Maternal vascular indices at 36 weeks' gestation in small and growth restricted fetuses.

OBJECTIVE: To compare maternal vascular indices and hemodynamic parameters at 35-37 weeks' gestation, in pregnancies complicated by small for gestational age (SGA) fetuses and those with fetal growth restriction (FGR). METHODS: This was a prospective observational non-intervention study in women with singleton pregnancies attending for a routine hospital visit at 35+0 to 36+6 weeks' gestation. The visit included recording of maternal demographic characteristics and medical history, vascular indices and hemodynamic parameters obtained by a non-invasive operator independent device, including pulse wave velocity, augmention index, cardiac output, stroke volume, central systolic and diastolic blood pressure, total peripheral resistance and fetal heart rate. Hypertensive disorders of pregnancy were excluded and the values in the SGA and FGR groups were compared between them and with unaffected pregnancies. Diagnosis of SGA was based on the birth of a baby with birthweight below the 10th percentile for gestational age. In FGR, in addition to a birthweight below the 10th percentile, at the 35-37 weeks scan Doppler studies had shown that the uterine artery or umbilical artery pulsatility index (PI) was above the 95th percentile for gestational age or the fetal middle cerebral artery PI was below the 5th percentile. RESULTS: In the 6,413 women included in the study there were 605 (9.4%) cases of SGA, 133 (2.1%) of FGR and 5,675 (88.5%) unaffected by SGA or FGR. Women with SGA or FGR, compared to unaffected pregnancies, had increased peripheral vascular resistance and reduced cardiac output. Central systolic and diastolic blood pressure were also increased, whereas aortic stiffness assessed by pulse wave velocity and augmentation index did not differ between affected and unaffected pregnancies. In the FGR, compared to the SGA group, central systolic and diastolic blood pressure were higher, whereas, heart rate was lower. CONCLUSIONS: In SGA and FGR pregnancies there are deranged maternal hemodynamic responses when these are compared to normal pregnancies. Mothers with FGR babies have higher central blood pressure compared to SGA ones, but it remains unclear whether these differences are driven by the size of the fetus or pathological fetal growth. This article is protected by copyright. All rights reserved.

First trimester screening identifies maternal cardiac maladaptation at mid-gestation.

BACKGROUND: First, a logistic regression model, based on maternal demographic characteristics and medical history and blood pressure at 11-13 weeks' gestation, can identify about 70% of women who develop future chronic hypertension (CH) in the three years following pregnancy, at screen positive rate of 10%. Second, at mid-gestation women who subsequently develop hypertensive disorders of pregnancy (HDP) have increased peripheral vascular resistance and mild cardiac functional and morphological alterations and these cardiovascular abnormalities persist for at least 2 years after delivery. OBJECTIVE: To examine whether the use of the first-trimester risk for subsequent development of CH can help to identify women at high risk for cardiovascular maladaptation at mid-gestation. METHODS: Prospective observational study in 3812 women with singleton pregnancies women attending for a routine hospital visit at 11+0 to 13+6 weeks' gestation and again at 19+1 to 23+3 weeks at King's College Hospital, London, UK between August 2019 and August 2020. The first-trimester visit included recording of maternal demographic characteristics and medical history and measurement of systolic and diastolic blood pressure. At mid-gestation detailed maternal cardiovascular assessment was carried out. The association of risk for development of CH, determined from first-trimester assessment, and cardiovascular indices at mid-gestation was examined. RESULTS: Women who are at high-risk for development of future CH, compared to those at low-risk, had a higher incidence of hypertensive disorders of pregnancy (HDP). In addition, high-risk women, had reduced systolic and diastolic function at mid-gestation. Among women with HDP, those who were high-risk for future CH, compared to those at low-risk, also had worse cardiac function at mid-gestation. CONCLUSION: Use of a model for first-trimester prediction of subsequent development of CH can identify women who show evidence of cardiac maladaptation at mid-gestation. Further studies are needed to clarify whether women who screen as high-risk for future CH, compared to those at low-risk, have reduced cardiac function beyond pregnancy. This article is protected by copyright. All rights reserved.

Impact of hypertensive disorders of pregnancy on offspring cardiovascular function. Study from fetal life to early childhood.

OBJECTIVE: Epidemiological studies suggest that children following in utero exposure to hypertensive disorders of pregnancy (HDP) may be at increased long term cardiovascular risk. However, data in early childhood are lacking. We aimed to investigate the independent influence of HDP on childhood heart after accounting for differences in childhood risk factor profile. METHODS: We performed detailed cardiovascular assessment in fetuses at mid-gestation and at a median of 2.3 years (IQR: 2.1, 2.4 years) postnatally in 71 cases where the mothers had HDP and 304 who did not have HDP. RESULTS: There were no differences in demographic characteristics between groups but in the HDP group delivery was earlier and birthweight was lower. In fetal life, there were no significant differences in cardiac function or structure between the HDP and non-HDP groups. In early childhood, in the HDP compared to the non-HDP group, there was greater relative wall thickness (0.7 SD 0.3 vs. 0.6 SD 0.3 mm, p=0.047) and increased left ventricular mass (80.9 SD 20.4 vs. 75.7 SD 16.5, p=0.024); however, these differences were abolished following multivariable analysis. Longitudinal analysis revealed that in HDP, compared to the non-HDP group, there was no difference in the change of cardiac functional indices from fetal life to early childhood. CONCLUSION: Epidemiological studies suggest that HDP have an adverse impact on offspring cardiovascular health, but such an effect is not apparent in fetal life or in early childhood. This article is protected by copyright. All rights reserved.

Long-term cardiovascular assessment of women who had a pregnancy complicated by a hypertensive disorder.

