Risk of adverse perinatal outcomes in pregnancies with "small" fetuses not meeting Delphi consensus criteria for fetal growth restriction.

BACKGROUND: Previous research endeavors examining the association between clinical characteristics, sonographic indices, and the risk of adverse perinatal outcomes in pregnancies complicated by fetal growth restriction have been hampered by a lack of agreement regarding its definition. In 2016, a consensus definition was reached by an international panel of experts via the Delphi procedure, but as it currently stands, this has not been endorsed by all professional organizations. OBJECTIVE: This study aimed to assess whether an independent association exists between estimated fetal weight and/or abdominal circumference of <10th percentile and adverse perinatal outcomes when consensus criteria for growth restriction are not met. STUDY DESIGN: Data were derived from a passive prospective cohort of singleton nonanomalous pregnancies at a single academic tertiary care institution (2010-2022) that fell into 3 groups: (1) consecutive fetuses that met the Delphi criteria for fetal growth restriction, (2) small-for-gestational-age fetuses that failed to meet the consensus criteria, and (3) fetuses with birthweights of 20th to 80th percentile randomly selected as an appropriately grown (appropriate-for-gestational-age) comparator group. This nested case-control study used 1:1 propensity score matching to adjust for confounders among the 3 groups: fetal growth restriction cases, small-for-gestational-age cases, and controls. Our primary outcome was a composite: perinatal demise, 5-minute Apgar score of <7, cord pH of ≤7.10, or base excess of ≥12. Pregnancy characteristics with a P value of <.2 on univariate analyses were considered for incorporation into a multivariable model along with fetal growth restriction and small-for-gestational-age to evaluate which outcomes were independently predictive of adverse perinatal outcomes. RESULTS: Overall, 2866 pregnancies met the inclusion criteria. After propensity score matching, there were 2186 matched pairs, including 511 (23%), 1093 (50%), and 582 (27%) patients in the small-for-gestational-age, appropriate-for-gestational-age, and fetal growth restriction groups, respectively. Moreover, 210 pregnancies (10%) were complicated by adverse perinatal outcomes. None of the pregnancies with small-for-gestational-age OR appropriate-for-gestational-age fetuses resulted in perinatal demise. Twenty-three of 511 patients (5%) in the small-for-gestational-age group had adverse outcomes based on 5-minute Apgar scores and/or cord gas results compared with 77 of 1093 patients (7%) in the appropriate-for-gestational-age group (odds ratio, 0.62; 95% confidence interval, 0.39-1.00). Furthermore, 110 of 582 patients (19%) with fetal growth restriction that met the consensus criteria had adverse outcomes (odds ratio, 3.08; 95% confidence interval, 2.25-4.20), including 34 patients with perinatal demise or death before discharge. Factors independently associated with increased odds of adverse outcomes included chronic hypertension, hypertensive disorders of pregnancy, and early-onset fetal growth restriction. Small-for-gestational age was not associated with the primary outcome after adjustment for 6 other factors included in a model predicting adverse perinatal outcomes. The bias-corrected bootstrapped area under the receiver operating characteristic curve for the model was 0.72 (95% confidence interval, 0.66-0.74). The bias-corrected bootstrapped area under the receiver operating characteristic curve for a 7-factor model predicting adverse perinatal outcomes was 0.72 (95% confidence interval, 0.66-0.74). CONCLUSION: This study found no evidence that fetuses with an estimated fetal weight and/or abdominal circumference of 3rd to 9th percentile that fail to meet the consensus criteria for fetal growth restriction (based on Doppler waveforms and/or growth velocity of ≥32 weeks) are at increased risk of adverse outcomes. Although the growth of these fetuses should be monitored closely to rule out evolving growth restriction, most cases are healthy constitutionally small fetuses. The management of these fetuses in the same manner as those with suspected pathologic growth restriction may result in unnecessary antenatal testing and increase the risk of iatrogenic complications resulting from preterm or early term delivery of small fetuses that are at relatively low risk of adverse perinatal outcomes.

Fetal overgrowth in pregnancies complicated by diabetes: validation of a predictive index in an external cohort.

