Prediction of preterm birth by measurement of cervical length on transvaginal ultrasound and magnetic resonance imaging in pregnancies complicated by twin-twin transfusion syndrome and treated with laser surgery.

OBJECTIVES: Twin pregnancies complicated by twin-twin transfusion syndrome (TTTS) are at particularly high risk of preterm birth. Cervical length (CL) measurement on transvaginal ultrasound (TVS) is a powerful predictor of preterm birth, but the predictive accuracy of CL measurement on magnetic resonance imaging (MRI) has not yet been established. We sought to investigate the correlation between CL measurements obtained on preoperative TVS and on MRI and to quantify their predictive accuracy for preterm birth among pregnancies complicated by TTTS that underwent selective fetoscopic laser photocoagulation (SFLP), to identify whether MRI is a useful adjunct to TVS. METHODS: This was a retrospective cohort study of pregnancies that were treated for TTTS with SFLP at a single center between April 2010 and June 2019 and that underwent TVS and MRI evaluation. Correlation was estimated using Pearson's coefficient, mean CL measurements were compared using the two-tailed paired t-test and the frequency at which a short cervix was detected by the two imaging modalities was compared using the χ-square test. Generalized linear models were used to estimate relative risk and receiver-operating-characteristics (ROC)-curve analysis was used to estimate the predictive accuracy of CL for preterm birth. RESULTS: Among 626 pregnancies complicated by TTTS that underwent SFLP, CL measurements were obtained on preoperative TVS in 579 cases and on preoperative MRI in 434. CL ≤ 2.5 cm was recorded in 39 (6.7%) patients on TVS and 47 (10.8%) patients on MRI (P = 0.0001). Measurements of CL made on MRI correlated well with those obtained on TVS overall (r = 0.63), but correlation was weak at the shortest CLs (r < 0.20). MRI failed to detect two (40.0%), three (18.8%), nine (32.1%) and 13 (28.9%) cases diagnosed as having a short cervix on TVS at cut-offs of ≤ 1.5 cm, ≤ 2.0 cm, ≤ 2.5 cm and ≤ 2.8 cm, respectively. Over half of the pregnancies with a preoperative CL of ≤ 2.5 cm delivered by 28 weeks' gestation, regardless of imaging modality. CL measurement on TVS was superior to that on MRI to predict preterm birth, the latter performing poorly at all CL cut-offs. A CL measurement of ≤ 2.0 cm on preoperative TVS had the highest predictive ability for preterm birth, with an area under the ROC curve for delivery before 32 weeks of 0.82. CONCLUSIONS: Although measurement of CL on MRI correlates well with that on TVS overall, it performs poorly at accurately detecting a short cervix. TVS outperforms MRI in evaluation of the cervix and remains the optimal modality for CL measurement in pregnancies at high risk for preterm birth, such as those undergoing SFLP for TTTS. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Early and late preterm birth rates in participants adherent to randomly assigned high dose docosahexaenoic acid (DHA) supplementation in pregnancy.