BACKGROUND: Women with hypertensive disorders of pregnancy (HDP) are at increased risk of developing hypertension and cardiovascular disease later in life. However, from studies so far, it is difficult to define whether this association reflects preexisting maternal cardiovascular risk or merely reflect a potentially causal relationship between HDP and later cardiovascular risk. OBJECTIVES: We performed detailed cardiovascular assessment in women at mid-gestation, prior to development of a HDP and at 2 years post-partum aiming to identify cardiovascular changes prior to development of HDP and to assess persistent cardiovascular alterations long after the HDP event. METHODS: This was a prospective observational study in which we performed detailed cardiovascular assessment at mid-gestation and at median of 2.3 years (interquartile range 2.1 to 2.4 years) post-partum. We examined 112 women who developed a HDP and 451 women whose pregnancy was not complicated by hypertension. We used conventional and more advanced echocardiographic techniques, i.e. speckle tracking, to accurately determine left ventricular systolic and diastolic function. We used M-mode measurements to determine left ventricular remodeling and estimate left ventricular mass. Maternal vascular status was assessed using ophthalmic artery Doppler and by calculating peak systolic velocity (PSV) ratio, as a marker of peripheral vascular resistance. RESULTS: At mid-gestation, women who subsequently developed HDP had increased ophthalmic artery PSV ratio. These women also had mild cardiac functional and morphological alterations which were mostly accounted for by maternal cardiovascular risk factors. At 2 years post-partum, women who experienced HDP, compared to those who did not, had cardiovascular abnormalities with reduction in left ventricular systolic and diastolic function which remained after multivariable analysis. Longitudinal analysis demonstrated that the evolution of cardiovascular changes in the HDP and non-HDP groups was similar. CONCLUSION: Mild cardiac functional and morphological alterations precede the development of HDP and such changes persist for at least 2 years postpartum. The cardiac changes are likely to be the consequence of preexisting maternal cardiovascular risk factors rather than an adverse consequence of HDP. This article is protected by copyright. All rights reserved.

Maternal cardiovascular function at mid-gestation is related to placental angiogenesis.

OBJECTIVE: To investigate whether placental function, reflected in the levels of angiogenic factors, is associated with maternal cardiac function and hemodynamic responses at 19 to 24 weeks' gestation after adjustment for maternal risk factors and pregnancy complications. METHODS: Prospective study on women with singleton pregnancies attending Kings' College Hospital, London, UK for a routine hospital visit at 19-24 weeks' gestation. We recorded maternal characteristics and measured mean arterial pressure, maternal heart rate, serum placental growth factor and soluble fms-like tyrosine kinase 1 (sFLT-1). We also performed maternal echocardiogram to assess cardiac output and peripheral vascular resistance as well as indices of diastolic and systolic function. RESULTS: Our cohort included 4006 women. Lower placental growth factor (PlGF) values were significantly associated with higher mean arterial pressure (MAP) (p<0.001), lower maternal heart rate (p<0.001), lower mitral valve s' velocity (p= 0.027) and higher left atrial volume (p=0.022) after adjustment for maternal characteristics and pregnancy complications. sFLT-1 was positively related to relative wall thickness (p= 0.012), whereas sFLT-1/ PlGF ratio was negatively associated with mitral valve A (p= 0.006) and positively associated with left atrial volume (p= 0.015) and MAP (p= 0.004). The magnitude of these associations was similar in the subgroup of women without any risk factors from their obstetric and medical history. CONCLUSION: A continuous link of moderate strength between angiogenic factors and subclinical maternal cardiac function alterations is present at mid-gestation, independently of preexisting maternal risk factors and pregnancy complications. Impaired placental function appears to be related to a mild systolic and diastolic dysfunction and cardiac remodeling. This article is protected by copyright. All rights reserved.

Ophthalmic artery Doppler at 36 weeks' gestation in prediction of pre-eclampsia: validation and update of previous model.

OBJECTIVE: To validate and extend a model incorporating maternal ophthalmic artery Doppler at 35-37 weeks' gestation in the prediction of subsequent development of pre-eclampsia (PE). METHODS: This was a prospective validation study of screening for PE (defined according to the 2019 American College of Obstetricians and Gynecologists criteria) by maternal ophthalmic artery peak systolic velocity (PSV) ratio in 6746 singleton pregnancies undergoing routine care at 35 + 0 to 36 + 6 weeks' gestation (validation dataset). Additionally, the data from the validation dataset were combined with those of 2287 pregnancies that were previously used for development of the model (training dataset), and the combined data were used to update the original model parameters. The competing-risks model was used to estimate the individual patient-specific risk of delivery with PE at any time and within 3 weeks from assessment by a combination of maternal demographic characteristics and medical history with PSV ratio alone and in combination with the established PE biomarkers of mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI), serum placental growth factor (PlGF) and serum soluble fms-like tyrosine kinase-1 (sFlt-1). We evaluated the predictive performance of the model by examining, first, the ability to discriminate between the PE and non-PE groups using the area under the receiver-operating-characteristics curve and the detection rate (DR) at fixed screen-positive (SPR) and false-positive rates of 10% and, second, calibration by measuring the calibration slope and calibration-in-the-large. McNemar's test was used to compare the performance of screening by a biophysical test (maternal factors, MAP, UtA-PI and PSV ratio) vs a biochemical test (maternal factors, PlGF and sFlt-1), low PlGF concentration (< 10th percentile) or high sFlt-1/PlGF concentration ratio (> 90th percentile). RESULTS: In the validation dataset, the performance of screening by maternal factors and PSV ratio for delivery with PE within 3 weeks and at any time after assessment was consistent with that in the training dataset, and there was good agreement between the predicted and observed incidence of PE. In the combined data from the training and validation datasets, good prediction for PE was achieved in screening by a combination of maternal factors, MAP, UtA-PI, PlGF, sFlt-1 and PSV ratio, with a DR, at a 10% SPR, of 85.0% (95% CI, 76.5-91.4%) for delivery with PE within 3 weeks and 65.7% (95% CI, 59.2-71.7%) for delivery with PE at any time after assessment. The performance of a biophysical test was superior to that of screening by low PlGF concentration or high sFlt-1/PlGF concentration ratio but not significantly different from the performance of a biochemical test combining maternal factors with PlGF and sFlt-1 for both PE within 3 weeks and PE at any time after assessment. CONCLUSION: Maternal ophthalmic artery PSV ratio at 35-37 weeks' gestation in combination with other biomarkers provides effective prediction of subsequent development of PE. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Ophthalmic artery Doppler and biomarkers of impaired placentation at 36 weeks' gestation in pregnancies with small fetuses.

