Meredith A. Reynolds

Perinatal outcome among singleton infants conceived through assisted reproductive technology in the United States

OBJECTIVE: To examine perinatal outcome among singleton infants conceived with assisted reproductive technology (ART) in the United States. METHODS: Subjects were 62,551 infants born after ART treatments performed in 1996–2000. Secular trends in low birth weight (LBW), very low birth weight (VLBW), preterm delivery, preterm LBW, and term LBW were examined. Detailed analyses were performed for 6,377 infants conceived in 2000. Observed numbers were compared with expected using a reference population from the 2000 U.S. natality file. Adjusted risk ratios were calculated. RESULTS: The proportion of ART singletons born LBW, VLBW, and term LBW decreased from 1996 to 2000. The proportion delivered preterm and preterm LBW remained stable. After adjustment for maternal age, parity, and race/ethnicity, singleton infants born after ART in 2000 had elevated risks for all outcomes in comparison with the general population of U.S. singletons: LBW standardized risk ratio 1.62 (95% confidence interval 1.49, 1.75), VLBW 1.79 (1.45, 2.12), preterm delivery 1.41 (1.32, 1.51), preterm LBW 1.74 (1.57, 1.90), and term LBW 1.39 (1.19, 1.59). Risk ratios for each outcome remained elevated after restriction to pregnancies with only 1 fetal heart or any of 7 other categories: parental infertility diagnosis of male factor, infertility diagnosis of tubal factor, conception using in vitro fertilization without intracytoplasmic sperm injection or assisted hatching, conception with intracytoplasmic sperm injection, conception in a treatment with extra embryos available, embryo culture for 3 days, and embryo culture for 5 days. CONCLUSION: Singletons born after ART remain at increased risk for adverse perinatal outcomes; however, risk for term LBW declined from 1996 to 2000, whereas preterm LBW was stable. LEVEL OF EVIDENCE: III

Are children born after assisted reproductive technology at increased risk for adverse health outcomes

As assisted reproductive technologies (ARTs) are increasingly used to overcome infertility, there is concern about the health of the children conceived. The empirical evidence for associations with outcomes related to child health is variable and should be evaluated with consideration of methodological shortcomings. Currently, there is convincing evidence that ART treatment may increase the risk of a few outcomes. Experimental laboratory studies document that various constituents in culture media affect various embryo characteristics both positively and negatively. Multiple-gestation pregnancy and birth are increased with ART, both because of multiple embryo transfer and embryo splitting. There is evidence of an increase in chromosomal abnormalities among pregnancies conceived using intracytoplasmic sperm injection and low birth weight and preterm delivery among singletons conceived with all types of ART; however, there remains uncertainty about whether these risks stem from the treatment or the parental infertility. For some outcomes, data of an increased risk with ART are suggestive at best largely because of lack of purposeful study of sufficient size and scope. These include specific perinatal morbidities, birth defects, developmental disabilities, and retinoblastoma. The evidence for an association between ART and spontaneous abortion is inconsistent and weak. There is inconclusive evidence that ART may be associated with genetic imprinting disorders. For childhood cancer, chronic conditions, learning and behavioral disorders, and reproductive effects there is insufficient empirical research to date, but given the data for more proximal outcomes, these outcomes merit further study. Future research needs to address the unique methodological challenges underlying study in this area.

Ectopic pregnancy risk with assisted reproductive technology procedures

OBJECTIVE: To assess the ectopic pregnancy risk among women who conceived with assisted reproductive technology (ART) procedures. METHODS: The ectopic rate for ART pregnancies was calculated from population-based data of pregnancies conceived with ART in U.S. clinics in 1999–2001. Variation in ectopic risk by patient and ART treatment factors was assessed by using bivariate analyses and multivariable logistic regression. RESULTS: Of 94,118 ART pregnancies, 2,009 (2.1%) were ectopic. Variation was observed by procedure type. In comparison with the ectopic rate (2.2%) among pregnancies conceived with in vitro fertilization and transcervical transfer of freshly fertilized embryos from the patient’s oocytes (fresh, nondonor IVF-ET), the ectopic rate was significantly increased when zygote intrafallopian transfer (ZIFT) was used (3.6%) and significantly decreased when donor oocytes were used (1.4%) or when a gestational surrogate carried the pregnancy (0.9%). Among fresh nondonor IVF-ET procedures, the risk for ectopic pregnancy was increased among women with tubal factor infertility (odds ratio [OR] 2.0, 95% confidence interval [CI] 1.7–2.4; referent group = ART for male factor), endometriosis (OR 1.3, 95% CI 1.0–1.6), and other nontubal female factors of infertility (OR 1.4, 95% CI 1.2–1.6) and decreased among women with a previous live birth (OR 0.6, 95% CI 0.5–0.7). Transfer of embryos with an indication of high implantation potential was associated with a decreased ectopic risk when 2 or fewer embryos were transferred (OR 0.7, 95% CI 0.5–0.9), but not when 3 or more embryos were transferred. CONCLUSION: Ectopic risk among ART pregnancies varied according to ART procedure type, reproductive health characteristics of the woman carrying the pregnancy, and estimated embryo implantation potential. LEVEL OF EVIDENCE: II-2