BACKGROUND: Intention-to-treat analyses do not address adherence. Per protocol analyses treat nonadherence as a protocol deviation and assess if the intervention is effective if followed. OBJECTIVE: To determine the rate of early preterm birth (EPTB, <34 weeks gestation) and preterm birth (PTB, <37 weeks gestation) in participants who adhered to a randomly assigned docosahexaenoic acid (DHA) dose of 1000 mg/day. STUDY DESIGN: Eleven hundred women with a singleton pregnancy were enrolled before 20-weeks' gestation, provided a capsule with 200 mg/day DHA and randomly assigned to two additional capsules containing a placebo or 800 mg of DHA. In the Bayesian Adaptive Design, new randomization schedules were determined at prespecified intervals. In each randomization, the group with the most EPTB was assigned fewer participants than the other group. Adherence was defined a priori as a postpartum red blood cell phospholipid DHA (RBC-PL-DHA) ≥5.5%.and post hoc as ≥8.0% RBC-PL-DHA, the latter after examination of postpartum RBC-PL-DHA. Bayesian mixture models were fitted for gestational age and dichotomized for EPTB and PTB as a function of baseline RBC-PL-DHA and dose-adherence. Bayesian hierarchical models were also fitted for EPTB by dose adherence and quartiles of baseline RBC-PL-DHA. RESULTS: Adherence to the high dose using both RBC-PL-DHA cut points resulted in less EPTB compared to 200 mg [Bayesian posterior probability (pp) = 0.93 and 0.92, respectively]. For participants in the two lowest quartiles of baseline DHA status, adherence to the higher dose resulted in lower EPTB (≥5.5% RBC-PL-DHA, quartiles 1 and 2, pp = 0.95 and 0.96; ≥8% RBC-PL-DHA, quartiles 1 and 2, pp = 0.94 and 0.95). Using the Bayesian model, EPTB was reduced by 65%, from 3.45% to 1.2%, using both cut points. Adherence also reduced PTB before 35, 36 and 37 weeks using both cut points (pp ≥ 0.95). In general, performance of the nonadherent subgroup mirrored that of participants assigned to 200 mg. CONCLUSION: Adherence to high dose DHA reduced EPTB and PTB. The largest effect of adherence on reducing EPTB was observed in women with low baseline DHA levels. CLINICALTRIALS: gov (NCT02626299).

Docosahexaenoic acid (DHA) intake estimated from a 7-question survey identifies pregnancies most likely to benefit from high-dose DHA supplementation.

BACKGROUND: Two randomized trials found women with low blood docosahexaenoic acid (DHA; an omega 3 fatty acid) had fewer early preterm births (<34 weeks gestation) if they were assigned to high dose DHA supplementation, however, there is currently no capacity for clinicians who care for pregnancies to obtain a blood assessment of DHA. Determining a way to identify women with low DHA intake whose risk could be lowered by high dose DHA supplementation is desired. OBJECTIVE: To determine if assessing DHA intake can identify pregnancies that benefit from high dose DHA supplementation. STUDY DESIGN: This secondary analysis used birth data from 1310 pregnant women who completed a 7-question food frequency questionnaire (DHA-FFQ) at 16.8 ± 2.5 weeks gestation that is validated to assess DHA status. They were then randomly assigned to a standard (200 mg/day) or high dose (800 or 1000 mg/day) DHA supplement for the remainder of pregnancy. Bayesian logistic regressions were fitted for early preterm birth and preterm birth as a function of DHA intake and assigned DHA dose. RESULTS: Participants who consumed less than 150 mg/day DHA prior to 20 weeks' gestation (n = 810/1310, 58.1%) had a lower Bayesian posterior probability (pp) of early preterm birth if they were assigned to high dose DHA supplementation (1.4% vs 3.9%, pp = 0.99). The effect on preterm birth (<37 weeks) was also significant (11.3% vs 14.8%, pp = 0.97). CONCLUSION: The DHA-FFQ can identify pregnancies that will benefit most from high dose DHA supplementation and reduce the risk of preterm birth. The DHA-FFQ is low burden to providers and patients and could be easily implemented in obstetrical practice.

Influence of interpregnancy interval on uterine rupture.

OBJECTIVE: This study aims to assess the independent influence of interpregnancy interval (IPI) on uterine rupture using a population-based cohort of all Ohio births, regardless of prior cesarean (PCS) or trial of labor (TOL) status. STUDY DESIGN: Population-based retrospective cohort study of all live births in Ohio (2006-2012). Frequency of uterine rupture was quantified and stratified by number of prior cesarean deliveries and IPI. The relative and adjusted risk of IPI on uterine rupture was calculated using multivariate logistic regression. RESULTS: Of 1,034,522 live births recorded during the 7-year study period, 249 cases of uterine rupture were identified for analysis. Two-thirds of uterine rupture cases (n = 158) occurred in women with one or more PCS and one-third (n = 91) had no prior cesarean. IPI 24-59 months had the lowest frequency of uterine rupture and was used as the referent group. IPI 12-23 and IPI ≥ 60 months were not significantly associated with risk of uterine rupture, p = .847, .540 respectively. In women with PCS, IPI < 12 months was associated with greater than two-fold increased risk of uterine rupture (aRR 2.4, CI 1.5-3.8). No association between IPI < 12 months and uterine rupture was observed in women with no PCS, p = .696. CONCLUSION: IPI < 12 months is independently associated with uterine rupture in women with prior cesarean, but does not appear to influence risk in women with an unscarred uterus.