OBJECTIVES: First, to compare ophthalmic artery peak systolic velocity (PSV) ratio and biomarkers of impaired placentation at 36 weeks' gestation in women who delivered a small-for-gestational-age (SGA) or growth-restricted (FGR) neonate, in the absence of hypertensive disorder, with those of women who developed pre-eclampsia (PE) or gestational hypertension (GH) and of women unaffected by SGA, FGR, PE or GH. Second, to examine the associations of PSV ratio, uterine artery pulsatility index (UtA-PI), placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) with birth-weight Z-score or percentile. METHODS: This was a prospective observational study of women with a singleton pregnancy attending for a routine hospital visit at 35 + 0 to 36 + 6 weeks' gestation. This visit included recording of maternal demographic characteristics and medical history, ultrasound examination of fetal anatomy and growth, and measurement of maternal ophthalmic artery PSV ratio, UtA-PI, PlGF and sFlt-1. Values of PSV ratio, UtA-PI, PlGF and sFlt-1 were converted to multiples of the median (MoM) or delta values. Median MoM or deltas of these biomarkers in the SGA, FGR, PE and GH groups were compared with those in the unaffected group. Regression analysis was used to examine the relationship of PSV ratio delta, UtA-PI MoM, PlGF MoM and sFlt-1 MoM with birth-weight Z-score, after exclusion of PE and GH cases. RESULTS: The study population of 9033 pregnancies included 7696 (85.2%) that were not affected by FGR, SGA, PE or GH, 182 (2.0%) complicated by FGR in the absence of PE or GH, 698 (7.7%) with SGA in the absence of FGR, PE or GH, 236 (2.6%) with PE and 221 (2.4%) with GH. Compared with unaffected pregnancies, in the FGR and SGA groups, the PSV ratio delta and sFlt-1 MoM were increased and PlGF MoM was decreased; UtA-PI MoM was increased in the FGR group but not the SGA group. The magnitude of the changes in biomarker values relative to the unaffected group was smaller in the FGR and SGA groups than that in the PE and GH groups. In non-hypertensive pregnancies, there were significant inverse associations of PSV ratio delta and UtA-PI MoM with birth-weight Z-score, such that the values were increased in small babies and decreased in large babies. There was a quadratic relationship between PlGF MoM and birth-weight Z-score, with low PlGF levels in small babies and high PlGF levels in large babies. There was no significant association between sFlt-1 MoM and birth-weight Z-score. CONCLUSIONS: Ophthalmic artery PSV ratio, reflective of peripheral vascular resistance, and UtA-PI, PlGF and sFlt-1, biomarkers of impaired placentation, are altered in pregnancies complicated by hypertensive disorder and, to a lesser extent, in non-hypertensive pregnancies delivering a SGA or FGR neonate. The associations between the biomarkers and birth-weight Z-score suggest the presence of a continuous physiological relationship between fetal size and peripheral vascular resistance and placentation, rather than a dichotomous relationship of high peripheral resistance and impaired placentation in small compared to non-small fetuses. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Three-dimensional echocardiography and strain cardiac imaging in women with pre-eclampsia with follow-up to 6 months postpartum.

OBJECTIVE: Epidemiological studies have established that women with pre-eclampsia (PE) are at increased long-term cardiovascular risk. Mild cardiac functional changes have been documented during pregnancy in women with PE, but their evolution from presentation to the postpartum period remains poorly defined. The aim of this study was to assess biventricular cardiovascular indices using novel and sensitive two-dimensional and three-dimensional (3D) echocardiographic modalities in pregnancy and to track alterations in both risk factors and cardiovascular indices in the postpartum period. METHODS: A total of 59 women with PE were examined at 34 (interquartile range, 31-37) weeks' gestation and at 2-3 days, 3 months and 6 months postpartum. During pregnancy, 118 women with a normotensive pregnancy were also recruited as controls. Biventricular ejection fraction and left ventricular mass were measured by 3D echocardiography. Biventricular global longitudinal strain and strain of the left atrium were assessed using speckle-tracking imaging. RESULTS: In women with PE, compared with controls, there was lower left ventricular diastolic function (left atrial reservoir strain, 44.1% vs 49.2%) and increased left ventricular mass index (148 vs 128 g/m2 ), but there was no significant difference in right ventricular functional indices. These alterations in cardiac indices were mostly explained by differences in maternal risk factors. In the postpartum period, most cardiac indices improved by 3 months. Multivariable linear mixed-model analysis demonstrated that this improvement was mostly attributed to reduction in weight and blood pressure. CONCLUSION: In women with PE, there is postpartum improvement in cardiac functional and structural indices in parallel with improvement in their risk factor profile. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Fetal cardiac function at midgestation and conception by in-vitro fertilization.

