Sara Crawford

Assisted Reproductive Technology Surveillance - United States, 2014.

Problem/Condition Since the first U.S. infant conceived with assisted reproductive technology (ART) was born in 1981, both the use of ART and the number of fertility clinics providing ART services have increased steadily in the United States. ART includes fertility treatments in which eggs or embryos are handled in the laboratory (i.e., in vitro fertilization [IVF] and related procedures). Women who undergo ART procedures are more likely than women who conceive naturally to deliver multiple-birth infants. Multiple births pose substantial risks to both mothers and infants, including obstetric complications, preterm delivery, and low birthweight infants. This report provides state-specific information for the United States (including the District of Columbia and Puerto Rico) on ART procedures performed in 2014 and compares birth outcomes that occurred in 2014 (resulting from ART procedures performed in 2013 and 2014) with outcomes for all infants born in the United States in 2014. Period Covered 2014. Description of System In 1996, CDC began collecting data on ART procedures performed in fertility clinics in the United States as mandated by the Fertility Clinic Success Rate and Certification Act of 1992 (FCSRCA) (Public Law 102–493). Data are collected through the National ART Surveillance System (NASS), a web-based data collection system developed by CDC. This report includes data from 52 reporting areas (the 50 states, the District of Columbia, and Puerto Rico). Results In 2014, a total of 169,568 ART procedures (range: 124 in Wyoming to 21,018 in California) with the intent to transfer at least one embryo were performed in 458 U.S. fertility clinics and reported to CDC. These procedures resulted in 56,028 live-birth deliveries (range: 52 in Wyoming to 7,230 in California) and 68,782 infants born (range: 64 in Wyoming to 8,793 in California). Nationally, the total number of ART procedures performed per million women of reproductive age (15–44 years), a proxy measure of the ART usage rate, was 2,647 (range: 364 in Puerto Rico to 6,726 in Massachusetts). ART use exceeded the national average in 13 reporting areas (Connecticut, Delaware, the District of Columbia, Hawaii, Illinois, Maryland, Massachusetts, New Hampshire, New Jersey, New York, Pennsylvania, Rhode Island, and Virginia). Eight reporting areas (Connecticut, the District of Columbia, Hawaii, Illinois, Maryland, Massachusetts, New Jersey, and New York) had rates of ART use exceeding 1.5 times the national average. Nationally, among ART transfer procedures in patients using fresh embryos from their own eggs, the average number of embryos transferred increased with increasing age of the woman (1.7 among women aged <35 years, 1.9 among women aged 35–37 years, and 2.3 among women aged >37 years). Among women aged <35 years, who typically are considered to be good candidates for elective single embryo transfer (eSET) procedures, the national eSET rate was 28.5% (range: 4.3% in Puerto Rico to 67.9% in Delaware). In 2014, ART contributed to 1.6% of all infants born in the United States (range: 0.4% in Puerto Rico to 4.7% in Massachusetts) and 18.3% of all multiple-birth infants (range: 5.5% in Alaska and West Virginia to 37.3% in Hawaii), including 18.0% of all twin infants (range: 5.2% in some states to 36.2% in Hawaii) and 26.4% of all triplets and higher-order infants (range: 0% in some states to 65.2% in Hawaii). Percentages of live births that were multiple-birth deliveries were higher among infants conceived with ART (39.4%; range: 11.5% in Delaware to 55.6% in Puerto Rico) than among all infants born in the total birth population (3.5%; range: 2.2% in Puerto Rico to 4.4% in New Jersey). Approximately 38.0% of ART-conceived infants were twin infants, and 2.0% were triplets and higher-order