Maternal Adaptation to High-altitude Pregnancy: An Experiment of Nature—A Review

A long and productive history of studies at high altitude has demonstrated that chronic hypoxia plays a key role in the aetiology of intrauterine growth restriction (IUGR) and pre-eclampsia. Susceptibility to altitude-associated IUGR varies among high-altitude populations in relation to their duration of altitude exposure, with multigenerational residents demonstrating one-third the birth weight fall present in shorter-resident groups. Higher uteroplacental blood flow during pregnancy in multigenerational high-altitude residents suggests that such population differences are due, at least in part, to differences in maternal vascular responses to pregnancy. We hypothesize that natural selection acting on hypoxia-inducible factor (HIF)-targeted or -regulatory genes has enabled maternal vascular adaptation to pregnancy in long-resident high-altitude groups. Preliminary evidence in support of this hypothesis demonstrates that the potent HIF-targeted vasoconstrictor, endothelin-1 (ET-1), is differentially regulated by pregnancy and chronic hypoxia in Andean vs European residents of high altitude. Andeans show the normal, pregnancy-associated fall in ET-1 levels previously reported at low altitude, whereas Europeans have higher ET-1 levels and little pregnancy-associated change, like pre-eclamptic women. Single nucleotide polymorphisms (SNPs) in the ET-1 gene also differ in Andeans compared with low-altitude populations. We conclude that high altitude serves as an experiment of nature for elucidating genetic factors underlying susceptibility to complications of pregnancy and fetal life. Such studies may be important for identifying persons at risk for these complications at any altitude.     

Correlation of fetal DNA levels in maternal plasma with Doppler status in pathological pregnancies

OBJECTIVES: To evaluate whether intrauterine growth restriction (IUGR) as seen in preeclampsia is associated with high levels of fetal DNA in maternal circulation, and whether fetal DNA is related to altered uterine and/or umbilical artery Doppler velocimetry. METHODS: Fetal DNA quantification was performed by real-time PCR on SRY sequences in 64 male-bearing pregnant women with IUGR and/or preeclampsia and 89 controls. RESULTS: Fetal DNA content was significantly elevated in IUGR pregnancies similar to preeclampsia and correlated with altered umbilical Doppler velocimetry, while no correlation was found with uterine Doppler status. CONCLUSION: Increased fetal DNA levels in maternal plasma may be a sign of placental or fetal pathology even in the presence of normal uterine Doppler velocimetry, allowing a more precise diagnostic evaluation. The finding that elevated fetal DNA in IUGR pregnancies correlates with abnormal umbilical Doppler velocimetry suggests that fetal DNA release is associated more with fetal chronic hypoxia than with fetal size.     

胎儿脑及脐动脉血流检测的临床意义

应用彩色多普勒超声，检测正常妊娠妇女４８例（正常妊娠组），妊高征患者３４例（妊高征组），妊高征合并胎儿生长迟缓（ＩＵＧＲ）５４例（ＩＵＧＲ组）儿大脑中动脉及脐动脉血流速波，计算血流的收缩末期峰值与舒张末期峰值的比值、脉搏指数、阻力指数。     

Investigation of the uteroplacental circulation by Doppler ultrasound

Doppler assessment of the uteroplacental circulation can be performed easily. In early pregnancy, it may identify pregnancies at risk of developing pregnancy-induced hypertension and IUGR. In late pregnancy, a high impedance in the uteroplacental vascular bed indicates that the fetus is at risk of developing hypoxia, but the fetal and umbilical FVW are the best indicators of immediate fetal well-being. Doppler ultrasound also offers the potential for noninvasive experimental hemodynamic studies of the uteroplacental circulation.     