PURPOSE: To assess validity of a fetal overgrowth index in an external cohort of women with diabetes in pregnancy METHODS: We performed a retrospective analysis of data derived from women with singleton gestations complicated by diabetes who delivered January 2015-June 2018. The following index variables were used to calculate risk of fetal overgrowth as defined by a customized birthweight ≥ 90th centile: age, history of fetal overgrowth in a prior pregnancy, gestational weight gain, fetal abdominal circumference measurement and fasting glucose between 24 and 30 weeks. RESULTS: In our validation cohort, 21% of 477 pregnancies were complicated by fetal overgrowth. The predictive index had a bias-corrected bootstrapped area under receiver operating characteristic curve of 0.90 (95% CI 0.86-0.93). 55% of the cohort had a low-risk index (≤ 3) which had a negative predictive value of 97% (95% CI 94-98%), while 18% had a high-risk index (≥ 8) that had a positive predictive value of 74% (95% CI 66-81%). CONCLUSION: The fetal overgrowth index incorporates five factors that are widely available in daily clinical practice prior to the period of maximum fetal growth velocity in the third trimester. Despite substantial differences between our cohort and the one studied for model development, we found the performance of the index was strong. This finding lends support for the general use of this tool that may aid counseling and allow for targeted allocation of healthcare resources among women with pregnancies complicated by diabetes.

Fetal overgrowth in pregnancies complicated by diabetes: development of a clinical prediction index.

PURPOSE: To develop an index to predict fetal overgrowth in pregnancies complicated by diabetes. METHODS: Data were derived from a cohort of 275 women with singleton gestations in a collaborative diabetes in pregnancy program. Regression analysis incorporated clinical factors available in the first 20-30 weeks of pregnancy that were assigned beta-coefficient-based weights, the sum of which yielded a fetal overgrowth index (composite score). RESULTS: Fifty-one (18.5%) pregnancies were complicated by fetal overgrowth. The derived index included five clinical factors: age ≤ 30, history of macrosomia, excessive gestational weight gain, enlarged fetal abdominal circumference, and fasting hyperglycemia. Area under the curve (AUC) for the index is 0.88 [95% confidence interval (CI) 0.82-0.92]. Cut-points were selected to identify "high-risk" and "low-risk" ranges (≥ 8 and ≤ 3) that have positive and negative predictive values of 84% (95% CI 70-98%) and 95% (95% CI 92-98%), respectively. The majority of women in our cohort (n = 182, 66%) had a "low-risk" index while 9% (n = 25) had a "high-risk" index. Sub-analyses of nulliparous women and women with gestational and pre-gestational diabetes revealed that the overgrowth index was equally or more predictive when applied separately to each of these groups. CONCLUSION: This fetal overgrowth index that incorporates five clinical factors provides a means of predicting fetal overgrowth and thereby serves as a tool for targeting the allocation of healthcare resources and treatment individualization.

Inflammatory Bowel Disease Increases Risk of Adverse Pregnancy Outcomes: A Meta-Analysis.

BACKGROUND: Inflammatory bowel disease may place women at greater risk of adverse pregnancy outcomes. AIM: To examine the association between inflammatory bowel disease and adverse pregnancy outcomes: preterm birth, small for gestational age (SGA) birth weight, congenital anomalies, and stillbirth. METHODS: We searched PubMed, EMBASE, the Cochrane Database of Systematic Reviews, and ClinicalTrials.gov for studies published from January 1980 through February 2014 and reference lists of relevant studies. We reviewed 1748 citations and identified studies evaluating outcomes of pregnancies complicated by inflammatory bowel disease. Selected studies evaluated one or more of the outcomes of interest, were in English, and gave sufficient details to perform meta-analysis. Three investigators independently reviewed articles for inclusion; discordant decisions were resolved by team review and consensus. Twenty-three studies that included 15,007 women with inflammatory bowel disease (5449 Crohn's, 6559 ulcerative colitis) and 4,614,271 controls met selection criteria. Random-effects analytical methods were used to generate pooled odds ratios. RESULTS: We found an increased odds of the outcomes studied among women with inflammatory bowel disease compared with non-diseased controls: 1.85 for preterm birth (22 studies; 95 % confidence interval [CI] 1.67-2.05), 1.36 for SGA birth weight (13 studies; 95 % CI 1.16-1.60), 1.57 for stillbirth (10 studies; 95 % CI 1.03-2.38), and 1.29 for congenital anomalies (11 studies; 95 % CI 1.05-1.58). The latter result, however, may be unreliable secondary to publication bias. CONCLUSION: Inflammatory bowel disease may increase the odds of adverse pregnancy outcomes.

An interference account of cue-independent forgetting in the no-think paradigm.

Memory suppression is investigated with the no-think paradigm, which produces forgetting following repeated practice of not thinking about a memory [Anderson MC, Green C (2001) Nature 410:366-369]. Because the forgotten item is not retrieved even when tested with an independent, semantically related cue, it has been assumed that this forgetting is due to an inhibition process. However, this conclusion is based on a single stage to recall, whereas global memory models, which produce forgetting through a process of interference, include both a sampling and a recovery stage to recall. By assuming that interference exists during recovery, these models can explain cue-independent forgetting. We tested several predictions of this interference explanation of cue-independent forgetting by modifying the think/no-think paradigm. We added a condition where participants quickly pressed enter rather than not thinking. We also manipulated initial memory strength and tested recognition memory. Most importantly, learning to quickly press enter produced as much cue-independent forgetting as no-think instructions. Demonstrating the adequacy of two-stage recall, a simple computational model (SAM-RI) simultaneously captured the original cue, independent cue, and recognition results.