Contribution of previable live births to disparity in infant mortality of US-born Puerto Ricans compared with infants of other Hispanic origins.

OBJECTIVES: Although US-born Hispanics experience infant mortality rates (IMRs) which are lower than the national rate, within the Hispanic population, infants of Puerto Rican origin experience higher IMRs than other Hispanics. We aimed to describe the contribution of deaths among previable live-born infants to disparity in IMRs comparing Puerto Rican infants to infants of other Hispanic origins. STUDY DESIGN: Retrospective, descriptive analysis. METHODS: We analyzed data from the Centers for Disease Control and Prevention (CDC) WONDER online database representing linked US live births and infant deaths from 2005 to 2014. Data were stratified by race and ethnicity as well as by Puerto Rican and non-Puerto Rican Hispanic origin. Live births <23 weeks of gestation were classified as previable. Ten-year IMRs were calculated as the number of deaths divided by the number of live births for each group over the entire decade. RESULTS: Puerto Rican IMR of 7.34 (per 1000 live births) was higher than the US rate of 6.34 as well as the non-Puerto Rican Hispanic IMR of 5.15. Approximately 22% of US deaths were attributable to previable live births compared with 27% among Puerto Ricans and 20% among non-Puerto Rican Hispanics. The contribution to IMR of previable births among Puerto Ricans measuring 1.96 per 1000 total live births was 42% higher than the US rate of 1.38 and 90% higher than the non-Puerto Rican Hispanic rate of 1.03. CONCLUSIONS: Further research is needed to develop interventions to reduce disparity in previable birth rates, particularly among infants of Puerto Rican origin.

Success of labor induction for pre-eclampsia at preterm and term gestational ages.

OBJECTIVE: Determine the impact of gestational age (GA) on vaginal delivery following induction of labor (IOL) for pre-eclampsia, and evaluate factors that influence successful induction. STUDY DESIGN: Population-based retrospective cohort of 1 034 552 live births in Ohio (2006-2012). The rate of vaginal delivery in women with pre-eclampsia who underwent induction was calculated with 95% confidence intervals, stratified by week of GA at birth. Factors associated with the decision to undergo IOL, and success of IOL were evaluated, and multivariable logistic regression estimated the strength of association. RESULTS: 18 296 (71.3%) of the patients who underwent IOL had a vaginal delivery. The majority achieved vaginal delivery at both preterm (66% at 23-36 weeks) and term GAs (72%). Factors most strongly associated with vaginal delivery following IOL for pre-eclampsia included prior vaginal delivery and young maternal age. CONCLUSION: The majority of women with pre-eclampsia who undergo IOL achieve vaginal birth, even at early GAs.

Optimal gestational weight gain: prepregnancy BMI specific influences on adverse pregnancy and infant health outcomes.