Doppler sonography of the uterine and the cubital arteries in normal pregnancies, preeclampsia and intrauterine growth restriction: evidence for a systemic vessel involvement

AIMS: The decrease in uterine resistance during normal pregnancy is known to be related to invading trophoblast cells which derive from placental tissue. Uterine and peripheral resistance is elevated in preeclampsia. The aim of the present study was to prospectively examine uterine and peripheral resistance in pregnancies complicated by preeclampsia (PE), fetal intrauterine growth restriction (IUGR) and pregnancy induced hypertension (PIH). METHODS: Sixty-seven women with normal pregnancies, 17 with PE, 12 with IUGR underwent Doppler sonographic investigation of the uterine and the cubital arteries. The Pulsatility Index (PI) was calculated for each vessel. Statistical analysis was performed and a P-value <0.05 was considered significant. RESULTS: Patients with preeclampsia and IUGR showed a significant higher resistance at the placental (mean PI 1.267 and 1.063), nonplacental (mean PI 1.631 and 1.124) and cubital artery (mean PI 3,777 and 3.995) compared to the normal pregnancy group (mean PI 0.678; 0.859 and 2.95 respectively). Mean birth weight in the PE group was 1409 g, in the IUGR group 1649 g and 3419 g in the normal pregnancy group. CONCLUSIONS: Pregnancies with IUGR are associated with elevated peripheral resistance in the maternal arterial system as seen in pregnancies with preeclampsia. Our findings encourage to further investigate the maternal vascular system in high risk pregnancies.     

Role of cytokines in altitude-associated preeclampsia

BACKGROUND: Preeclampsia (PE) is more common at high than low altitude and contributes to the altitude-related decline in birth weight. Since inflammatory markers are implicated in PE, we asked if such markers differed in PE vs. normotensive pregnant (NORM) women residing at high altitude (3600-4100 m), and were related to uterine artery blood flow (UA BF) or fetal growth. METHODS: Subjects were 33 Andean pregnant residents of Bolivia, comprising six with early-onset PE (≤ 34 wk), 12 with late-onset PE (> 34 wk), and 15 gestational-age matched NORM. Maternal pro- and anti-inflammatory cytokines were measured using a multiplex bead-based assay and UA BF by Doppler ultrasound. RESULTS: PE compared to NORM women had higher levels of the pro-inflammatory cytokines IL-6 and IL-8 as well as higher levels of the anti-inflammatory cytokine IL-1ra, but only IL-6 levels were higher when gestational age was controlled. Women with early- vs. late-onset PE had higher TNFα levels, and higher IL-6 was negatively correlated with birth weight in all women at ≤ 34 wk. We suggest that pro-inflammatory factors influence both the timing and severity of PE at high altitude.     

Uteroplacental unit as a source of elevated circulating prorenin levels in normal pregnancy

Circulating levels of inactive renin, that is, prorenin, are increased in normal pregnant women. To determine whether the uteroplacental unit secretes prorenin into the maternal circulation, we measured enzymatically active and inactive renin in plasma simultaneously obtained from the radial artery and uterine vein of 12 normotensive, nonlaboring patients undergoing elective cesarean section at term. We also measured these forms of renin in the umbilical arterial and venous blood of these patients. Our data reveal that the levels of inactive renin in both arterial and uterine venous blood of normal pregnant women are significantly higher than in peripheral venous blood of nonpregnant, normotensive control subjects; normotensive term patients have a ratio of plasma inactive to active renin of 9:1 in contrast to the 1:1 ratio in normotensive nonpregnant subjects; there is a significant uterine arteriovenous difference of prorenin (66.2 +/- 24.4 ng/ml/hr, p less than 0.05) but not of active renin (1.8 +/- 1.5 ng/ml/hr, not significant). These results suggest that the uteroplacental unit contributes to the elevated prorenin levels at term pregnancy.     

Remodelling of uteroplacental arteries is decreased in high altitude placentae

Uterine blood flow and birth weight are reduced and the risk of pre-eclampsia is increased in high-altitude pregnancies. Since IUGR and pre-eclampsia are associated with reduced invasion and remodelling of maternal spiral arteries we asked whether the terminal ends of uteroplacental arteries located at the maternal-foetal decidual interface evidenced less remodelling in 19 high (3100 m) compared with 13 moderate (1600 m) altitude placentae from normal pregnancies. Previous work has demonstrated marked villous angiogenesis in high altitude placentae. We asked whether such changes are compensatory for reduced modelling and/or whether they contribute to increased birth weight. Placentae were randomly sampled and examined with immunohistochemistry to evaluate vessel remodelling and foetal capillary density. The decidual ends of uteroplacental arteries were 8-fold more likely to be remodelled at 1600 vs. 3100 m (OR=8.1; CI 2.4, 27.0,P< 0.001). There were more than twice as many uteroplacental arteries observed in the high vs. moderate altitude placentae (OR=2.1; CI: 1.3, 3.5, P=0.006). Foetal capillary density was greater at 3100 vs. 1600 m (P< 0.001), but did not relate to remodelling nor to birth weight. In this in vivo model for chronic hypoxia, remodelling is reduced, and villous angiogenesis is not fully compensatory for reduced PO(2).     

