T.A. Molinaro

Pregnancy of unknown location: a consensus statement of nomenclature, definitions, and outcome

OBJECTIVE To improve the interpretation of future studies in women who are initially diagnosed with a pregnancy of unknown location (PUL), we propose a consensus statement with definitions of population, target disease, and final outcome. DESIGN A review of literature and a series of collaborative international meetings were used to develop a consensus for definitions and final outcomes of women initially diagnosed with a PUL. RESULT(S) Global differences were noted in populations studied and in the definitions of outcomes. We propose to define initial ultrasound classification of findings into five categories: definite ectopic pregnancy (EP), probable EP, PUL, probable intrauterine pregnancy (IUP), and definite IUP. Patients with a PUL should be followed and final outcomes should be categorized as visualized EP, visualized IUP, spontaneously resolved PUL, and persisting PUL. Those with the transient condition of a persisting PUL should ultimately be classified as nonvisualized EP, treated persistent PUL, resolved persistent PUL, or histologic IUP. These specific categories can be used to characterize the natural history or location (intrauterine vs. extrauterine) of any early gestation where the initial location is unknown. CONCLUSION(S) Careful definition of populations and classification of outcomes should optimize objective interpretation of research, allow objective assessment of future reproductive prognosis, and hopefully lead to improved clinical care of women initially identified to have a PUL.

Ovarian stimulation and low birth weight in newborns conceived through in vitro fertilization.

OBJECTIVE: Singleton neonates born after in vitro fertilization (IVF) are at increased risk for low birth weight, preterm delivery, or both. We sought to assess whether the alteration of the peri-implantation maternal environment resulting from ovarian stimulation may contribute to increased risk of low birth weight in IVF births. METHODS: The Society for Assisted Reproductive Technologies database was used to identify IVF-conceived neonates born in the United States between 2004 and 2006. Associations were assessed in neonates born after fresh compared with frozen and thawed embryo transfer in women of similar ovarian responsiveness, in paired analysis of neonates born to the same woman after both types of embryo transfer, and in neonates born after oocyte donation. RESULTS: Of 56,792 neonates identified, 38,626 and 18,166 were conceived after transfer of fresh and frozen embryos, respectively. In singletons, there was no difference in preterm delivery. However, the odds of overall low birth weight (10% compared with 7.2%; adjusted odds ratio [OR] 1.35; 95% confidence interval [CI] 1.20–1.51), low birth weight at term (2.5% compared with 1.2%, adjusted OR 1.73, 95% CI 1.31–2.29), and preterm low birth weight (34.1% compared with 23.8%, adjusted OR 1.49, 95% CI 1.24–1.78) were all significantly higher after fresh embryo transfer. In singletons, after either fresh or frozen embryo transfer in the same patient, this association was even stronger (low birth weight: 11.5% compared with 5.6%, adjusted OR 4.66, 95% CI 1.18–18.38). In oocyte donor recipients who do not undergo any ovarian hormonal stimulation for either a fresh or a frozen embryo transfer, no difference in low birth weight was demonstrated (11.5% compared with 11.3% adjusted OR 0.99, 95% CI 0.82–1.18). CONCLUSION: The ovarian stimulation-induced maternal environment appears to represent an independent mediator contributing to the risk of low birth weight, but not preterm delivery, in neonates conceived after IVF. LEVEL OF EVIDENCE: II

The association of in vitro fertilization and perinatal morbidity.

In recent years, there has been increasing concern regarding the safety of in vitro fertilization (IVF) because of the potential health impact on these infants. Multiple pregnancy contributes the vast majority of morbidity associated with IVF and, initially, many thought that adverse outcomes after IVF were solely attributable to the high incidence of twin pregnancies. More recently, multiple studies have suggested that IVF singleton pregnancies may be at increased risk for preterm birth, low birth weight, congenital anomalies, perinatal mortality, and several other pregnancy-related complications compared with unassisted singleton pregnancies. We have focused this review on the increased risk of adverse outcomes in IVF singleton conceptions compared with that of unassisted conceptions. The available evidence evaluating the association between IVF and low birth weight, preterm delivery, placental abruption, preeclampsia, congenital anomalies, and perinatal mortality in singleton pregnancies is summarized. In addition, data reporting an increased risk of congenital and chromosomal anomalies after IVF are presented.

