Assisted Reproductive Technology Births Research Articles

Accuracy of assisted reproductive technology information on the Massachusetts birth certificate, 1997–2000

To evaluate the accuracy of assisted reproductive technology (ART) reporting on the Massachusetts birth certificate and to explore the individual and hospital-level characteristics associated with ART reporting. Validity analysis of population-based data. Live-birth deliveries by Massachusetts-resident mothers during 1997-2000. Live births and delivery mothers. The ART data maintained by the Centers for Disease Control and Prevention were linked with the live birth-infant death records in Massachusetts. Successfully linked records were used as the gold standard for ART-related deliveries in evaluating the validity of the ART information reported on the Massachusetts birth certificate. Sensitivity and specificity. The sensitivity of ART reporting on the birth certificate was 27% and the specificity >99%. Sensitivity of ART reporting was higher among women with multiple deliveries (twins: 32%; triplets+: 43%) and preterm deliveries (36%). During the period evaluated, reporting of ART information on the birth certificate was incomplete, and ART births identified through the birth certificate were a biased sample of the population of ART births. Using delivery hospital data as the sole source of ART information for the standard birth certificate may yield inaccurate information.

Implications of epigenetics and genomic imprinting in assisted reproductive technologies

There have been several reports of an increased risk of genomic imprinting disorders associated with assisted reproductive technology (ART). However, the connection between imprinting defects and ART is tenuous. In this review, this putative association is investigated in detail, with emphasis on particular steps of the ART process, and which of these may be prone to induction of imprinting errors due to synchrony with major imprinting events during gametogenesis, fertilization, and early embryonic development. While contributions from in vitro manipulation of gametes and embryos cannot be ruled out, it appears that superovulation and/or the condition of infertility, itself, may be largely responsible for the increased risk of genomic imprinting disorders observed with ART births. However, two significant shortcomings of all of these studies preclude rigorous exploration of this issue: the lack of large, longitudinal studies on specific cohorts of ART-conceived children, and questions surrounding the primary generation of expression and epigenetic data from oocytes and embryos. Future directions for study are proposed, along with a preview of what may be in store as the art of ART advances.

ART and major structural birth defects in the United States

Sir, We read with interest the study by Reefhuis et al. (2009) showing that assisted reproductive technology (ART) treatment is a risk for structural birth defects. The authors recognize that this risk may be over-stated because underlying subfertility may in itself be an important risk factor for such defects. In our meta-analysis of 19 studies (Rimm et al., 2004), where we found an overall risk of 1.29, we noted the failure of each of those 19 studies to use the most appropriate control group, namely infertile couples conceiving spontaneously. Responding to the concern we raised, Zhu et al. (2006) attempted to design an analysis with a control group made up of subfertile couples. They compared three groups of children: those born of fertile couples (Group A), those born of infertile couples who conceived spontaneously after 12 months (Group B) and those born of infertile couples who conceived after ART treatment (Group C). They found that when compared with Group A, singletons in Group B and in Group C both had a higher incidence of congenital malformations. The adjusted hazard ratios were 1.20 [95% confidence interval (CI): 1.07 –1.35] and 1.39, respectively (95% CI: 1.23– 1.57). When the singletons in Group C were compared with those in Group B, the adjusted hazard ratio was 1.17 (95% CI: 1.00– 1.36). Zhu et al. suggested that some of the determinants of infertility might share a common causal pathway with mechanisms that cause congenital malformations. We were surprised that the Reefhuis study presents no overall rate of malformations in women aged 35 and over. Apparently there is a very large difference in the age distribution of the ART group and the non-ART group as shown in Table 1 for those without major birth defects. Only 13% of the non-ART mothers were 35 and older, whereas 55% of the ART mothers were 35 or older. The authors failed to show the age of the ART and non-ART mothers with a major defect. When there is such a large difference in the age distribution between the two groups, adjustment for age is not a sensitive method of analysis. Stratifying by age is more sensitive because it takes interaction into account.