OBJECTIVE: The Institute of Medicine (IOM) 2009 gestational weight gain (GWG) guidelines are based on prepregnancy body mass index (BMI) categories. We intended to refine optimal GWG for each prepregnancy BMI unit in relation to the risk of small- and large-for-gestational-age (SGA and LGA) births, cesarean section (C-section) and infant death. STUDY DESIGN: We used data from 836,841 Ohio birth records from 2006 to 2012, and applied generalized additive models to calculate optimal GWG by prepregnancy BMI unit. RESULTS: The suggested optimal GWG was generally similar to IOM 2009 GWG guidelines for prepregnancy BMIs <25 kg m-2, but higher for prepregnancy BMIs 25 to 32 kg m-2 and lower for BMIs 38 to 50 kg m-2. The suggested optimal GWG was 14 to 18.5, 13 to 17, 11.5 to 16, 8.5 to 12.5, 4 to 10, 3 to 7, 1.5 to 6 and 1.5 to 4.5 kg for prepregnancy BMIs 15, 20, 25, 30, 35, 40, 45 and 50 kg m-2, respectively. CONCLUSION: This research suggests that GWG recommendations may be refined at individual prepregnancy BMI levels.

Influence of gestational weight gain and BMI on cesarean delivery risk in adolescent pregnancies.

OBJECTIVE: Obesity and excessive gestational weight gain (GWG) increase cesarean delivery (CD) risk; however, their influence on teen pregnancies is less clear. We describe the influence of GWG and pre-pregnancy body mass index (BMI) on primary CD (PCD) risk in adolescent compared with adult pregnancies. STUDY DESIGN: Population-based cohort study of Ohio births (2006 to 2012), n=1 034 552. Analyses were limited to 251 398 singleton live births in term (37 to 42 weeks) primiparas. Multivariate logistic regression estimated the association between BMI, GWG and CD risk in teens compared with adults (20 to 34 years), adjusting for maternal race, smoking status and labor induction. RESULTS: The primary cesarean rate (PCD) for primiparous women was 25.6%. It was lower for adolescents (17% <15 years, 17% 15 to 17 years, 19% 18 to 19 years) compared with adults (26%, P<0.001). The PCD rate increased with excessive (29%) vs Institute of Medicine (IOM)-recommended GWG (20%). The PCD rate was also increased in mothers who were overweight (29%), and obese (39%) vs those with normal pre-pregnancy BMI (20%, P<0.001). The lowest PCD rate (11.6%) observed in normal weight teens <18 years was with appropriate GWG (adjusted odds ratio (aOR) 0.61; 95% CI 0.54 to 0.69). Compared with adults, teens have 43% lower PCD risk (aOR 0.57; 95% CI 0.55 to 0.60). Excessive GWG increased the risk for PCD in adults by 64% (aOR 1.64; 95% CI 1.59 to 1.68). Excessive GWG increased PCD in the highest risk groups, obese adults (aOR 1.24; 1.17 to 1.32) and obese teens (aOR 1.26; 95% CI 1.08 to 1.46). CONCLUSION: Excessive GWG increases the risk of PCD. Young maternal age was protective of this effect. However, excessive GWG increased PCD risk in both teen and adult mothers. To reduce the primary cesarean rate, efforts should target interventions to promote optimal GWG, especially in those at highest risk, obese women of all ages.

Tocolytics used as adjunctive therapy at the time of cerclage placement: a systematic review.

OBJECTIVE: To review the published literature on whether the use of empiric perioperative tocolytic medications could provide additional benefit when used in combination with cerclage. STUDY DESIGN: Systematic review of published medical literature reporting the efficacy of empiric tocolytics used as a perioperative adjunct to vaginal cerclage in high-risk patients. A PubMed search without date criteria of various tocolytics and cerclage yielded 42 studies. Review articles were excluded, as were reports of abdominal cerclage, emergent cerclage, or cerclage for the purpose of delayed interval delivery in twin gestations. RESULT: Only five publications on the topic of perioperative tocolytic use at the time of history or ultrasound-indicated vaginal cerclage placement were identified. These included zero clinical trials, three retrospective cohort studies, one case series and one case report. Only one cohort study compared cerclage with indomethacin and cerclage without indomethacin and suggested no difference between the groups. The other two published cohort studies had no referent group who received cerclage without tocolysis. One case series and one case report were also published reporting cerclage with empiric beta-mimetic and progesterone adjunctive therapy. CONCLUSION: There is a paucity of published data on the topic of adjunctive perioperative tocolytics with cerclage. Adequately powered clinical trials on perioperative use of tocolysis with cerclage compared with a standard cerclage placement alone are needed to establish efficacy. Until adequately studied, this practice should be considered investigational.