Prediction of preeclampsia or intrauterine growth restriction by second trimester serum screening and uterine Doppler velocimetry

OBJECTIVE: To assess the performance of screening for preeclampsia and intrauterine growth restriction by combining second trimester maternal serum screening and uterine Doppler ultrasound. METHODS: A cohort of 2,615 women underwent both maternal serum screening (using human chorionic gonadotropin (hCG) and alpha-fetoprotein (AFP)), and second trimester uterine artery Doppler. The sensitivity, specificity and predictive value of different combinations of both tests were compared. RESULTS: The mean values for hCG and AFP were significantly higher in women with subsequent preeclampsia (p < 0.0003 and p < 0.03, respectively). Taking into account obstetrical history, hCG and AFP levels, notching on uterine artery Doppler and parity, the adjusted odds ratios were significantly higher for a high level of hCG for preeclampsia, intrauterine growth restriction (IUGR) and pregnancy-induced hypertension. AFP level >1.5 MoM (multiples of the median) was significantly correlated with subsequent IUGR. The presence of a uterine notch was associated with a significantly higher risk of both preeclampsia and IUGR. The combination of an elevated serum level and the presence of a uterine notch had a positive predictive value (PPV) for preeclampsia of 25 and 21% for hCG and AFP, respectively. The combination of a bilateral notch with a low level of hCG or a high level of AFP had a PPV for IUGR of 50 and 43%, respectively. The sensitivity of the different tests ranged from 2 to 40%. CONCLUSION: The combination of serum markers and abnormal uterine Doppler ultrasound improves the identification of women at risk for subsequent pregnancy complications. These results should encourage care providers to perform a uterine Doppler ultrasound when serum markers are abnormal. However, the sensitivity of these tests is too low to provide an efficient generalized screening.     

Comparison of low- and high-altitude Doppler velocimetry in the peripheral and central circulations of normal fetuses

OBJECTIVE: Our aim was to test the hypothesis that Doppler velocimetry of the peripheral and central circulations in normal fetuses is not affected by moderately high altitude (Denver, Colo-1609 m) compared with sea level (Milan, Italy-40 m). STUDY DESIGN: One hundred nineteen patients with singleton pregnancies underwent Doppler waveform analysis of the following: umbilical artery, uterine artery, middle cerebral artery, ductus venosus, and the tricuspid and mitral valves. RESULTS: Birth weights were reduced at Denver's altitude (P<.001). The early/late diastolic inflow ratios of the atrioventricular valves increased with gestational age (P<.01), whereas systolic/diastolic ratios of the uterine and umbilical arteries decreased with gestational age (P<.01). There were no Doppler velocimetry differences in any vessel between Denver's and Milan's altitudes. CONCLUSIONS: Gestational age has the same effect on Doppler index at both high and low altitudes. Moderately high altitude does not affect uteroplacental or fetal vascular Doppler index and may reflect normal acclimatization in the smaller Denver fetuses.     

Changes in uterine blood flow during human pregnancy

A transvaginal duplex Doppler ultrasonography system was used to measure blood flow characteristics in the ascending uterine artery before and during pregnancy. The system uses a 5 MHz Doppler transducer coupled to a 6.5 MHz imaging probe. There was a steady increase in volume flow rate in the left ascending uterine artery from a mean of 94.5 ml/min before pregnancy to a mean of 342 ml/min in late gestation (reflecting a 3.5-fold increase). With the assumption of equal flow on both uterine arteries, the fraction of the cardiac output that is distributed to these vessels was calculated to be 3.5% in early pregnancy and to reach 12% near term. The mean diameter of this vessel in the nonpregnant state was 1.6 mm, increasing to 3.7 mm toward term. The resistance to flow, expressed as the peak systolic to end-diastolic flow velocity ratio, declined from a mean of 5.3 in the nonpregnant state to a mean of 2.3 near term. These changes reflect the perpetual growth and development of the uteroplacental circulation, which provides the metabolic demands of the growing fetus throughout gestation.     