infants. ART-conceived twins accounted for approximately 95.3% of all ART-conceived infants born in multiple deliveries. Nationally, infants conceived with ART contributed to 5.5% of all low birthweight (<2,500 g) infants (range: 1.2% in West Virginia to 14.2% in Massachusetts). Among ART-conceived infants, 27.8% were low birthweight (range: 10.6% in Delaware to 44.4% in Puerto Rico), compared with 8.0% among all infants (range: 5.9% in Alaska to 11.3% in Mississippi). ART-conceived infants contributed to 4.7% of all preterm (<37 weeks) infants (range: 1.2% in Puerto Rico to 13.4% in Massachusetts). Percentages of preterm births were higher among infants conceived with ART (33.2%; range: 18.9% in the District of Columbia to 45.9% in Puerto Rico) than among all infants born in the total birth population (11.3%; range: 8.5% in California to 16.0% in Mississippi). The percentage of ART-conceived infants who were low birthweight was 8.9% (range: 3.2% in some states to 16.1% in Vermont) among singletons and 55.2% (range: 38.5% in Delaware to 77.8% in Alaska) among twins; the corresponding percentages of low birthweight infants among all infants born were 6.3% for singletons (range: 4.6% in Alaska, North Dakota, and Oregon to 9.5% in Puerto Rico) and 55.2% for twins (range: 46.1% in Alaska to 65.6% in Mississippi). The percentage of ART-conceived infants who were preterm was 13.2% (range: 7.5% in Rhode Island to 23.4% in West Virginia) among singletons and 62.2% (range: 33.3% in some states to 81.4% in Mississippi) among twins; the corresponding percentages of preterm infants among all infants were 9.7% for singletons (range: 1.7% in the District of Columbia to 14.2% in Mississippi) and 56.6% for twins (range: 47.2% in Vermont to 66.9% in Wyoming). Interpretation The percentage of infants conceived with ART varied considerably by reporting area. Multiple births from ART contributed to a substantial proportion of all twins, triplets, and higher-order infants born. Low birthweight and preterm infant birth rates were disproportionately higher among ART-conceived infants than among the overall birth population. Although women aged <35 years are typically considered good candidates for eSET, on average two embryos were transferred per ART procedure with women in this group. Compared with ART-conceived singletons, ART-conceived twins were approximately five times more likely to be born preterm and approximately six times more likely to be born with low birthweight. Singleton infants conceived with ART had higher percentages of preterm birth and low birthweight than all singleton infants born in the United States. ART use per population unit was geographically variable, with 13 reporting areas showing ART use higher than the national rate. Of the four states (Illinois, Massachusetts, New Jersey, and Rhode Island) with comprehensive statewide-mandated health insurance coverage for ART procedures (i.e., coverage for at least four cycles of IVF), three (Illinois, Massachusetts, and New Jersey) had rates of ART use exceeding 1.5 times the national rate. This type of mandated insurance has been associated with greater use of ART and likely accounts for some of the difference in per capita ART use observed among states. Public Health Action Reducing the number of embryos transferred and increasing use of eSET when clinically appropriate could help reduce multiple births and related adverse health consequences. Because twins account for the majority of ART-conceived multiple births, improved provider practices and patient education and counseling on the maternal and infant health risks of having twins are needed. Although ART contributes to high percentages of multiple births, other factors not investigated in this report (e.g., delayed childbearing and use of non-ART fertility treatments) also contribute to multiple births and warrant further study.