OBJECTIVE: To assess differences in cardiac morphology and function at midgestation in fetuses conceived by in-vitro fertilization (IVF), using fresh or frozen embryo transfer, compared with those conceived naturally. METHODS: This was a prospective study of 5801 women with a singleton pregnancy attending for a routine ultrasound examination at 19 + 0 to 23 + 6 weeks' gestation, including 343 that conceived by IVF. Conventional and more advanced echocardiographic modalities, including speckle-tracking analysis, were used to assess fetal cardiac function in the right and left ventricles. The morphology of the fetal heart was assessed by calculating the right and left sphericity index. Placental perfusion and function were assessed by measurement of uterine artery pulsatility index (UtA-PI) and serum placental growth factor (PlGF), respectively. RESULTS: Fetuses that were conceived by IVF, compared with those conceived spontaneously, had significantly lower right and left ventricular sphericity index, higher left ventricular global longitudinal strain and lower left ventricular ejection fraction. There were no significant differences in any of the cardiac indices within the IVF group between the fresh and frozen embryo transfers. In the IVF group, compared with spontaneously conceived pregnancies, UtA-PI was lower and PlGF was higher, suggesting better placental perfusion and function. CONCLUSIONS: Our study demonstrates that, in IVF pregnancies, compared with those conceived spontaneously, there is evidence of fetal cardiac remodeling at midgestation, which is not related to the use of fresh or frozen embryo transfer. In the IVF group, compared with naturally conceived pregnancies, fetal heart was globular and left ventricular systolic function was mildly reduced. Whether these cardiac changes are accentuated later in pregnancy and remain in the postnatal period remains to be established. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Vascular phenotype at 35-37 weeks' gestation in women with gestational diabetes mellitus.

OBJECTIVES: To examine the vascular phenotype at 35-37 weeks' gestation of women with gestational diabetes mellitus (GDM) and compare it to that in women without GDM, using ophthalmic artery Doppler and carotid-femoral pulse-wave velocity. METHODS: This was a prospective observational study of women attending for a routine hospital visit at 35 + 0 to 37 + 6 weeks' gestation. This visit included recording of maternal demographic characteristics and medical history, ophthalmic artery Doppler for calculation of the peak systolic velocity (PSV) ratio and assessment of cardiac output, stroke volume, total peripheral resistance, central systolic and diastolic blood pressure, carotid-femoral pulse-wave velocity and augmentation index. All measurements were standardized to remove the effects of maternal characteristics and elements from the medical history, and the adjusted values in the GDM group were compared with those in the non-GDM group. RESULTS: The study population of 2018 pregnancies contained 218 (10.8%) that developed GDM, including 78 (35.8%) that were treated with diet alone, 81 (37.2%) treated with metformin and 59 (27.1%) treated with insulin with or without metformin. In the GDM group, compared with the non-GDM group, there were significantly higher ophthalmic artery PSV ratio, carotid-femoral pulse-wave velocity and central systolic blood pressure, but there was no significant difference in cardiac output, stroke volume, total peripheral resistance, central diastolic blood pressure or augmentation index. In the GDM group, women treated with metformin or insulin had a higher ophthalmic artery PSV ratio compared with those treated with diet alone. Additionally, compared with the diet group, the metformin group had higher central systolic blood pressure and the insulin group had a higher carotid-femoral pulse-wave velocity. CONCLUSION: Women with GDM have evidence of early vascular disease, and this may contribute to their long-term cardiovascular risk. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Ophthalmic artery Doppler at 11-13 weeks' gestation in prediction of pre-eclampsia.

OBJECTIVES: To examine the potential value of maternal ophthalmic artery Doppler at 11-13 weeks' gestation, alone and in combination with the established first-trimester biomarkers of pre-eclampsia (PE), including uterine artery pulsatility index (UtA-PI), mean arterial pressure (MAP), serum placental growth factor (PlGF) and serum pregnancy-associated plasma protein-A (PAPP-A), in the prediction of subsequent development of PE. METHODS: This was a prospective observational study in women attending for a routine hospital visit at 11 + 0 to 13 + 6 weeks' gestation. This visit included recording of maternal demographic characteristics and medical history, ultrasound examination for fetal anatomy and growth, assessment of flow velocity waveforms from the maternal ophthalmic arteries and calculation of the second-to-first peak systolic velocity (PSV) ratio, and measurement of MAP and serum PAPP-A. In addition, a case-control study was carried out for measurement of PlGF in stored samples from cases that developed PE and unaffected controls. The values of PSV ratio, UtA-PI, MAP, PAPP-A and PlGF were converted to multiples of the median or deltas to remove the effects of maternal characteristics and medical history. The competing-risks model was used to estimate the individual patient-specific risk of delivery with PE at < 37 and < 41 + 3 weeks' gestation for various combinations of markers. Performance was assessed using detection rates, at a fixed false-positive rate (FPR), and areas under the receiver-operating-characteristics curves. Modeled performance was also assessed. RESULTS: The study population of 4066 pregnancies contained 114 (2.8%) that developed PE, including 25 (0.6%) that delivered with PE at < 37 weeks' gestation. The PSV ratio was significantly increased in PE pregnancies, and the effect of PE depended on gestational age at delivery, with the deviation from normal being greater for early than for late PE. Modeling demonstrated that the addition of PSV ratio improved the detection rate, at a 10% FPR, of preterm PE provided by maternal risk factors alone (from 46.3% to 58.4%), maternal factors, MAP and UtA-PI (65.9% to 70.6%), and maternal factors, MAP, UtA-PI and PlGF (74.6% to 76.7%). The PSV ratio did not improve the prediction of term PE provided by any combination of biomarkers. CONCLUSION: Ophthalmic artery PSV ratio at 11-13 weeks' gestation is a potentially useful biomarker for prediction of subsequent development of preterm PE, but larger studies are needed to validate this finding. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Midgestation cardiovascular phenotype in women who develop gestational diabetes and hypertensive disorders of pregnancy: comparative study.