Compared with various assisted reproductive technology birth of the baby's birth defects in 1,540 cases

Compared with various assisted reproductive technology birth of the baby's birth defects in 1,540 cases

The effects of competition on assisted reproductive technology outcomes

To evaluate the relationship between competition among fertility clinics and assisted reproductive technology (ART) treatment outcomes, particularly multiple births. Using clinic-level data from 1995 to 2001, we examined the relationship between competition and clinic-level ART outcomes and practice patterns. National database registry. Clinics performing ART. The number of clinics within a 20-mile (32.19-km) radius of a given clinic. Clinic-level births, singleton births, and multiple births per ART cycle; multiple births per ART birth; average number of embryos transferred per cycle; and the proportion of cycles for women under age 35 years. The number of competing clinics is not strongly associated with ART birth and multiple birth rates. Relative to clinics with no competitors, the rate of multiple births per cycle is lower (-0.03 percentage points) only for clinics with more than 15 competitors. Embryo transfer practices are not statistically significantly associated with the number of competitors. Clinic-level competition is strongly associated with patient mix. The proportion of cycles for patients under 35 years old is 6.4 percentage points lower for clinics with more than 15 competitors than for those with no competitors. Competition among fertility clinics does not appear to increase rates of multiple births from ART by promoting more aggressive embryo transfer decisions.

Profound phenotypic variation among mice deficient in the maintenance of genomic imprints

An alteration in the mechanism that maintains the monoallelic, imprinted expression of genes can result in their biallelic expression and lead to disruptions in fetal development. Here, we examined the consequences of a loss of maintenance methylation at one specific stage of preimplantation, induced by a deficiency of the oocyte-derived Dnmt1o protein and known to produce biallelic expression of imprinted genes. Phenotypes of mid-gestation Dnmt1o-deficient mouse embryos were assessed by a scoring system based on the developmental stage of 17 anatomical features and by magnetic resonance microscopy. Many mid-gestation embryos developing without Dnmt1o protein exhibited significant developmental delays of multiple organ systems (P < 0.05) and a wide variety of morphologic anomalies compared with wild-type embryos. Most of the remaining mid-gestation Dnmt1o-deficient embryos appeared normal. These findings indicate that a profound range of gestational phenotypes can be induced by the loss of a single protein at a specific preimplantation developmental stage. This is best explained by the formation of epigenetic mosaic early embryos, composed of somatic cells with different spectra of normal intact genomic imprints. These findings have important implications for understanding the types of embryonic phenotypes related to the disruption of inherited imprints, and thus may provide a model of altered imprinting in humans. In particular, because Dnmt1o functions in the preimplantation embryo, a complete or partial loss of Dnmt1o function may play a role in epigenetic abnormalities seen in assisted reproduction technology births.

A survey of assisted reproductive technology births and imprinting disorders

Genomic imprinting is an epigenetic process in which allele-specific gene expression is dependent on the parental inheritance. Although only a minority of human genes are imprinted, those that have been identified to date have been preferentially implicated in prenatal growth and neurodevelopment. Mutations or epimutations in imprinted genes or imprinting control centres are associated with imprinting disorders such as Angelman syndrome (AS) and Beckwith-Wiedemann syndrome (BWS). Recently, an increased frequency of assisted reproductive technology (ART) conceptions has been reported in children with BWS and AS. However, the risk of imprinting disorders in ART children is unknown. We undertook a survey of 2492 children born after ART in the Republic of Ireland and Central England with the aim of detecting cases (both clinically diagnosed and previously unrecognized) of BWS and AS in this cohort. The response rate to an initial questionnaire was 61%, corresponding to data for 1524 children. After evaluation of the questionnaire, 70 children were invited for a detailed clinical assessment, and 47 accepted (response rate of 67%). In this entire cohort, we detected one case of BWS and no cases of AS. We did not find evidence that there exists a significant group of ART children with unrecognized milder forms of AS or BWS. Although previous studies have suggested an increased relative risk of BWS and AS after ART, our findings suggest that the absolute risk of imprinting disorders in children conceived by ART is small (<1%). Precise risk estimates of risk are difficult to define because of the rarity of the conditions and incomplete response rates to the questionnaire and clinical examination invitations. Hence further investigations are indicated to (i) refine the absolute and relative risks of imprinting disorders after ART and (ii) ensure that changes in ART protocols are not associated with increased frequencies of epigenetic changes and imprinting disorders in children born after ART.