Infertility therapy associated-multiple pregnancies (births): an ongoing epidemic

Multiple gestation is now recognized as a major problem associated with both assisted reproductive technologies (ART) and also with ovulation induction therapies. Although some countries are beginning to adopt measures to address this issue, either through legislation or the development of clinical guidelines, there is a clear need to ensure recognition and a consistent approach to this problem worldwide. In particular, there is a need to educate both healthcare professionals and the lay population that multiple gestations are not a desirable outcome for the infertile couple.

Does insurance coverage decrease the risk for multiple births associated with assisted reproductive technology

OBJECTIVE To determine whether insurance coverage for ART is associated with transfer of fewer embryos and decreased risk of multiple births. DESIGN Retrospective cohort study of a population-based sample of IVF procedures performed in six U.S. states during 1998. SETTING Three states with mandated insurance coverage (Illinois, Massachusetts, and Rhode Island) and three states without coverage (Indiana, Michigan, and New Jersey). PARTICIPANT(S) Seven thousand, five hundred sixty-one IVF transfer procedures in patients < or = 35 years of age. MAIN OUTCOME MEASURE(S) Number of embryos transferred, multiple-birth rate, triplet or higher order birth rate, and triplet or higher order gestation rate. RESULT(S) A smaller proportion of procedures included transfer of three or more embryos in Massachusetts (64%) and Rhode Island (74%) than in the noninsurance states (82%). The multiple-birth rate in Massachusetts (38%) was less than in the noninsurance states (43%). The insurance states all had protective odds ratios for triplet or higher order births, but only the odds ratio (0.2) for Massachusetts was significant. This decreased risk in Massachusetts resulted from several factors, including a smaller proportion of patients with three or more embryos transferred, lower implantation rates when three or more embryos were transferred, and greater rates of fetal loss among triplet or higher order gestations. CONCLUSION(S) Insurance appears to affect embryo transfer practices. Whether this translates into decreased multiple birth risk is less clear.

Epidemiology of Varicella Hospitalizations in the United States, 1995–2005

To describe the impact of the varicella vaccination program on varicella-related hospitalizations (VRHs) in the United States, data from the Varicella Active Surveillance Project (VASP) were used to compare rates of hospitalization and rates of complications among patients hospitalized for varicella-related conditions from 1995 to 2005. Of the 26,290 varicella cases reported between 1995 and 2005, 170 cases resulted in VRHs, including 1 case that resulted in death. Both VRH rates per 100,000 population and complications during VRH per 100,000 population decreased significantly between the early vaccination period (1995-1998) and the middle/late vaccination period (1999-2005). Infants and adults were at highest risk for VRH, and having been vaccinated against varicella was a protective factor. Varicella vaccination may have prevented a significant number of VRHs. The fact that 4 vaccinated children required hospitalization for varicella-related complications demonstrates that 1 dose of varicella vaccine does not prevent serious disease in all cases, even among previously healthy children.

An outbreak of varicella in elementary school children with two-dose varicella vaccine recipients--Arkansas, 2006.