OBJECTIVE: Women with gestational diabetes mellitus (GDM) and/or hypertensive disorders of pregnancy (HDP) are at increased long-term cardiovascular risk. Mild cardiac functional alterations have been detected in women with GDM or HDP in midgestation, prior to clinical onset of the disease, but these functional alterations have not been found to be useful as screening tools. In contrast, increased impedance to peripheral blood flow, measured by echocardiography or ophthalmic artery Doppler, has been shown to provide incremental value to maternal characteristics for the prediction of pre-eclampsia. However, it is unknown whether similar changes can be detected in women at risk of GDM. In this study, we performed detailed cardiovascular phenotyping in a large, unselected population of women in midgestation to identify similarities and differences in cardiovascular adaptation in women who are at risk of GDM and/or HDP. METHODS: This was a prospective observational study in women attending for a routine hospital visit at 19 + 1 to 23 + 3 weeks' gestation. This visit included assessment of flow velocity waveforms from the maternal ophthalmic arteries, echocardiography for assessment of maternal cardiovascular function and measurement of uterine artery pulsatility index and serum placental growth factor (PlGF) for assessment of placental perfusion and function. The measured indices were converted to either multiples of the median (MoM) values or deviation from the median (delta) after adjusting for maternal characteristics and elements of medical history. Biomarker delta or MoM values in the GDM and HDP groups were compared with those in the unaffected group using 95% CI and t-tests. RESULTS: The study population of 5214 pregnancies contained 4429 (84.9%) that were unaffected by GDM or HDP, 509 (9.8%) complicated by GDM without HDP, 41 (0.8%) with GDM and HDP, and 235 (4.5%) with HDP without GDM. In HDP cases, with or without GDM, there was evidence of impaired placentation, with a decrease in PlGF, and increased impedance to flow in the peripheral circulation, suggested by an increase in ophthalmic artery peak systolic velocity (PSV) ratio, peripheral vascular resistance assessed on echocardiography and mean arterial pressure. In the GDM group without HDP, there was no evidence of altered placental perfusion or function and ophthalmic artery PSV ratio was not significantly different from that in the unaffected group; peripheral vascular resistance and mean arterial pressure were increased but to a lesser degree than in the HDP group. In the HDP group, there was an increase in global longitudinal systolic strain and slight increase in isovolumic relaxation time, while in the GDM group, there was an increase in mitral valve E/e', myocardial performance index and global longitudinal systolic strain. CONCLUSIONS: In midgestation, women who subsequently develop HDP or GDM have a mild subclinical reduction in left ventricular function. In HDP cases, with or without GDM, there is evidence of impaired placentation and all biomarkers of impedance to peripheral blood flow are consistently increased. In contrast, in the GDM group without HDP, biomarkers of placental function are normal and those of impedance to peripheral blood flow are either marginally increased or not significantly different from those in normal pregnancies. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Ophthalmic artery Doppler at 19-23 weeks' gestation in pregnancies that deliver small-for-gestational-age neonates.

OBJECTIVES: First, to explore hemodynamic differences between pregnancies delivering a small-for-gestational-age (SGA) neonate in the absence of hypertensive disorders and those that develop pre-eclampsia (PE) or gestational hypertension (GH), by comparing the ophthalmic artery peak systolic velocity (PSV) ratio and first (PSV1) and second (PSV2) PSV at 19-23 weeks' gestation, and second, to compare these pregnancies for markers of placental perfusion and function. METHODS: This was a prospective observational study in women attending for a routine hospital visit at 19 + 1 to 23 + 3 weeks' gestation. This visit included recording of maternal demographic characteristics and medical history, ultrasound examination for assessment of fetal anatomy and growth, and measurement of maternal ophthalmic artery PSV ratio, PSV1, PSV2, mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI) and serum placental growth factor (PlGF). The values of PSV ratio, PSV1, PSV2, MAP, UtA-PI and PlGF were converted to multiples of the median (MoM) or deltas. Mean MoMs or deltas of these biomarkers in the SGA, PE and GH groups were compared with those in the unaffected group. The definition of SGA was birth weight below the 10th percentile in the absence of PE or GH. RESULTS: The study population of 5214 pregnancies contained 4375 (83.9%) that were unaffected by SGA, PE or GH, 563 (10.8%) complicated by SGA, 157 (3.0%) with PE and 119 (2.3%) with GH. There were three main findings of the study. First, in the SGA, PE and GH groups, compared with unaffected pregnancies, the PSV ratio delta, PSV2 MoM, MAP MoM and UtA-PI MoM were increased and PlGF MoM was decreased; however, the magnitude of most changes was smaller in the SGA group than in PE and GH groups. Second, in the PE and GH groups, but not in the SGA group, PSV1 MoM was increased. Third, in general, in the pathological pregnancies, the magnitude of deviation of biomarkers from unaffected pregnancies was greater for those delivering at < 37 than at ≥ 37 weeks' gestation. CONCLUSION: In mid-gestation, pregnancies that subsequently develop hypertensive disorders and those delivering a SGA neonate, compared with unaffected pregnancies, have abnormal uteroplacental measurements and increased maternal ophthalmic artery PSV ratio. These data suggest similar pathophysiology in the two conditions, with evidence of placental dysfunction and increased peripheral vascular resistance, but the magnitude of abnormalities is greater in hypertensive disorders. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Maternal cardiac function in twin pregnancy at 19-23 weeks' gestation.