Administration of the PARP inhibitor Pj34 ameliorates the impaired vascular function associated with eNOS(-/-) mice

A low-resistance/high-flow uteroplacental circulation is integral to a healthy pregnancy. Impaired flow in the uterine circulation is associated with intrauterine growth restriction (IUGR) and preeclampsia (PE). Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme which has been associated with oxidative stress-induced vascular dysfunction. Using the endothelial nitric oxide synthase (eNOS(-/ -)) knockout mouse model, which features vascular dysfunction and IUGR, we tested the hypothesis that administration of a PARP inhibitor may ameliorate the vascular dysfunction associated with the eNOS(-/-) model. eNOS(-/-) animals were characterized by impaired uterine artery function when compared to controls. Administration of the PARP inhibitor PJ34 prevented this dysfunction. Gestational day (GD) 17.5 eNOS(-/-) mice did not exhibit altered systolic blood pressure when compared to control mice. However, treatment of eNOS(-/-) mice with PJ34 significantly reduced systolic blood pressure when compared to vehicle-treated eNOS(-/-). Administration of a PARP inhibitor protects uterine artery function in the face of eNOS(-/-) deficiency.     

Could first-trimester assessment of placental functions predict preeclampsia and intrauterine growth restriction? A prospective cohort study

Objective: To examine the role of first-trimester uterine artery Doppler, serum β-hCG and pregnancy-associated placental protein-A (PAPP-A) in prediction of preeclampsia and IUGR.

Methods: A total of 100 pregnant women in the 11–14 weeks’ gestation were examined using uterine artery Doppler, serum β-hCG and PAPP-A. All women were followed-up for development of preeclampsia or IUGR.

Results: A total of 94 women completed the study of which 7 (7.4%) developed complications. Uterine artery PI and RI were significantly higher whereas serum β-hCG and PAPP-A levels were significantly reduced in patients who developed complications when compared with those who did not. Uterine artery PI had the highest sensitivity (100%) but a low specificity (56% and 45%) in prediction of preeclampsia and IUGR, respectively. Adding PAPP-A to uterine artery PI elevated the specificity into 94.44% and 95.51%, respectively. Combined PI and β-hCG elevated the specificity into 88.89% and 89.89%, respectively.

Conclusion: Our study suggests that first-trimester uterine artery impedance, as measured by Doppler ultrasound as well as low serum biomarkers (β-hCG and PAPP-A) can be used for prediction of preeclampsia and IUGR. The most sensitive is uterine artery PI. Adding β-hCG to PI improves specificity in prediction of both preeclampsia and IUGR. Uterine artery PI plus PAPP-A is the best combination for prediction of both preeclampsia and IUGR     

Doppler examinations of fetal and uteroplacental blood flow in AGA and IUGR fetuses before and after maternal physical exercise with the bicycle ergometer