Pulse pressure as a predictor of response to treatment for severe hypertension in pregnancy.

BACKGROUND: Pulse pressure is a proposed means of tailoring antihypertensive therapy for treatment of acute-onset, severe hypertension in pregnancy. OBJECTIVE: This study aimed to determine whether pulse pressure predicts response to the various first-line antihypertensive medications. STUDY DESIGN: This is a retrospective cohort study from a single academic tertiary care center between 2015 and 2018. Patients were screened for inclusion if they had severe hypertension (defined as systolic blood pressure of ≥160 mm Hg or diastolic blood pressure of ≥110 mm Hg) lasting at least 15 minutes and were initially treated with intravenous labetalol, intravenous hydralazine, or immediate-release oral nifedipine. If a patient had multiple episodes of acute treatment during the pregnancy, only one episode was included in the analysis. The primary outcome was time to resolution (in minutes) of severe hypertension. To adjust for factors that may have affected time to resolution, we first compared baseline characteristics on the basis of the antihypertensive agent received. We then assessed the association between baseline characteristics and resolution of severe hypertension within 60 minutes of treatment. Regression analysis incorporated pulse pressure and antihypertensive agents into a model to predict resolution within 60 minutes of onset of severe hypertension. RESULTS: A total of 479 women hospitalized with severe maternal hypertension met the inclusion criteria. Hydralazine was the initial antihypertensive agent administered to 113 women, whereas 233 received labetalol, and 133 received nifedipine. Those who initially received nifedipine had a shorter mean time to resolution of severe hypertension (32.6 minutes vs 46.3 for hydralazine and 50.3 for labetalol; P<.01) and were more likely to have resolution of severe hypertension within 60 minutes (91.0% vs 77.9% for hydralazine and 76.8% for labetalol; P<.01). Nifedipine also resulted in a lower mean posttreatment blood pressure. Regression analysis revealed that a lack of resolution of severe hypertension within 60 minutes was independently associated with 2 measures of hypertension severity (mean arterial pressure of ≥125 mm Hg and the need for ≥2 doses of medication) and pulse pressure of >75 mm Hg at the time of treatment, initial treatment with labetalol, and gestational age of <37 weeks at the time of the hypertensive event (or at delivery if treatment was after delivery). The model's bias-corrected bootstrapped area under the receiver operating characteristic curve was 0.85 (95% confidence interval, 0.79-0.88). Interaction terms between pulse pressure and each antihypertensive agent were not significant and therefore not incorporated into the final model. CONCLUSION: Pulse pressure did not predict response to the various first-line antihypertensive agents. Initial treatment with oral nifedipine was associated with a higher likelihood of resolution of severe hypertension within 60 minutes of treatment than with intravenous labetalol.

Magnetic resonance imaging of hypoxic injury to the murine placenta.

We assessed the use of magnetic resonance imaging (MRI) to define placental hypoxic injury associated with fetal growth restriction. On embryonic day 18.5 (E18.5) we utilized dynamic contrast-enhanced (DCE)-MRI on a 4.7-tesla small animal scanner to examine the uptake and distribution of gadolinium-based contrast agent. Quantitative DCE parameter analysis was performed for the placenta and fetal kidneys of three groups of pregnant C57BL/6 mice: 1) mice that were exposed to Fi(O(2)) = 12% between E15.5 and E18.5, 2) mice in normoxia with food restriction similar to the intake of hypoxic mice between E15.5 and E18.5, and 3) mice in normoxia that were fed ad libitum. After imaging, we assessed fetoplacental weight, placental histology, and gene expression. We found that dams exposed to hypoxia exhibited fetal growth restriction (weight reduction by 28% and 14%, respectively, P < 0.05) with an increased placental-to-fetal ratio. By using MRI-based assessment of placental contrast agent kinetics, referenced to maternal paraspinous muscle, we found decreased placental clearance of contrast media in hypoxic mice, compared with either control group (61%, P < 0.05). This was accompanied by diminished contrast accumulation in the hypoxic fetal kidneys (23%, P < 0.05), reflecting reduced transplacental gadolinium transport. These changes were associated with increased expression of placental Phlda2 and Gcm1 transcripts. Exposure to hypoxia near the end of mouse pregnancy reduces placental perfusion and clearance of contrast. MRI-based DCE imaging provides a novel tool for dynamic, in vivo assessment of placental function.