Influence of interpregnancy interval on birth timing.

OBJECTIVE: To assess the influence of inadequate birth spacing on birth timing distribution across gestation. DESIGN: Population-based retrospective cohort study using vital statistics birth records. SETTING: Ohio, USA. STUDY POPULATION: Singleton, non-anomalous live births ≥20 weeks to multiparous mothers, 2006-2011. METHODS: Birth frequency at each gestational week was compared following short IPIs of <6, 6-12 and 12-18 months versus referent group, normal IPI≥18 months. MAIN OUTCOME MEASURES: Frequency of birth at each gestational week; preterm <37 weeks; <39 and ≥40 weeks. RESULTS: Of 454,716 births, 87% followed a normal IPI≥18 months, 10.7% had IPI 12-18 months and 2.2% with IPI<12 months. The risk of delivery<39 weeks was higher following short IPI<12 months, adj OR (odds ratio) 2.78 (95% CI 2.64, 2.93). 53.3% of women delivered before the 39th week after IPI<12 months compared with 37.5% of women with normal IPI, P<0.001. Likewise, birth at ≥40 weeks was decreased (16.9%) following short IPI<12 months compared to normal IPI, 23.2%, adj OR 0.67 (95% CI 0.64, 0.71). This resulted in a shift of the frequency distribution curve of birth by week of gestation to the left for pregnancies following a short IPI<12 months and 12-18 months compared to, birth spacing≥18 months. CONCLUSIONS: While short IPI is a known risk factor for preterm birth, our data show that inadequate birth spacing is associated with decreased gestational age for all births. Pregnancies following short IPIs have a higher frequency of birth at all weeks of gestation prior to 39 and fewer births≥40 weeks, resulting in overall shortened pregnancy duration.

Placental pathologic aberrations in cases of familial idiopathic spontaneous preterm birth.

OBJECTIVE: To test the hypothesis that placental histologic characteristics in familial spontaneous preterm birth (sPTB) differ by gestational age (GA) and reflect possible mechanisms of pathogenesis. STUDY DESIGN: Secondary analysis from prospective cohort study in women with sPTB <35 weeks and a first degree family member with PTB. Placental specimens (n = 79) were categorized by maternal and/or fetal inflammatory response (MIR, FIR) and compared among three preterm GA categories. RESULTS: Inflammatory changes were common. MIR was most frequent at the earliest GAs, 85% with PTB <28 weeks [(adj)OR 77.5 (95% CI 5, 1213.1)], and 57% at 28-32 weeks [(adj)OR 6.1 (0.8, 48.5)] compared to later PTBs occurring at 32-35 weeks (22%). FIR also occurred most frequently in the earliest cases of PTB <28 weeks. CONCLUSIONS: Placental inflammatory responses are common in women with familial sPTB. This data suggests that inflammation plays an important role in the onset of parturition in cases otherwise classified as idiopathic or spontaneous in nature, especially at the earliest GAs when neonatal outcomes are the poorest.

Effect of progesterone on cervical shortening in women at risk for preterm birth: secondary analysis from a multinational, randomized, double-blind, placebo-controlled trial.