Differences in clinical manifestations among Cryptosporidium species and subtypes in HIV-infected persons

We performed a cross-sectional study to determine the epidemiology of Cryptosporidium in human immunodeficiency virus (HIV)-infected persons at 3 diagnostic levels: microscopy, genotypes of Cryptosporidium, and subtype families of C. hominis and C. parvum. The study enrolled 2,490 HIV-infected persons in Lima, Peru, and 230 were microscopy positive for Cryptosporidium infection. Specimens from 193 participants were available for genotyping. They had C. hominis (141 persons), C. parvum (22 persons), C. meleagridis (17 persons), C. canis (6 persons), C. felis (6 persons), and C. suis (1 person) infection. Although microscopy results showed that Cryptosporidium infections were associated with diarrhea, only infections with C. canis, C. felis, and subtype family Id of C. hominis were associated with diarrhea, and infection with C. parvum was associated with chronic diarrhea and vomiting. These results demonstrate that different Cryptosporidium genotypes and subtype families are linked to different clinical manifestations.

Plasma IP-10, apoptotic and angiogenic factors associated with fatal cerebral malaria in India.

BackgroundPlasmodium falciparum in a subset of patients can lead to cerebral malaria (CM), a major contributor to malaria-associated mortality. Despite treatment, CM mortality can be as high as 30%, while 10% of survivors of the disease may experience short- and long-term neurological complications. The pathogenesis of CM is mediated by alterations in cytokine and chemokine homeostasis, inflammation as well as vascular injury and repair processes although their roles are not fully understood. The hypothesis for this study is that CM-induced changes in inflammatory, apoptotic and angiogenic factors mediate severity of CM and that their identification will enable development of new prognostic markers and adjunctive therapies for preventing CM mortalities.MethodsPlasma samples (133) were obtained from healthy controls (HC, 25), mild malaria (MM, 48), cerebral malaria survivors (CMS, 48), and cerebral malaria non-survivors (CMNS, 12) at admission to the hospital in Jabalpur, India. Plasma levels of 30 biomarkers ((IL-1β, IL-1ra, IL-2, IL-4, IL-5, IL-6, IL-8, IL-9, IL-10, IL-12 (p70), IL-13, IL-15, IL-17, Eotaxin, FGF basic protein, G-CSF, GM-CSF, IFN-γ, IP-10, MCP-1 (MCAF), MIP-1α, MIP-1β, RANTES, TNF-α, Fas-ligand (Fas-L), soluble Fas (sFas), soluble TNF receptor 1 (sTNF-R1) and soluble TNF receptor 2 (sTNFR-2), PDGF bb and VEGF)) were simultaneously measured in an initial subset of ten samples from each group. Only those biomarkers which showed significant differences in the pilot analysis were chosen for testing on all remaining samples. The results were then compared between the four groups to determine their role in CM severity.ResultsIP-10, sTNF-R2 and sFas were independently associated with increased risk of CM associated mortality. CMNS patients had a significantly lower level of the neuroprotective factor VEGF when compared to other groups (P < 0.0045). The ratios of VEGF to IP-10, sTNF-R2, and sFas distinguished CM survivors from non survivors (P < 0.0001).ConclusionThe results suggest that plasma levels of IP-10, sTNF-R2 and sFas may be potential biomarkers of CM severity and mortality. VEGF was found to be protective against CM associated mortality and may be considered for adjunctive therapy to improve the treatment outcome in CM patients.

Antenatal and delivery care in rural western Kenya: the effect of training health care workers to provide "focused antenatal care"

BackgroundMaternal mortality remains high in developing countries and data to monitor indicators of progress in maternal care is needed. We examined the status of maternal care before and after health care worker (HCW) training in WHO recommended Focused Antenatal Care.MethodsAn initial cross-sectional survey was conducted in 2002 in Asembo and Gem in western Kenya among a representative sample of women with a recent birth. HCW training was performed in 2003 in Asembo, and a repeat survey was conducted in 2005 in both areas.ResultsAntenatal clinic (ANC) attendance was similar in both areas (86%) in 2005 and not significantly different from 2002 (90%). There was no difference in place of delivery between the areas or over time. However, in 2005, more women in Asembo were delivered by a skilled assistant compared to Gem (30% vs.23%, P = 0.04), and this proportion increased compared to 2002 (17.6% and 16.1%, respectively). Provision of iron (82.4%), folic acid (72.0%), sulfadoxine-pyrimethamine (61.7%), and anthelminths (12.7%) had increased in Asembo compared to 2002 (2002: 53.3%, 52.8%, 20.3%, and 4.6%, respectively), and was significantly higher than in Gem in 2005 (Gem 2005: 69.7%, 47.8%, 19.8%, and 4.1%, respectively) (P < 0.05 for all). Offering of tests for sexually transmitted diseases and providing information related to maternal health was overall low (<20%) and did not differ by area. In 2005, more women rated the quality of the antenatal service in Asembo as very satisfactory compared to Gem (17% vs. 6.5%, P < 0.05).ConclusionsWe observed improvements in some ANC services in the area where HCWs were trained. However, since our evaluation was carried out 2 years after three-day training, we consider any significant, sustained improvement to be remarkable.