Pregnancy duration with use of 17-α-hydroxyprogesterone caproate in a retrospective cohort at high risk of recurrent preterm birth.

BACKGROUND: The use of 17-α-hydroxyprogesterone caproate for the prevention of recurrent spontaneous preterm birth has become widespread, yet there are conflicting data regarding its efficacy. OBJECTIVE: We sought to determine whether administration of 17-α-hydroxyprogesterone caproate was associated with pregnancy prolongation in women at a high risk of recurrent spontaneous preterm birth. STUDY DESIGN: This is a retrospective cohort study of women with singleton pregnancies and a history of spontaneous preterm birth at <37 weeks' gestation who received care at our academic tertiary care center between 2009 and 2019. We included women with gestations that progressed beyond 16 weeks. We excluded those who underwent history-indicated cerclage placement. We first examined the characteristics of women who received 17-α-hydroxyprogesterone caproate and those who did not. Covariates with a P value of ≤.2 on this univariate analysis were considered for incorporation into a Cox proportional hazards model to assess the association between 17-α-hydroxyprogesterone caproate use and pregnancy prolongation up to 35 weeks. RESULTS: Of 861 women included in the study, 570 (66.2%) reported non-Hispanic black racial identity, 237 (27.5%) lived in zip codes with a high infant mortality rate (≥12.1/1000 infants), 287 (33.3%) had more than 1 previous spontaneous preterm birth, 372 (43.2%) had previous spontaneous preterm birth at ≤32 weeks' gestation, and 242 (28.1%) were smokers. Here, 152 pregnancies (17.6%) were complicated by spontaneous preterm birth at <35 weeks' gestation. Factors independently associated with pregnancy duration up to 35 weeks included weight gain of <0.2 kg (0.5 lb) per week, first recorded weight of <98 kg (215 lb), obstetrical history, non-Hispanic white racial identity, lack of prenatal care, and vaginal bleeding. Gestational age at delivery was also independently associated with interventions typically employed for midtrimester cervical shortening and/or dilation, including ultrasound- and examination-indicated cerclage, pessary placement, and vaginal progesterone administration. The use of 17-α-hydroxyprogesterone caproate was not associated with pregnancy prolongation (adjusted hazard ratio, 0.83; 95% confidence interval, 0.60-1.15). CONCLUSION: The risk profile of our cohort is similar to that of women enrolled in the landmark trial that led to the Food and Drug Administration's approval of 17-α-hydroxyprogesterone caproate. Despite the high-risk nature of the pregnancies examined, we found no association between use of the medication in daily clinical practice and pregnancy prolongation up to 35 weeks. This finding adds to the mounting evidence that calls into question the drug's efficacy in reducing the risk of recurrent spontaneous preterm birth.

Cardiac troponin I elevation after orogenital sex during pregnancy.

BACKGROUND: Venous air embolism due to orogenital sex in pregnancy is an uncommon clinical event. CASE: A previously healthy, 29-week pregnant woman presented to the emergency room unconscious 1 hour after engaging in orogenital sex with her partner. The cardiology service was consulted due to troponin elevation. Assessment was that the patient had likely suffered an air embolism with associated troponin leak. CONCLUSION: Although a rare clinical event, air embolism from air insufflation of the vagina can result in troponin elevation and should be considered in the differential diagnosis in pregnant patients with a history of orogenital sex.

Fetal heart rate accelerations and the risk of cerebral lesions and poor neurodevelopmental outcome in very low birthweight neonates.

The risk of intraventricular hemorrhage and periventricular leukomalacia correlates with fetal brain immaturity. Given that the appearance of fetal heart rate (FHR) accelerations is associated with brain maturation, we tested the hypothesis that neonatal cerebral lesions and developmental delay in very low birthweight newborns are associated with absent reactivity of the FHR tracing prior to delivery. We analyzed the FHR tracing of 97 fetuses with birthweight < 1200 g who underwent head ultrasound at day 3 and Bayley Scales of Infant Development testing at age 1 year. We used multivariate analysis to adjust for confounding variables. We found that the absence of two FHR accelerations of 10 beats per minute (bpm) for 10 seconds twice in a 20-minute window 1 hour before delivery was associated with intraventricular hemorrhage and/or periventricular leukomalacia ( P < 0.01) and a significant risk for mental and psychomotor delays by Bayley testing ( P < 0.001). The absence of accelerations of 15 bpm for 15 seconds was not associated with these abnormalities. The absence of FHR accelerations before delivery suggests a greater risk for cerebral injury and developmental delay in the very premature neonate.