Background: In June 2006, the Advisory Committee on Immunization Practices (ACIP) expanded its June 2005 recommendation for a second dose of varicella vaccine during outbreaks to a recommendation for routine school entry second dose varicella vaccination. In October 2006, the Arkansas Department of Health was notified of a varicella outbreak among students where some received a second dose during an outbreak-related vaccination campaign in February 2006. Methods: The outbreak was investigated using a school-wide parental survey with a follow-up survey of identified case patients. Vaccination status was verified using state and local immunization records. Limited laboratory testing confirmed circulation of wild-type varicella, including varicella in 2-dose vaccine recipients. Results: Vaccination information was available for 871 (99%) of the 880 children. Varicella vaccination coverage was 97% (2-dose, 39%; 1-dose, 58%). A review of the February vaccination clinic found no deficiencies; lot numbers did not differ between cases and noncases. Varicella was confirmed by PCR in 5 (42%) of 12 lesion specimens and by IgM in 1 (6%) of 16 serum specimens. Varicella was reported in 84 children, including 25 (30%) two-dose and 53 (63%) one-dose recipients. Attack rates among 2-dose recipients (10.4%) and 1-dose recipients (14.6%) were not significantly different (RR: 0.72, 95% CI: 0.44–1.15). All 2-dose recipients and 80% of 1-dose recipients reported having 50 or fewer skin lesions. Conclusion: This outbreak is the first to document varicella in both 1- and 2-dose vaccine recipients; both groups had mild disease. The vaccine effectiveness of 1 and 2 doses were similar.

Varicella seroprevalence in the U.S.: data from the National Health and Nutrition Examination Survey, 1999-2004.

Objective. We estimated the varicella seroprevalence among the U.S. population aged 6–49 years based on retested National Health and Nutrition Examination Survey (NHANES) specimens collected between 1999 and 2004—originally tested using a method unsuitable for detecting vaccine-induced immunity—and compared it with historical estimates. Methods. We performed a confirmatory test suitable for detecting vaccine-induced immunity on all available specimens from 6- to 19-year-olds who originally tested negative (n=633), and on 297 randomly selected specimens that had tested positive. Retest results superseded original results for determining seroprevalence. We assessed seroprevalence for the entire sample aged 6–49 years (n=16,050) by participant demographic characteristics and compared it with historical estimates (NHANES 1988–1994). Results. The percentage of false-negative results for the original test was higher for specimens from younger children (6–11 years of age: 27.5%; 12–19 years of age: 13.3%) and for specimens collected most recently (2001–2004: 26.0%; 1999–2000: 12.6%). The age-adjusted rate of varicella seroprevalence for 1999–2004 was 93.6% for 6- to 19-year-olds and 98.0% for adults aged 20–49 years compared with 90.0% and 98.1%, respectively, for 1988–1994. We found an increase in seropositivity between the survey periods, from 93.2% to 97.2% (p<0.001) among 12- to 19-year-olds. For children, non-Hispanic black ethnicity and younger age were associated with lower seroprevalence in both survey periods. Conclusions. Varicella seroprevalence increased with age among children and was uniformly high in the U.S. adult population between 1999 and 2004. The original testing produced false-negative seroprevalence results among childrens specimens collected between 1999 and 2004 from 6- to 19-year-olds.

Validity of Self-Reported Varicella Disease History in Pregnant Women Attending Prenatal Clinics

Objective. The purpose of this study was to assess the validity of self-reported history for varicella disease relative to serological evidence of varicella immunity in pregnant women attending antenatal care at clinics located in two diverse geographical locations in the U.S. (Antelope Valley, California, and Philadelphia) with high varicella vaccination coverage. Methods. Pregnant women attending prenatal care appointments who needed blood drawn as part of their routine care were eligible to participate. Self-reported varicella disease history was obtained via questionnaire. Varicella serostatus was determined using a whole-cell enzyme-linked immunosorbent assay to test for varicella zoster virus-specific immunoglobulin G (VZV IgG) antibodies. Results. Of the 309 study participants from Antelope Valley and the 528 participants from Philadelphia who self-reported having had chickenpox disease, 308 (99.7%; 95% confidence interval [CI]: 98.2, 100) and 517 (97.9%; 95% CI: 96.3, 99.0), respectively, had serological evidence of immunity to varicella. Only 6.8% (95% CI: 3.9, 11.0) and 17.4% (95% CI: 13.1, 22.5) of women who self-reported having a negative or uncertain varicella disease history in Antelope Valley and Philadelphia, respectively, were seronegative for varicella antibodies. Conclusion. Despite the dramatic changes in the epidemiology of varicella that have occurred since 1995 due to the introduction and subsequent widespread use of the varicella vaccine, self-reported history of varicella continues to be a strong predictor of VZV IgG antibodies in pregnant women. Negative or uncertain history remains poorly predictive of negative serostatus.

Validity of self-reported use of assisted reproductive technology treatment among women participating in the Pregnancy Risk Assessment Monitoring System in five states, 2000.

Objectives: 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. Methods: 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. Results: 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. Conclusion: These findings suggest women responding to PRAMS may be reporting past ART use in addition to current. The findings by plurality support this hypothesis.