Laboratory wash resistance of long-lasting insecticidal nets

Long‐lasting insecticidal nets (LLINs) may eliminate the need for retreatment of mosquito nets used for the control of malaria and other vector‐borne diseases. The efficacy of LLINs after repeated washing under laboratory conditions has been used to predict long‐lasting efficacy under field conditions. We evaluated under laboratory conditions the wash resistance of two LLINs (PermaNet® 1.0, Vestergaard‐Frandsen, Denmark; Olyset®, Sumitomo Chemical Co., Japan), two candidate LLINs (Dawa®, Siamdutch Mosquito Netting Co., Thailand; Insector, Athanor, France) and a net treated with a process designed to increase its wash resistance and compared them with conventionally treated nets (deltamethrin, 25 mg/m2). Nets of all six types were washed using a standard protocol and tested weekly using WHO cone bioassays with Anopheles gambiae (Kisumu strain). The PermaNet® 1.0 was the most wash resistant with >50% mosquito mortality in WHO cone bioassays after as many as 20 washes. The Dawa® net also retained some activity after repeated washing but exhibited wide variation in insecticide retention and biological activity. The remaining nets lost >90% of their biological activity after six washes as measured by 24‐h mortality of A. gambiae in WHO cone tests. After 20 washes, all nets lost >50% of their initial insecticide concentrations except for the Olyset® net. After 20 washes, nets were heated for 4 h at 60 °C to determine whether biological activity could be restored by heat‐assisted regeneration. Only the Olyset® net was regenerated by heating, with average mosquito mortality and knockdown in WHO cone tests rising to >90% after heating for 4 h at 60 °C. However, regeneration of the biological activity of Olyset® nets that had been washed three times did not occur at 30 °C or 35 °C after 12 weeks. The wash resistance of these LLINs corresponded well to their retention of biological activity observed in a field trial, suggesting that wash resistance may be a good predictor of the longevity of insecticidal activity of LLINs under field conditions.

Trends and Outcomes for Donor Oocyte Cycles in the United States, 2000-2010

IMPORTANCE The prevalence of oocyte donation for in vitro fertilization (IVF) has increased in the United States, but little information is available regarding maternal or infant outcomes to improve counseling and clinical decision making. OBJECTIVES To quantify trends in donor oocyte cycles in the United States and to determine predictors of a good perinatal outcome among IVF cycles using fresh (noncryopreserved) embryos derived from donor oocytes. DESIGN, SETTING, AND PARTICIPANTS Analysis of data from the Centers for Disease Control and Preventions National ART Surveillance System, to which fertility centers are mandated to report and which includes data on more than 95% of all IVF cycles performed in the United States. Data from 2000 to 2010 described trends. Data from 2010 determined predictors. MAIN OUTCOMES AND MEASURES Good perinatal outcome, defined as a singleton live-born infant delivered at 37 weeks or later and weighing 2500 g or more. RESULTS From 2000 to 2010, data from 443 clinics (93% of all US fertility centers) were included. The annual number of donor oocyte cycles significantly increased, from 10,801 to 18,306. Among all donor oocyte cycles, an increasing trend was observed from 2000 to 2010 in the proportion of cycles using frozen (vs fresh) embryos (26.7% [95% CI, 25.8%-27.5%] to 40.3% [95% CI, 39.6%-41.1%]) and elective single-embryo transfers (vs transfer of multiple embryos) (0.8% [95% CI, 0.7%-1.0%] to 14.5% [95% CI, 14.0%-15.1%]). Good perinatal outcomes increased from 18.5% (95% CI, 17.7%-19.3%) to 24.4% (95% CI, 23.8%-25.1%) (P < .001 for all listed trends). Mean donor and recipient ages remained stable at 28 (SD, 2.8) years and 41 (SD, 5.3) years, respectively. In 2010, 396 clinics contributed data. For donor oocyte cycles using fresh embryos (n = 9865), 27.5% (95% CI, 26.6%-28.4%) resulted in good perinatal outcome. Transfer of an embryo at day 5 (adjusted odds ratio [OR], 1.17 [95% CI, 1.04-1.32]) and elective single-embryo transfers (adjusted OR, 2.32 [95% CI, 1.92-2.80]) were positively associated with good perinatal outcome; tubal (adjusted OR, 0.72 [95% CI, 0.60-0.86]) or uterine (adjusted OR, 0.74 [95% CI, 0.58-0.94]) factor infertility and non-Hispanic black recipient race/ethnicity (adjusted OR, 0.48 [95% CI, 0.35-0.67]) were associated with decreased odds of good outcome. Recipient age was not associated with likelihood of good perinatal outcome. CONCLUSIONS AND RELEVANCE In the United States from 2000 to 2010, there was an increase in number of donor oocyte cycles, accompanied by an increase in good outcomes. Further studies are needed to understand the mechanisms underlying the factors associated with less successful outcomes.

