive complications, particularly with higher incidence of preeclampsia. The main source of controversy stems from the diversity of effect modifiers modulating the association between ART-oriented pregnancy and hypertensive disorders. Indeed, women undergoing an ART procedure are affected by diverse causes of infertility, are frequently characterized by different genetic patterns with respect to their artificially conceived embryo and experienced multiple gestations. In order to investigate whether ART modalities are associated with increased incidence of hypertensive complications in pregnancy, we reviewed all published studies carried out before the end of 2010 and identified in the PubMed database. Among the 47 studies finally selected and by acknowledging the potential of shortcomings related to the different study design and populations, the overall evidence suggests that ART-oriented pregnancies-especially the in-vitro fertilization techniques-are accompanied by increased risk for gestational hypertension and preeclampsia as compared with non-ART pregnancies, even after adjustment for confounders. Multiple gestations, advanced age and underlying polycystic ovary syndrome resulted in constant confounders of the questioned association. Reducing multiple gestations by implementing single embryo techniques might be the therapeutic limiting step to lower the rate of hypertensive complications in assisted pregnancies.

Neurodevelopmental outcomes of extremely premature infants conceived after assisted conception: a population based cohort study.

OBJECTIVE: To compare neurodevelopmental outcomes of extremely preterm infants conceived after assisted conception (AC) compared with infants conceived spontaneously (non-AC). DESIGN: Population-based retrospective cohort study. SETTING: Geographically defined area in New South Wales and the Australian Capital Territory, Australia served by a network of 10 neonatal intensive care units. PATIENTS: Infants <29 weeks' gestation born between 1998 and 2004. INTERVENTION: At 2-3 years corrected age, 1473 children were assessed with either the Griffiths Mental Developmental Scales or the Bayley Scales of Infant Development. MAIN OUTCOME MEASURE: Moderate/severe functional disability defined as developmental delay (Griffiths General Quotient or Bayley Mental Developmental Index >2 SD below the mean), cerebral palsy (unable to walk without aids), deafness (bilateral hearing aids or cochlear implant) or blindness (visual acuity <6/60 in the better eye). RESULTS: Mortality and age at follow-up were comparable between the AC and non-AC groups. Developmental outcome was evaluated in 217 (86.5%) AC and 1256 (71.7%) non-AC infants. Using multivariate adjusted analysis, infants born after in-vitro fertilisation at 22-26 weeks' gestation (adjusted OR 1.79, 95% CI 1.05 to 3.05, p=0.03) but not at 27-28 weeks' gestation (adjusted OR 0.81, 95% CI 0.37 to 1.77; p=0.59) had higher rate of functional disability than those born after spontaneous conception. CONCLUSIONS: AC is associated with adverse neurodevelopmental outcome among high risk infants born at 22-26 weeks' gestation. This finding warrants additional exploration.

Probabilistic linkage of assisted reproductive technology information with vital records, Massachusetts 1997-2000.

To assess the validity of probabilistic linkage (PL) in combining national surveillance data on assisted reproductive technology (ART) with Massachusetts birth and infant death data, for the purpose of monitoring maternal and child health outcomes of ART. A study conducted in 2006 utilized direct identifiers to match Massachusetts birth records with records on ART procedures performed to Massachusetts residents in fertility clinics located in Massachusetts and Rhode Island, achieving a linkage rate of 87.5%. The present study employed PL using the program Link Plus, without access to direct identifiers. The primary linking variables were maternal and infant dates of birth, and plurality. Ancillary variables such as maternal ZIP code and gravidity helped resolve duplicate matches and capture additional matches. PL linked 5,390 (87.8%) of 6,139 deliveries, correctly identifying 96.4% of the matches previously obtained using deterministic linkage methods. PL yielded a high linkage rate with satisfactory validity; this method may be applied in other states to help monitor the maternal and child health outcomes of ART.

Increased maternal cardiovascular mortality associated with pregnancy in women with Turner syndrome.