A decrease in serum estradiol levels after human chorionic gonadotrophin administration predicts significantly lower clinical pregnancy and live birth rates in in vitro fertilization cycles

BACKGROUND Although close observation of serum estradiol (E2) levels remains a mainstay of assessing clinical response to controlled ovarian stimulation, the prognostic value of any change in E2 levels after administration of hCG remains unclear. The objective of this study is to evaluate the relationship between serum E2 response after hCG administration and the clinical pregnancy and live birth rates in fresh IVF cycles. METHODS We conducted a retrospective cohort study of women aged 21-45 years undergoing their first IVF cycle from 1999 to 2008 at a single practice. We compared the post-hCG serum E2 level with values on the day of hCG trigger. IVF cycles were stratified by post-hCG E2 response and appropriate parametric and non-parametric statistics were performed. Clinical intrauterine pregnancy and live births were the primary outcomes of interest. Multivariable logistic regression models were created to identify predictive factors associated with outcomes while adjusting for potential confounders. RESULTS Among the 1712 IVF cycles, 1065 exhibited a >10% increase (Group A), 525 had a plateau (± 10%, Group B) and 122 showed a >10% decrease (Group C) in post-hCG E2 levels. While the E2 levels on the day of hCG were similar across groups, Group C had more patients with diminished ovarian reserve, required higher gonadotrophin doses and had the lowest implantation rates. After adjusting for age, total gonadotrophin dose, infertility diagnosis, number of oocytes and number of transferred embryos, the associations between post-hCG E2 decline (Group C) and clinical pregnancy [adjusted odds ratio (aOR): 0.53; 95% confidence interval (CI): 0.33-0.84, P= 0.007] and live birth (aOR: 0.40; 95% CI: 0.22-0.71, P= 0.002) were significant. We also found significant associations between E2 plateau (Group B) and clinical pregnancy (aOR: 0.73; 95% CI: 0.57-0.94, P= 0.013) and live birth (aOR: 0.74; 95% CI: 0.56-0.97, P= 0.032) when adjusting for the same factors. CONCLUSIONS In our study, >10% decrease in E2 levels after hCG administration was associated with 40-50% reduction in clinical pregnancy and live birth rates. Similarly, post-hCG E2 plateau (± 10%) lowered the clinical pregnancy and live birth rates by >25%. Our study suggests that the change in the post-hCG E2 level is another parameter that can be used by clinicians to counsel patients regarding their likelihood of success with assisted reproductive technologies prior to oocyte retrieval.

Defining the “sweet spot” for administered luteinizing hormone-to-follicle-stimulating hormone gonadotropin ratios during ovarian stimulation to protect against a clinically significant late follicular increase in progesterone: an analysis of 10,280 first in vitro fertilization cycles

OBJECTIVE To determine whether different ratios of administered LH-to-FSH influence the risk of clinically relevant late follicular P elevations and whether there is an optimal range of LH-to-FSH to mitigate this risk. DESIGN Retrospective cohort. SETTING Private academic center. PATIENT(S) A total of 10,280 patients undergoing their first IVF cycle. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) The ratio of exogenous LH-to-FSH throughout stimulation and association with absolute serum P level≥1.5 ng/mL on the day of hCG administration. RESULT(S) Stimulations using no administered LH (N=718) had the highest risk of P elevation≥1.5 ng/mL (relative risk [RR]=2.0; 95% confidence interval [CI] 1.8-2.2). The lowest risk of P increase occurred with an LH-to-FSH ratio of 0.30:0.60 (20%; N=4,732). In contrast, ratios<0.30, reflecting proportionally less administered LH (N=4,847) were at increased risk for premature P elevation (32%, RR=1.6; 95% CI 1.5-1.7) as were ratios>0.60 (23%, RR 1.1; 95% CI 1.0-1.3). This pattern of lowest risk in the 0.30-0.60 range held true for cycles characterized by low, normal, and high response. When performing a logistic regression to control for multiple confounding variables this relationship persisted. CONCLUSION(S) Absent or inadequate LH dosing is associated with a risk for a late follicular elevation in P sufficient to induce suboptimal outcomes. A total LH-to-FSH ratio of 0.30:0.60 was associated with the lowest risk of P elevation. Optimization of this parameter should be considered when making gonadotropin dosing decisions.