Computer programs for the concordance correlation coefficient

The CCC macro is presented for computation of the concordance correlation coefficient (CCC), a common measure of reproducibility. The macro has been produced in both SAS and R, and a detailed presentation of the macro input and output for the SAS program is included. The macro provides estimation of three versions of the CCC, as presented by Lin [L.I.-K. Lin, A concordance correlation coefficient to evaluate reproducibility, Biometrics 45 (1989) 255-268], Barnhart et al. [H.X. Barnhart, J.L. Haber, J.L. Song, Overall concordance correlation coefficient for evaluating agreement among multiple observers, Biometrics 58 (2002) 1020-1027], and Williamson et al. [J.M. Williamson, S.B. Crawford, H.M. Lin, Resampling dependent concordance correlation coefficients, J. Biopharm. Stat. 17 (2007) 685-696]. It also provides bootstrap confidence intervals for the CCC, as well as for the difference in CCCs for both independent and dependent samples. The macro is designed for balanced data only. Detailed explanation of the involved computations and macro variable definitions are provided in the text. Two biomedical examples are included to illustrate that the macro can be easily implemented.

Embryo transfer practices and multiple births resulting from assisted reproductive technology: an opportunity for prevention

OBJECTIVE To evaluate assisted reproductive technology (ART) ET practices in the United States and assess the impact of these practices on multiple births, which pose health risks for both mothers and infants. DESIGN Retrospective cohort analysis using the National ART Surveillance System data. SETTING US fertility centers reporting to the National ART Surveillance System. PATIENT(S) Noncanceled ART cycles conducted in the United States in 2012. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Multiple birth (birth of two or more infants, at least one of whom was live-born). RESULT(S) Of 134,381 ART transfer cycles performed in 2012, 51,262 resulted in live births, of which 13,563 (26.5%) were multiple births: 13,123 twin and 440 triplet and higher order births. Almost half (46.1%) of these multiple births resulted from the following four cycle types: two fresh blastocyst transfers among favorable or average prognosis patients less than 35 years (1,931 and 1,341 multiple births, respectively), two fresh blastocyst transfers among donor-oocyte recipients (1,532 multiple births), and two frozen/thawed ETs among patients less than 35 years (1,452 multiple births). More than half of triplet or higher order births resulted from the transfer of two embryos (52.5% of births among fresh autologous transfers, 67.2% of births among donor-oocyte recipient transfers, and 42.9% among frozen/thawed autologous transfers). CONCLUSION(S) A substantial reduction of ART-related multiple (both twin and triplet or higher order) births in the United States could be achieved by single blastocyst transfers among favorable and average prognosis patients less than 35 years of age and donor-oocyte recipients.