Gestational age estimates from singleton births conceived using assisted reproductive technology

Information on gestational age for public health research and surveillance in the US is usually obtained from vital records and is primarily based on the first day of the woman's last menstrual period (LMP). However, using LMP as a marker of conception is subject to a variety of errors and results in misclassification of gestational age. Pregnancies conceived through assisted reproductive technology (ART) are unique in that the estimates of gestational age are not based on the LMP, but on the date when fertilisation actually occurred, and thus most gestational age errors are likely to be due to errors introduced in recording and data entry. The purpose of this paper was to examine the birthweight distribution by gestational age for ART singleton livebirths reported to a national ART surveillance system. Gestational age was categorised as 20-27, 28-31, 32-36 and 37-44 weeks; birthweight distributions were plotted for each category. The distributions of very-low-birthweight (VLBW; <1500 g), moderately low-birthweight (1500-2499 g) and normal-birthweight infants for each gestational week were examined. At both 20-27 and 28-31 weeks, there was an extended right tail to the distribution and a small second mode. At 32-36 weeks, there were long tails in either direction and at 37-44 weeks, an extended tail to the left. There was a high proportion of VLBW infants at low gestational ages and a decreasing proportion of VLBW infants with increasing gestational age. However, there was also a fairly constant proportion of normal-birthweight infants at every gestational age below 34 weeks, which suggested misclassification of gestational age. Approximately 12% of ART births classified as 28-31 weeks' gestation had a birthweight in the second mode of the birthweight distribution compared with approximately 29% in national vital statistics data. Even when the birthweight and dates of conception and birth are known, questions remain regarding the residual amount of misclassification and the true nature of the birthweight distributions.

The relative contribution of assisted reproductive technologies and ovulation induction to multiple births in the United States 5 years after the Society for Assisted Reproductive Technology/American Society for Reproductive Medicine recommendation to limit the number of embryos transferred

To examine the effect of the 1998 Society for Assisted Reproductive Technology/American Society for Reproductive Medicine (SART/ASRM) Practice Committee recommendation to limit the number of embryos transferred on high order multiple births (HOMB) due to assisted reproduction technology (ART) and ovulation induction (OI) in the United States. None. Analysis of U.S. natality files, and U.S. Centers for Disease Control and Prevention (CDC) and ASRM/SART registry reports. None. None. None. Number and ratio of twin, triplet, and quadruplet or higher order (quadruplet/+) multiple births. Percentage of HOMB due to ART, OI, natural conception, and unexplained. Between 1998 and 2003, the number of twin births (number of live-born infants in twin deliveries) in the United States increased 17%, and the number of HOMB was unchanged. Since 1998, total births due to ART increased 67%, twin births increased 65%, triplet births deceased 8%, and quadruplet/+ births decreased 35%. The ratio of twin, triplet, and quadruplet/+ births to total ART births decreased 2%, 45%, and 61% respectively. In 2003, the estimated percentages of multiple births due to ART and OI were twins 16% and 21%, triplets 45% and 37%, and quadruplets/+ 30% and 62%, respectively. Following publication of the SART/ASRM recommended limits on number of embryos transferred, the ratio of HOMB births to total ART births decreased substantially; however, U.S. HOMB did not decrease due to a 67% increase in total ART births and an increase in triplet births from OI.

Validity of self-reported use of assisted reproductive technology treatment among women participating in the pregnancy risk assessment monitoring system in five states, 2000

To assess the validity of a question on assisted reproductive technology (ART) incorporated into the Pregnancy Risk Assessment Monitoring System (PRAMS) in 2000. While the intent of the question is to ascertain whether the index infant was conceived using ART, the phrasing was ambiguous for women who had used ART while trying to conceive the index infant but became pregnant after discontinuing treatment. We compared weighted PRAMS estimates from five states that incorporated the ART question in 2000 with data from the U.S. ART Surveillance System (ART-SS) maintained by the Centers for Disease Control and Prevention (CDC). U.S. medical practices are mandated to report data for every ART procedure to CDC annually; thus, the ART-SS is highly specific and complete. ART use was reported for 156 of the PRAMS births in our study population, representing 4,571 (95% Confidence Limit, 3,452-5,690) births from the total birth cohort in the five states of interest in 2000. For the same maternal residency states and year, 1,768 births were reported to the ART-SS. Thus, we calculate that PRAMS overestimated ART use by 2,803 births. PRAMS estimated 2.59 times as many ART births as reported to the ART-SS. While for singletons, a large excess in estimated births from PRAMS was observed (ratio=3.50), there was little difference between the PRAMS estimates and ART-SS for twin and triplet births. These findings suggest women responding to PRAMS may be reporting past ART use in addition to current. The findings by plurality support this hypothesis.

Linking Birth and Infant Death Records With Assisted Reproductive Technology Data: Massachusetts, 1997–1998

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. 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. 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. 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.