Blastocyst transfer is not associated with increased rates of monozygotic twins when controlling for embryo cohort quality

OBJECTIVE To compare monozygotic twinning (MZT) rates in patients undergoing blastocyst or cleavage-stage ET. DESIGN Retrospective cohort. SETTING Academic research center. PATIENT(S) Autologous, fresh IVF cycles resulting in a clinical pregnancy from 1999 to 2014. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Monozygotic twin pregnancy in blastocyst-stage transfer vs. cleavage-stage transfer when controlling for patient prognosis and embryo cohort quality factors. RESULT(S) There were a total of 9,969 fresh transfer cycles resulting in a pregnancy during the study period. Of these pregnancies, 234 monozygotic twin pregnancies were identified (2.4%). Of all transfers, 5,191 were cleavage-stage and 4,778 were blastocyst-stage transfers. There were a total of 99 MZT identified in the cleavage-stage group (1.9%) and 135 MZT in the blastocyst ET group (2.4%), which was significant. Multivariable logistic regression revealed that increasing age was associated with a significant reduction in MZT, regardless of transfer order. Embryo cohort quality factors, including the number and proportion of six- to eight-cell embryos and availability of supernumerary embryos, were also significant. When controlling for patient age, time period during which the cycle took place, the number and proportion of six- to eight-cell embryos, and availability of supernumerary embryos, there was no longer a difference in MZT rate between blastocyst and cleavage transfer. CONCLUSION(S) Patient prognosis and embryo cohort quality seem to be major factors in MZT rate in women undergoing blastocyst transfer. Although technology-based effects cannot be excluded, patient and embryo characteristics play an important role.

Does a prediction model for pregnancy of unknown location developed in the UK validate on a US population

BACKGROUND A logistic regression model (M4) was developed in the UK to predict the outcome for women with a pregnancy of unknown location (PUL) based on the initial two human chorionic gonadotrophin (hCG) values, 48 h apart. The purpose of this paper was to assess the utility of this model to predict the outcome for a woman (PUL) in a US population. METHODS Diagnostic variables included log-transformed serum hCG average of two measurements, and linear and quadratic hCG ratios. Outcomes modeled were failing PUL, intrauterine pregnancy (IUP) and ectopic pregnancy (EP). This model was applied to a US cohort of 604 women presenting with symptomatic first-trimester pregnancies, who were followed until a definitive diagnosis was made. The model was applied before and after correcting for differences in terminology and diagnostic criteria. RESULTS When retrospectively applied to the adjusted US population, the M4 model demonstrated lower areas under the curve compared with the UK population, 0.898 versus 0.988 for failing PUL/spontaneous miscarriage, 0.915 versus 0.981 for IUP and 0.831 versus 0.904 for EP. Whereas the model had 80% sensitivity for EP using UK data, this decreased to 49% for the US data, with similar specificities. Performance only improved slightly (55% sensitivity) when the US population was adjusted to better match the UK diagnostic criteria. CONCLUSIONS A logistic regression model based on two hCG values performed with modest decreases in predictive ability in a US cohort for women at risk for EP compared with the original UK population. However, the sensitivity for EP was too low for the model to be used in clinical practice in its present form. Our data illustrate the difficulties of applying algorithms from one center to another, where the definitions of pathology may differ.