Tubal Factor Infertility and Perinatal Risk After Assisted Reproductive Technology

OBJECTIVE: To assess trends of tubal factor infertility and to evaluate risk of miscarriage and delivery of preterm or low birth weight (LBW) neonates among women with tubal factor infertility using assisted reproductive technology (ART). METHODS: We assessed trends of tubal factor infertility among all fresh and frozen, donor, and nondonor ART cycles performed annually in the United States between 2000 and 2010 (N=1,418,774) using the National ART Surveillance System. The data set was then limited to fresh, nondonor in vitro fertilization cycles resulting in pregnancy to compare perinatal outcomes for cycles associated with tubal compared with male factor infertility. We performed bivariate and multivariable analyses controlling for maternal characteristics and calculated adjusted risk ratios (RRs) and 95% confidence intervals (CI). RESULTS: The percentage of ART cycles associated with tubal factor infertility diagnoses decreased from 2000 to 2010 (26.02–14.81%). Compared with male factor infertility, tubal factor portended an increased risk of miscarriage (14.0% compared with 12.7%, adjusted RR 1.08, 95% CI 1.04–1.12); risk was increased for both early and late miscarriage. Singleton neonates born to women with tubal factor infertility had an increased risk of preterm birth (15.8% compared with 11.6%, adjusted RR 1.27, 95% CI 1.20–1.34) and LBW (10.9% compared with 8.5%, adjusted RR 1.28, 95% CI 1.20–1.36). Significant increases in risk persisted for early and late preterm delivery and very low and moderately LBW delivery. A significantly elevated risk was also detected for twin, but not triplet, pregnancies. CONCLUSION: Tubal factor infertility, which is decreasing in prevalence in the United States, is associated with an increased risk of miscarriage, preterm birth, and LBW delivery as compared with couples with male factor infertility using ART. LEVEL OF EVIDENCE: II

Polymorphisms in genes of interleukin 12 and its receptors and their association with protection against severe malarial anaemia in children in western Kenya

BackgroundMalarial anaemia is characterized by destruction of malaria infected red blood cells and suppression of erythropoiesis. Interleukin 12 (IL12) significantly boosts erythropoietic responses in murine models of malarial anaemia and decreased IL12 levels are associated with severe malarial anaemia (SMA) in children. Based on the biological relevance of IL12 in malaria anaemia, the relationship between genetic polymorphisms of IL12 and its receptors and SMA was examined.MethodsFifty-five tagging single nucleotide polymorphisms covering genes encoding two IL12 subunits, IL12A and IL12B, and its receptors, IL12RB1 and IL12RB2, were examined in a cohort of 913 children residing in Asembo Bay region of western Kenya.ResultsAn increasing copy number of minor variant (C) in IL12A (rs2243140) was significantly associated with a decreased risk of SMA (P = 0.006; risk ratio, 0.52 for carrying one copy of allele C and 0.28 for two copies). Individuals possessing two copies of a rare variant (C) in IL12RB1 (rs429774) also appeared to be strongly protective against SMA (P = 0.00005; risk ratio, 0.18). In addition, children homozygous for another rare allele (T) in IL12A (rs22431348) were associated with reduced risk of severe anaemia (SA) (P = 0.004; risk ratio, 0.69) and of severe anaemia with any parasitaemia (SAP) (P = 0.004; risk ratio, 0.66). In contrast, AG genotype for another variant in IL12RB1 (rs383483) was associated with susceptibility to high-density parasitaemia (HDP) (P = 0.003; risk ratio, 1.21).ConclusionsThis study has shown strong associations between polymorphisms in the genes of IL12A and IL12RB1 and protection from SMA in Kenyan children, suggesting that human genetic variants of IL12 related genes may significantly contribute to the development of anaemia in malaria patients.