OBJECTIVES: To determine whether progesterone supplementation alters cervical shortening in women at increased risk for preterm birth. METHODS: We performed a planned secondary analysis from a large, multinational preterm birth prevention trial of daily intravaginal progesterone gel, 90 mg, compared with placebo in women with a history of spontaneous preterm birth or premature cervical shortening. Transvaginal cervical length measurements were obtained in all randomized patients at baseline (18 + 0 to 22 + 6 weeks' gestation) and at 28 weeks' gestation. For this secondary analysis, the difference in cervical length between these time points was compared for the study population with a history of spontaneous preterm birth and for a population with premature cervical shortening (< or = 30 mm) at randomization. Differences between groups in cervical length for the 28-week examination were analyzed using ANCOVA, including adjustment for relevant clinical parameters and maternal characteristics. RESULTS: Data were analyzed from 547 randomized patients with a history of preterm birth. The progesterone-treated patients had significantly less cervical shortening than the placebo group (difference 1.6 (95% CI, 0.3-3.0) mm; P = 0.02, ANCOVA). In the population of 104 subjects with premature cervical shortening at randomization, the cervical length also differed significantly on multivariable analysis, with the treatment group preserving more cervical length than the placebo group (difference 3.3 (95% CI, 0.3-6.2) mm; P = 0.03, ANCOVA), with adjustment for differences in cervical length at screening. A significant difference was also observed between groups for categorical outcomes including the frequency of cervical length progression to < or = 25 mm and a > or = 50% reduction in cervical length from baseline in this subpopulation. CONCLUSIONS: Intravaginal progesterone enhances preservation of cervical length in women at high risk for preterm birth.

The genetics of birth timing: insights into a fundamental component of human development.

The timing of birth necessitates the coupling of fetal maturation with the onset of parturition, and occurs at characteristic, but divergent gestations between mammals. Preterm birth in humans is an important but poorly understood outcome of pregnancy that uncouples fetal maturation and birth timing. The etiology of preterm birth is complex, involving environmental and genetic factors whose underlying molecular and cellular pathogenic mechanisms remain poorly understood. Animal models, although limited by differences with human physiology, have been crucial in exploring the role of various genetic pathways in mammalian birth timing. Studies in humans of both familial aggregation and racial disparities in preterm birth have contributed to the understanding that preterm birth is heritable. A significant portion of this heritability is due to polygenic causes with few true Mendelian disorders contributing to preterm birth. Thus far, studies of the human genetics of preterm birth using a candidate gene approach have met with limited success. Emerging research efforts using unbiased methods may yield promising results if concerns about study design can be adequately addressed. The findings from this frontier of research may have direct implications for the allocation of public health and clinical resources as well as spur the development of more effective therapeutics.

Vaginal progesterone is associated with a decrease in risk for early preterm birth and improved neonatal outcome in women with a short cervix: a secondary analysis from a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To investigate the efficacy of vaginal progesterone to prevent early preterm birth in women with sonographic evidence of a short cervical length in the midtrimester. METHODS: This was a planned, but modified, secondary analysis of our multinational, multicenter, randomized, placebo-controlled trial, in which women were randomized between 18 + 0 and 22 + 6 weeks of gestation to receive daily treatment with 90 mg of vaginal progesterone gel or placebo. Cervical length was measured with transvaginal ultrasound at enrollment and at 28 weeks of gestation. Treatment continued until either delivery, 37 weeks of gestation or development of preterm rupture of membranes. Maternal and neonatal outcomes were evaluated for the subset of all randomized women with cervical length < 28 mm at enrollment. The primary outcome was preterm birth at

Progesterone vaginal gel for the reduction of recurrent preterm birth: primary results from a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: Preterm birth is the leading cause of perinatal morbidity and mortality worldwide. Treatment of preterm labor with tocolysis has not been successful in improving infant outcome. The administration of progesterone and related compounds has been proposed as a strategy to prevent preterm birth. The objective of this trial was to determine whether prophylactic administration of vaginal progesterone reduces the risk of preterm birth in women with a history of spontaneous preterm birth. METHODS: This randomized, double-blind, placebo- controlled, multinational trial enrolled and randomized 659 pregnant women with a history of spontaneous preterm birth. Between 18 + 0 and 22 + 6 weeks of gestation, patients were assigned randomly to once-daily treatment with either progesterone vaginal gel or placebo until either delivery, 37 weeks' gestation or development of preterm rupture of membranes. The primary outcome was preterm birth at