A strict infertility diagnosis has poor agreement with the clinical diagnosis entered into the Society for Assisted Reproductive Technology registry

Based on a recent review of the medical literature, a clinical diagnosis of infertility may not agree with strict criteria. Standardized definitions of diagnostic categories are essential for accurate patient prognosis and future research.

Donor sperm insemination cycles: are two inseminations better than one?

The objective of this study was to determine the clinical pregnancy rate with 2 inseminations compared to a single intrauterine insemination (IUI) in a given cycle using frozen-thawed donor sperm. This was a retrospective study at a university practice; patients were women using donor sperm. We conducted a comparison of single IUI, intracervical insemination (ICI) followed by an IUI on the next day, and double IUI (2 consecutive days); clinical pregnancy rate was the main outcome measure. The cycle-specific and total pregnancy rates were not significantly different between the 3 protocol groups (306 cycles). The average pregnancy rate over 3 cycles was 10.2% for IUI, 15.3% for ICI/IUI, and 13.7% for IUI/IUI (P = .47). After controlling for repeated measures per subject and age, gravidity, and use of Clomid, there was no significant difference between protocols. The ICI/IUI (odds ratio [OR] = 1.70; 95% confidence interval [CI], 0.83-3.51) and IUI/IUI (OR = 1.5; 95% CI, 0.52-4.33) protocols appeared more likely to result in a clinical pregnancy than the single IUI protocol. Current information on the optimal number of inseminations per cycle using donor sperm is limited. Our large study using 3 protocols found an increase in pregnancy rate with the addition of either an ICI or IUI to a single IUI protocol in a natural or Clomid cycle but did not meet statistical significance. Additional prospective studies are needed to better counsel patients using donor sperm.

CYP1A1 3801T>C polymorphism implicated in altered xenobiotic metabolism is not associated with variations in sperm production and function as measured by total motile sperm and fertilization rates with intracytoplasmic sperm injection

OBJECTIVE To evaluate the cytochrome P450 3801T>C polymorphisms frequency in relation to semen production, as determined by semen analysis parameters, and sperm function, as determined by fertilization rates with intracytoplasmic sperm injection (ICSI). DESIGN Case-control study. SETTING Academic-affiliated private practice. PATIENT(S) This study included patients undergoing IVF from 2004 to 2014 grouped into categories based on semen analysis parameters performed at a single andrology laboratory. Cases were patients with total motile sperm (TMS) counts of ≤20 × 10(6). Frequency-matched controls were selected with TMS of >20 × 10(6). INTERVENTION(S) The 3801T>C polymorphism was identified using DNA from serum samples with real-time quantitative polymerase chain reaction. MAIN OUTCOME MEASURE(S) CYP1A1 3801T>C polymorphism frequency in TMS groups and distribution in fertilization rate outcomes with ICSI. RESULT(S) A total of 460 cases were identified with ≤20 × 10(6) TMS, and 489 age-matched controls with >20 × 10(6) TMS were selected across the study time frame. For those with <5 × 10(6) vs. >20 × 10(6) TMS there was no difference when comparing heterozygous (odds ratio [OR] 0.96; 95% confidence interval [CI] 0.66-1.40) or homozygous mutant (OR 1.33; 95% CI 0.52-3.20) with the wild-type patients. Additionally, no difference was seen when analyzing subgroups <5 × 10(6), 5-20 × 10(6), and >20 × 10(6) TMS in a similar fashion. Receiver operating characteristic (ROC) curve analysis did not find a significant TMS count based on presence of the polymorphism (area under the ROC curve = 0.51). There were 460 patients who underwent IVF/ICSI, and fertilization rates did not differ with presence of the polymorphism (area under the ROC curve = 0.50). CONCLUSION(S) Allele frequency of the 3801T>C polymorphism does not correlate with semen production as determined by TMS counts or sperm function as determined by fertilization rates with ICSI. The use of neither semen analysis parameters nor fertilization rates with ICSI helps identify CYP1A1 polymorphism carriers.