OBJECTIVES: To compare maternal cardiovascular indices at 19-23 weeks' gestation between twin and singleton pregnancies and assess the impact of chorionicity on these parameters. METHODS: This was a prospective observational study in women with twin pregnancy attending for a hospital visit at 19 + 1 to 24 + 3 weeks' gestation. This visit included recording of maternal demographic characteristics and medical history and maternal cardiovascular assessment. In a previous study of 4795 women with singleton pregnancies at 19-23 weeks' gestation, multivariable linear regression models were fitted between the various cardiovascular indices and elements of maternal characteristics and medical history. In this study, we calculated multiples of the median (MoM) and delta values according to the singleton models and assessed the distributional properties of these MoM and delta values in twin as compared with singleton pregnancies. RESULTS: The study population of 155 women with twin pregnancy included 86 dichorionic and 69 monochorionic cases. In general, there was a similar distribution of maternal cardiovascular indices in monochorionic and dichorionic twin pregnancies. In both types of twin pregnancy, compared with singleton pregnancy, there was an increase in isovolumetric relaxation time, left atrial area and myocardial performance index, and a decrease in mitral valve E/A. Left ventricular mass indexed for body surface area and relative wall thickness were also increased in twin compared with singleton pregnancy. The magnitude of the increase in left atrial area was greater in dichorionic compared with monochorionic pregnancies. Additionally, mitral valve E was decreased and left atrial volume was increased in dichorionic but not in monochorionic pregnancies, while isovolumetric contraction time was increased in monochorionic but not in dichorionic pregnancies. Left ventricular myocardial deformation was similar between twin and singleton pregnancies. CONCLUSIONS: In twin pregnancies at mid-gestation, maternal systolic and diastolic function is reduced when compared with singletons. The patterns of cardiovascular adaptation are similar between monochorionic and dichorionic pregnancies and resemble those reported in uncomplicated singleton pregnancy later in gestation. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Ophthalmic artery Doppler at 35-37 weeks' gestation in pregnancies with small or growth-restricted fetuses.

OBJECTIVES: First, to compare the ophthalmic artery peak systolic velocity (PSV) ratio at 35-37 weeks' gestation among women who delivered small-for-gestational-age (SGA) or growth-restricted (FGR) neonates in the absence of hypertensive disorders, women who developed pre-eclampsia (PE) or gestational hypertension (GH) and those without SGA, FGR, PE or GH. Second, to examine the association of PSV ratio with placental growth factor (PlGF) and mean arterial pressure (MAP). Third, to assess the associations of PSV ratio, PlGF and MAP with birth-weight Z-score and percentile. METHODS: This was a prospective observational study in women attending for a routine hospital visit at 35 + 0 to 36 + 6 weeks' gestation. This visit included recording of maternal demographic characteristics and medical history, ultrasound examination of fetal anatomy and growth, and measurement of maternal ophthalmic artery PSV ratio, first (PSV1) and second (PSV2) peaks of systolic velocity, MAP and serum PlGF. The values of PSV ratio, MAP and PlGF were converted to multiples of the median (MoM) or delta values, and the median MoM or delta of these variables in the SGA, FGR, PE and GH groups were compared with those in the unaffected group. Regression analysis was used to examine the relationship of PSV ratio delta, PlGF MoM and MAP MoM with birth-weight Z-score after exclusion of PE and GH cases. Regression analysis was also used to examine the association of PSV ratio delta with log10 PlGF MoM and log10 MAP MoM. RESULTS: The study population included 2287 pregnancies, of which 1954 (85.4%) were not affected by FGR, SGA, PE or GH, 49 (2.1%) were complicated by FGR in the absence of PE or GH, 160 (7.0%) had SGA in the absence of FGR, PE or GH, 60 (2.6%) had PE and 64 (2.8%) had GH. Compared with unaffected pregnancies, in both the FGR and SGA groups, the means of PSV ratio delta (0.042 (95% CI, 0.007-0.076) and 0.032 (95% CI, 0.016-0.049), respectively) and MAP MoM (1.028 (95% CI, 1.006-1.050) and 1.048 (95% CI, 1.035-1.060), respectively) were increased, while the mean of PlGF MoM was decreased (0.495 (95% CI, 0.393-0.622) and 0.648 (95% CI, 0.562-0.747), respectively). However, the magnitude of these changes was smaller than in the PE and GH groups. Ophthalmic artery waveform analysis revealed that the predominant feature of pregnancies complicated by SGA in the absence of hypertensive disorders was a reduction in PSV1, whereas, in those with hypertensive disorders, there was an increase in PSV2. In non-hypertensive pregnancies, there were linear inverse associations of PSV ratio delta and MAP MoM with birth-weight Z-score, with increased values in small neonates and decreased values in large neonates. There was a quadratic relationship between PlGF MoM and birth-weight Z-score, with low PlGF levels in small neonates and high PlGF levels in large neonates. There was a significant correlation of ophthalmic artery PSV ratio delta with both log10 MAP MoM (0.124 (95% CI, 0.069-0.178)) and log10 PlGF MoM (-0.238 (95% CI, -0.289 to -0.185)). CONCLUSION: Assuming that the ophthalmic artery PSV ratio is a reflection of the interplay between cardiac output and peripheral vascular resistance, the linear association between PSV ratio and birth-weight Z-score in non-hypertensive pregnancies suggests the presence of a continuous physiological relationship between fetal size and cardiovascular response rather than a dichotomous relationship between high peripheral resistance and low cardiac output in small compared with non-small fetuses. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Three-dimensional echocardiography and cardiac strain imaging in women with gestational diabetes mellitus.