OBJECTIVE: To study changes in uteroplacental and fetal circulation after maternal exercise in appropriate-for-gestational-age fetuses (AGA) and intrauterine-growth-retarded fetuses (IUGR). MATERIALS AND METHOD: 33 women with an uncomplicated course of pregnancy and ten women with IUGR were examined. Physical stress was caused through a bicycle ergometer with 1.25 W/kg maternal weight. Doppler examinations were performed in the umbilical artery, fetal aorta, middle cerebral and in the uterine artery. Fetal heart rate was documented by monitoring. Maternal lactate and glucose levels as well as maternal blood pressure and heart rate were recorded. RESULTS: No significant changes after cycling could be observed in umbilical and uterine vessels either in the normal pregnancies or in pregnancies with IUGR. In contrast, in the fetal aorta an increase of the RI was recorded in both groups (an increase of 16% [P<0.01] and 18% [P<0.05], respectively for AGA and IUGR cases). In cerebral arteries a decrease of the RI was observed after cycling in both groups (a decrease of 24% [P<0.01] and 13% [P<0.05], respectively for AGA and IUGR cases). In AGA fetuses the RI of the aorta and middle cerebral artery returned to pre-test level by the 18th minute of examination. In IUGR fetuses the RI of the aorta and middle cerebral artery did not return to pre-test levels at the end of the test. Fetal heart rate remained unchanged in both groups. Maternal blood pressure and heart rate increased during the exertion phase but returned to initial values at the end of the test. A 21% and 24% (for AGA and IUGR groups respectively) reduction of maternal glucose values after exercise was observed (P<0.001). Lactate values doubled in both groups after exercise (P<0.001). CONCLUSION: From the results obtained we conclude that maternal exercise does not significantly alter uterine and umbilical perfusion in AGA and IUGR pregnancies, suggesting an absence of change in the uterine vascular bed resistance. However, submaximal maternal exercise was followed by fetal cerebral vasodilatation and an increase of resistance in the fetal aorta that was more evident in IUGR fetuses. This might be due to slight fetal hemoglobin desaturation in those cases.     

Role of placental growth hormone in the alteration of maternal arterial resistance in pregnancy

OBJECTIVE: To investigate the relation between arterial resistance and placental growth hormone (hGH-V) levels in the maternal circulation. STUDY DESIGN: Sixty-seven women with normal pregnancy, 13 with preeclampsia (PE) and 11 with intrauterine fetal growth restriction (IUGR) underwent Doppler sonography of the placental and nonplacental uterine and cubital artery and blood sampling. hGH-V was measured with a highly sensitive sandwich-type immunofluorometric assay and pituitary growth hormone (hGH-N) and insulinlike growth factor I (IGF-I) with a chemiluminescence assay. A p value of < 0.05 was considered significant. RESULTS: During normal pregnancy the arterial pulsatility index (PI) decreased (p < 0.001), serum levels of hGH-V and IGF-I increased (p < 0.0001), and hGH-N decreased (p < 0.0001). Pathologic pregnancies (PE, IUGR) showed a significant higher PI in all arteries, but hGH-V and the IGF-I were decreased. CONCLUSION: Our data demonstrate a strong correlation between decreasing uterine and peripheral arterial resistance and increasing hGH-V during normal pregnancies with impaired uterine blood flow there were lowered serum levels of hGH-V, hGH-N and IGF-I. Lower levels of hGH-V and hGH-N might contribute to impaired uteroplacental circulation.     

Uterine Artery Pseudoaneurysm in a Pregnant Patient with Retrocervical Endometriosis

A pseudoaneurysm of the uterine artery or its branches is usually a result of vascular trauma during invasive procedures such as a cesarean section, vaginal delivery, myomectomy, hysterotomy, or dilatation and curettage. A uterine artery pseudoaneurysm rupture is a rare, yet life-threatening event. Deep infiltrating endometriosis usually involves a decrease in symptoms and imaging findings throughout pregnancy, with the notable exception of the phenomenon of decidualization. We present the case of a pregnant woman with a recent diagnosis of endometriosis, who conceived spontaneously and presented with disabling pain at 13 weeks’ gestation. She was diagnosed with a left, huge (and rapidly growing) retrocervical endometriosis nodule encompassing a uterine artery pseudoaneurysm. Selective transarterial embolization was performed at 22 weeks’ gestation owing to enlargement of the pseudoaneurysm sac, and the pseudoaneurysm was obliterated successfully. The patient was followed intensively throughout the pregnancy and the baby was delivered at term by cesarean section. After delivery, the nodule returned to the pregestational size.     

Abdominal pregnancy: a perfusion confusion?

Background

The uteroplacental blood supply is usually portrayed as a ‘series’ circuit. Differences seen in the uterine artery (UA) waveform in pregnancies destined to develop pre-eclampsia are often attributed to back pressure effects from the downstream flow through the spiral arteries of the placental bed.

Case

A third trimester abdominal pregnancy was successfully delivered by laparotomy at 30 weeks gestation. The UA waveforms of were recorded at 27 weeks. Both were ‘normal’ for the gestation, despite limited blood supply from the right uterine and the left not supplying the placenta at all.