In women with Turner syndrome, the risk of death from aortic dissection or rupture during pregnancy may be 2%, and this risk persists during the postpartum period owing to pregnancy-related aortic changes. Turner syndrome is a relative contraindication for pregnancy; however, it is an absolute contraindication for pregnancy in a patient with a documented cardiac anomaly. This document replaces the 2008 document of the same name.

Predicting the impact of in vitro fertilisation and other forms of assisted conception on perinatal and infant mortality in England and Wales: examining the role of multiplicity.

The increased risk of perinatal and infant mortality observed among in vitro fertilisation (IVF) births and other assisted conception births is thought to be largely attributable to multiplicity. Using mortality statistics and estimates of the proportion of births following infertility treatment, we predicted the excess stillbirths and infant deaths associated with twins and higher order births resulting from assisted conception in England and Wales. According to our results, approximately 73 deaths could have been avoided in 2001 if all IVF infants had been born as singletons or as naturally occurring monozygotic twins, equating to a population attributable risk fraction of around 1% for perinatal and infant deaths. If we include all types of assisted conception, this figure was estimated to be around 4% of deaths-more than 220 perinatal and infant deaths in 2001. We confirm the public health importance of multiple births associated with assisted conception.

Linking birth and infant death records with assisted reproductive technology data: Massachusetts, 1997-1998.

OBJECTIVES: To link data from the US assisted reproductive technology (ART) registry with the Massachusetts birth-infant death file to create a comprehensive dataset on the circumstances surrounding conception and maternal and infant outcomes for a population of ART-conceived infants. METHODS: The authors sought to link data for 3704 ART-conceived live-born infants from 2703 deliveries in 1997-1998 involving Massachusetts resident mothers who gave birth in Massachusetts, Rhode Island, New Hampshire, or Connecticut to their corresponding Massachusetts birth record using a two-stage algorithm. Maternal and infant dates of birth served as the primary linkage variables. Maternal names for a subset of the ART-conceived infants were obtained and used in the second stage of the algorithm to confirm a sample of records that matched in Stage I, to resolve duplicate matches, and to link unmatched records. RESULTS: In Stage I, 78% of ART deliveries matched with only one Massachusetts record, 2% matched with two records, and 20% remained unmatched. Overall, the complete algorithm using maternal name data for a portion of records yielded an 89% linkage rate. Nearly all of the records that matched during Stage I that were evaluated with maternal name data in Stage II were confirmed as correctly linked. CONCLUSIONS: This project confirms that high-yield data linkage can be achieved in the absence of specific identifiers (e.g., name and social security number). Nonetheless, additional matches were achieved when name data were obtained. This linkage creates the first population-based file in the US capturing detailed information on ART births.

Effective use of assisted reproduction.

Subfertility affects one in seven couples in the western world. Although the availability of assisted reproduction has changed the outlook for many childless couples, the procedures themselves have far-reaching implications in terms of invasiveness, acceptability and cost. There is now greater awareness that effective care involves using treatments that combine efficacy, appropriateness and efficiency with safety. Randomized trials addressing assisted reproduction are few and generally tend to suffer from a number of methodological inadequacies. Although IVF continues to be the treatment of choice for couples with persistent infertility, there is currently insufficient evidence from trial data to indicate that IVF is more effective than the other treatment options available for unexplained infertility. Intracytoplasmic sperm injection is beneficial in severe male factor infertility but is not warranted in other situations. There is an urgent need to focus on developing strategies to improve success rates of assisted reproduction and minimize the side-effects such as ovarian hyperstimulation and multiple pregnancy. Multiple pregnancy is the most common major complication of IVF and has a profound effect on maternal and neonatal morbidity as well as health service costs.

Risks and complications in assisted reproduction techniques: Report of an ESHRE consensus meeting.

Assisted reproduction technique (ART) is an efficacious treatment in subfertile couples. So far little attention has been paid to the safety of ART, i.e. to its adverse events and complications. The consensus meeting on Risks and Complications in ART held in Maastricht in May 2002 focused on four topics: multiple pregnancies, long-term effects of ART on women, effects of ART on offspring, and morbidity/mortality registries.