OBJECTIVES: Gestational diabetes mellitus (GDM) is associated with premature cardiovascular disease and adverse cardiovascular outcome in the mother. Subclinical cardiac functional changes in the left ventricle have been reported during pregnancy in women with GDM using conventional echocardiography, but results are inconsistent. The aims of the current study were to assess whether GDM is associated with biventricular systolic dysfunction in the mother and whether these cardiac changes can be detected using the novel echocardiographic modalities of strain imaging and three-dimensional (3D) echocardiography. METHODS: This was a cross-sectional study in women with GDM and controls examined at 26-40 weeks of gestation. All women underwent echocardiography, and 3D volumes of the left and right ventricles and left atrium were collected. Ejection fraction and left ventricular mass were measured using 3D echocardiography. Left ventricular mass was indexed to body surface area. Speckle-tracking echocardiography was used to assess global longitudinal strain of the left and right ventricles and strain of the left atrium. RESULTS: The study population included 123 women with GDM and 246 controls. Women with GDM, compared to controls, were older (35.1 ± 5.2 vs 32.4 ± 5.5 years; P < 0.001), had higher body mass index (30.6 (interquartile range (IQR), 26.2-35.2) vs 27.5 (IQR, 24.7-30.7) kg/m2 ; P < 0.001) and had higher systolic blood pressure (119.9 ± 11.2 vs 116.4 ± 12.0 mmHg; P = 0.007). In all women with GDM, there was good glycemic control. In women with GDM, compared to controls, there was lower global longitudinal strain of the left ventricle (-19.3% (IQR, -21.4 to -17.6%) vs -20.1% (IQR, -22.1 to -18.7%); P = 0.002) and right ventricle (-22.2% (IQR, -26.1 to -19.8%) vs -24.1% (IQR, -27.0 to -21.9%); P < 0.001). There was no significant difference between the groups in ejection fraction, left ventricular mass, diastolic function assessed by left atrial strain, or 3D functional indices. CONCLUSIONS: Women with GDM, compared to women with uncomplicated pregnancy, have lower left and right ventricular myocardial deformation. Volumetric assessment using 3D echocardiography does not provide additional information about maternal cardiac function. Strain imaging is a sensitive echocardiographic modality to detect early cardiac functional changes in women with GDM. Further studies are needed to assess the pattern of deterioration of cardiac function with advancing age in women with a history of GDM. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Relationship between ophthalmic artery Doppler and maternal cardiovascular function.

OBJECTIVE: In mid-gestation, the finding of an increase in the ophthalmic artery second to first peak of systolic velocity ratio (PSV ratio) provides useful prediction of subsequent development of pre-eclampsia (PE). The objective of this study of an unselected population at 19-23 weeks' gestation was to gain a better understanding of the factors that influence ophthalmic artery Doppler by examining the possible association between the PSV ratio and maternal cardiovascular function. METHODS: This was a prospective observational study in women attending for a routine hospital visit at 19 + 1 to 23 + 3 weeks' gestation. This visit included assessment of flow velocity waveforms from the maternal ophthalmic arteries and assessment of maternal cardiovascular function. The following nine cardiovascular indices were examined: E/A ratio; E/e' ratio; myocardial performance index; global longitudinal systolic strain; left ventricular ejection fraction; peripheral vascular resistance; left ventricular cardiac output; left ventricular mass indexed for body surface area; and mean arterial pressure. The ophthalmic artery PSV ratio and the nine cardiovascular indices were converted to either log10 multiples of the median (MoM) values or deviations from the median (deltas) values after adjustment for maternal characteristics and elements of medical history. Regression analysis was then used to examine the significance of the association between PSV ratio delta and MoM or delta values of each cardiovascular index in the total population and in the subgroup that developed PE. RESULTS: The study population of 2853 pregnancies contained 76 (2.7%) that developed PE. In the total population, there were significant but weak associations between the PSV ratio and most of the cardiovascular indices, with r-values of < 0.1, except for mean arterial pressure with r = 0.178. In the subgroup that developed PE, a moderately strong association between the PSV ratio and left ventricular mass indexed for body surface area was noted (r = 0.308). CONCLUSIONS: The findings of this study suggest that Doppler assessment of PSV ratio in the ophthalmic artery provides information about peripheral vascular status. The increase in PSV ratio in women who develop PE is associated with increased afterload and an increase in left ventricular thickness. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Maternal cardiac function at 19-23 weeks' gestation in prediction of gestational diabetes mellitus.

OBJECTIVES: To examine differences in maternal cardiovascular indices at 19-23 weeks' gestation between pregnancies that develop gestational diabetes mellitus (GDM) and those without GDM, and to determine whether such cardiovascular changes are the consequence of maternal demographic characteristics and medical history or GDM per se. METHODS: This was a prospective observational study in women attending for a routine hospital visit at 19 + 1 to 23 + 3 weeks' gestation. This visit included recording of maternal demographic characteristics and medical history, and maternal echocardiography for assessment of E/A ratio, E/e' ratio, myocardial performance index, global longitudinal systolic strain, left ventricular ejection fraction, peripheral vascular resistance, left ventricular cardiac output and left ventricular mass indexed for body surface area. The measurements of the maternal cardiac indices were standardized to remove the effects of maternal characteristics and elements from the medical history, and the adjusted values in the GDM group were compared to those in the non-GDM group. Likelihood ratios were derived for those indices that were altered significantly in GDM, and these were used to modify the prior risk derived from maternal demographic characteristics and medical history. The area under the receiver-operating-characteristics curve and the detection rate of GDM, at 10%, 20% and 40% false-positive rates, in screening by a combination of maternal factors with cardiovascular indices were determined. RESULTS: The study population of 2853 pregnancies contained 199 (7.0%) that developed GDM. In pregnancies that developed GDM, there were significant differences from the non-GDM group in E/A ratio, E/e' ratio, myocardial performance index and global longitudinal systolic strain. After adjustment for maternal demographic characteristics and factors from the medical history known to affect cardiac indices, the only cardiovascular indices that were significantly different between the GDM and non-GDM groups were peripheral vascular resistance and myocardial performance index, both of which were marginally increased in the GDM group. The performance of screening for GDM by maternal demographic characteristics and medical history was not improved by the addition of cardiovascular indices. CONCLUSIONS: Women with GDM have subtle functional and hemodynamic cardiac changes prior to the development of GDM. These cardiac changes are mostly related to the adverse risk-factor profile of these women. Maternal cardiac assessment at 20 weeks does not offer additional predictive information for GDM development in pregnancy to that calculated based on demographic characteristics and medical history. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Ophthalmic artery Doppler in combination with other biomarkers in prediction of pre-eclampsia at 35-37 weeks' gestation.