Conclusion

In the absence of pre-eclampsia, UAs can convert to a ‘low resistance’ waveform even when not directly connected to the placental bed. This case report adds to the evidence against the ‘cause and effect’ mechanism often used to explain the correlation between trophoblastic invasion and the UA waveform. Both may independently develop in response to a common underlying mechanism.     

血液动力学指标预测胎儿缺氧及酸中毒的价值

目的：评价血液动力学指标预测胎儿缺氧及酸中毒的价值。方法：用彩色多普勒超声检测了４６例正常晚期妊娠（正常组）和３２例高危妊娠（高危组）妇女子宫动脉（ＵｔＡ）和胎儿脐动脉（ＵｍＡ）、大脑中动脉（ＭＣＡ）、肾动脉（ＲＡ）的血流速度波型，并且测定高危组脐动脉血气。结果：高危组ＵｔＡ、ＵｍＡ、ＲＡ的阻力指数（ＲＩ）、搏动指数（ＰＩ）及收缩期最大血流速度（Ｓ）与舒张末期血流速度（Ｄ）的比值（Ｓ／Ｄ值）均高于正常组，而ＭＣＡ的ＰＩ及Ｓ／Ｄ值均明显低于正常组（Ｐ＜０．０５）。与ＵｍＡＰＯ２＞２．５ｋＰａ的高危妊娠病例比较，ＵｍＡＰＯ２≤２．５ｋＰａ者ＵｔＡ的Ｓ／Ｄ值、ＵｍＡ的ＰＩ、Ｓ／Ｄ值以及ＲＡ的ＲＩ、ＰＩ、Ｓ／Ｄ值均明显增高，ＭＣＡ的ＰＩ明显降低（Ｐ＜０．０５）。ＵｍＡ及ＲＡ的ＰＩ与ＵｍＡＰＯ２和ｐＨ值呈负相关，与ＰＣＯ２呈正相关；ＭＣＡ的ＰＩ与ＵｍＡ的ｐＨ、ＰＯ２呈正相关，与ＰＣＯ２呈负相关。结论：高危妊娠胎儿缺氧时ＭＣＡ血流阻力降低，而周围血管，特别是肾血管血流阻力明显升高；胎儿血液动力学变化与缺氧及酸碱平衡失调呈良好相关性，可预测胎儿缺氧及酸中毒的程度。     

子宫螺旋动脉重铸障碍在复发性流产中的研究进展

复发性流产是一种常见的病理妊娠,其病因和发病机制至今尚未完全阐明。足够的子宫胎盘血供对于正常妊娠是至关重要的,这有赖于广泛的子宫螺旋动脉生理性重铸所形成高流量、低阻力的母胎血液循环系统。子宫螺旋动脉血流反映母胎之间的血液循环,是子宫与妊娠母体的终末分支,能提供充足的胎盘血流和养分,满足胚胎的生长发育。滋养细胞的侵袭及其介导的子宫螺旋动脉细胞的凋亡是重铸过程的两个关键环节,若重铸障碍则胎盘灌注量不足,继而胚胎缺血、缺氧,导致一系列病理妊娠。早期研究表明复发性流产患者蜕膜组织中滋养细胞侵袭减少,螺旋动脉重铸障碍,因此对复发性流产这一特征性病理改变产生的研究成为阐明病因的关键。     

Fetal and maternal hemodynamic responses to exercise in pregnancy assessed by Doppler ultrasonography

It is common for women to undertake vigorous exercise in the late phase of pregnancy. This may have detrimental effects on the blood flow to the uterus and placenta or from the fetus to the placenta. Fifteen pregnant women with no obstetric or medical complications were subjected to a 5-minute exercise period. The maternal heart rate and blood pressure were elevated after exercise. The uteroplacental and umbilical circulations were assessed with Doppler ultrasonography. The ratio of the systolic/diastolic velocity in the uterine artery was elevated, which suggests that uteroplacental vascular resistance increased. The fetal heart rate was elevated after exercise, whereas the systolic/diastolic velocity ratio in the umbilical artery was unaltered. We conclude that moderate maternal exercise causes increased resistance to blood flow in the uterine circulation, whereas the umbilical circulation remains unaltered.