OBJECTIVE: To examine the potential value of maternal ophthalmic artery Doppler at 35-37 weeks' gestation in combination with the established biomarkers of pre-eclampsia (PE), including mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI), serum placental growth factor (PlGF) and serum soluble fms-like tyrosine kinase-1 (sFlt-1), in the prediction of subsequent development of PE. METHODS: This was a prospective observational study in women attending for a routine hospital visit at 35 + 0 to 36 + 6 weeks' gestation. This visit included recording of maternal demographic characteristics and medical history, ultrasound examination for fetal anatomy and growth, assessment of flow velocity waveforms from the maternal ophthalmic arteries, and measurement of MAP, UtA-PI, serum PlGF and serum sFlt-1. The competing-risks model was used to estimate the individual patient-specific risks of delivery with PE at any time and at < 3 weeks after assessment by a combination of maternal demographic characteristics and medical history with biomarkers. The area under the receiver-operating-characteristics curve and detection rate (DR) of delivery with PE, at a 10% false-positive rate (FPR), in screening by combinations of maternal factors with ophthalmic artery second to first peak of systolic velocity ratio (PSV ratio), MAP, UtA-PI, serum PlGF and serum sFlt-1 were determined. The modeled performance of screening for PE was also estimated. RESULTS: The study population of 2287 pregnancies contained 60 (2.6%) that developed PE, including 19 (0.8%) that delivered with PE at < 3 weeks after assessment. The PSV ratio improved the prediction of PE with delivery at any stage after assessment provided by maternal factors alone (from 25.4% to 50.6%), maternal factors and MAP (54.3% to 62.7%), maternal factors, MAP and PlGF (68.3% to 70.8%) and maternal factors, MAP, PlGF and sFlt-1 (75.7% to 76.7%), at a FPR of 10%. The PSV ratio also improved the prediction of PE with delivery at < 3 weeks after assessment provided by maternal factors alone (from 31.0% to 69.4%), maternal factors and MAP (74.1% to 83.4%), maternal factors, MAP and UtA-PI (77.1% to 85.0%) and maternal factors, MAP and PlGF (84.8% to 88.6%). The empirical results for DR at a 10% FPR were consistent with the modeled results. Screening by a combination of maternal factors with MAP and PSV ratio also detected 59.4% (95% CI, 58.6-82.5%) of cases of gestational hypertension with delivery at any stage after assessment, and 86.7% (95% CI, 82.4-100%) of those with delivery at < 3 weeks after assessment. CONCLUSION: Ophthalmic artery Doppler could potentially improve the performance of screening for PE at 35-37 weeks, especially imminent PE with delivery within 3 weeks after assessment, but further studies are needed to validate this finding. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Cardiac function in gestational diabetes mellitus: A longitudinal study from fetal life to infancy.

OBJECTIVE: To determine whether cardiac functional and structural changes in fetuses of mothers with gestational diabetes mellitus (GDM) persist in the offspring beyond the neonatal period. DESIGN: Longitudinal study. SETTING: Fetal Medicine Unit in a UK teaching hospital. METHODS: 73 women with GDM and 73 women with uncomplicated pregnancy were recruited and fetal cardiac scans were performed at 35-36 weeks' gestation. Repeat echocardiogram was performed in their offspring during infancy. MAIN OUTCOME MEASURES: Fetal and infant cardiac functional and structural changes. RESULTS: Fetuses of mothers with GDM, compared with controls, had more globular right ventricles (sphericity index 0.7, interquartile range [IQR] 0.6/0.7 versus 0.6, IQR 0.5/0.6, P < 0.001) and reduced right global longitudinal systolic strain (-16.4, IQR -18.9/-15.3 versus -18.5, IQR -20.6/-16.8, P = 0.001) and left global longitudinal systolic strain (-20.1, IQR -22.5/-16.9 versus -21.3, IQR -23.5/-19.5), P = 0.021). In the GDM group, compared with controls, in infancy there was higher left ventricular E/e' (8.7, IQR 7.3/9.7 versus 7.9 IQR, 6.8/8.9 P = 0.011) and lower left ventricular global longitudinal systolic strain (-21.0, IQR -22.5/-19.4 versus -22.3, IQR -23.5/-20.7, P = 0.001) and tricuspid annular plane systolic excursion (13.8, IQR 12.7/16.1 versus 15.2, IQR 13.8/16.8, P = 0.003). These differences remained following multivariable analysis. CONCLUSION: Gestational diabetes mellitus is associated with alterations in fetal cardiac function and structure compared with controls and persistent cardiac changes in infancy. TWEETABLE ABSTRACT: Gestational diabetes mellitus, even when well controlled, is associated with fetal cardiac changes and these persist in infancy.