Uteroplacental Blood Flow

Basic Principles of Human Uteroplacental Blood Flow

The uteroplacental circulation provides nutrient and oxygen delivery and removal of waste products for the developing fetus. Understanding the regulation of uteroplacental circulation is an important foundation for the management of obstetric diseases and for the safe provision of obstetric anesthesia. The uteroplacental circulation can be affected by maternal disease, medications, parturition, and anesthesia. Abnormalities in uteroplacental circulation are implicated in the “Great Obstetric Syndromes” of preeclampsia, preterm birth, and intrauterine growth restriction. Much of the available knowledge on the uteroplacental circulation comes from animal studies, which limits applicability to clinical care. Recently, computational modeling has provided new insights into the uteroplacental circulation. Despite advances in our understanding, additional research is needed on the mechanisms underlying the establishment and regulation of uteroplacental blood flow, the effect of pharmacologic agents for improving pathologic conditions related to blood flow, and how alterations in uteroplacental blood flow affect pregnancy outcomes.

The physiology and pathophysiology of uteroplacental blood flow have been studied extensively in animals, especially sheep and rodents. However, major differences in placental organization, structure, and function exist among species. Therefore, caution must be exercised when extrapolating animal studies to clinical practice.

Some of the differences between animal and humans include:

1.
Degree of Separation of Maternal and Fetal Blood

The human placenta is hemochorial , with maternal blood in direct contact with fetal chorionic villi, while the sheep placenta is epitheliochorial, where maternal blood is separated from fetal chorionic tissue by maternal vascular endothelium and uterine epithelium.
2.
Organization of Units of Maternal-Fetal Exchange

The human placenta is discoid . The cotyledon is the basic unit of maternal-fetal placental exchange, consisting of a branching stem chorionic villus from the fetal side that traverses intervillous space to establish an anchoring villus in the decidua basalis of the maternal uterus. Within the chorioallantoic placenta, 15 to 25 cotyledons develop, which are tightly packed, separated by septa and sandwiched between the chorionic and basal plates of the placental disc. By contrast, thesheep has a polycotyledonal placenta, where cotyledons are discrete and widely separated throughout the placenta.
3.
Depth of Trophoblast Remodeling of Uterine Vasculature in Pregnancy

Normal human pregnancy is characterized by extensive remodeling of uterine spiral arteries by invading trophoblasts; this converts the high-resistance, low-flow, nonpregnant spiral arteries into low-resistance, high-flow spiral arteries. Trophoblast invasion occurs throughout the full depth of the decidua and into the inner third of the myometrium, which contrasts with limited invasion in rodents. Although rodents and humans both have hemochorial discoid placentas, the differences in the extent of trophoblast invasion and vascular remodeling make extrapolation between the two species problematic. For example, phenylephrine causes uterine artery vasoconstriction and impaired uteroplacental perfusion in rodents and sheep but not in human pregnancy. Indeed, failure to appreciate interspecies differences previously led to ephedrine long being considered the vasopressor of choice in obstetric anesthesia.

Anatomy

The blood supply to the uterus is derived mainly from the uterine arteries ( Fig. 3.1 ) with a smaller, variable contribution from the ovarian arteries. The uterine artery arises bilaterally from the anterior division of the internal iliac (hypogastric) artery, whereas the ovarian artery arises from the anterolateral abdominal aorta below the renal arteries. Vessel diameter and blood flow are greater in the uterine artery on the ipsilateral side of the placenta, compared with the contralateral artery. Anastomoses are formed with the contralateral uterine artery, the vaginal arteries, and the ovarian arteries. The uterine arteries pass medially to the side of the uterus, where they supply branches to the cervix and vagina and ascend between the two layers of the broad ligament, yielding arcuate arteries that supply the body of the uterus to the junction with the fallopian tubes.

A labeled diagram shows the ovary, uterus, bladder, urethra, and vagina with arrows pointing to ovarian, uterine, vaginal, and internal iliac arteries. — Fig. 3.1

The arcuate arteries give rise to small branches that supply the outer myometrium and large-diameter radial arteries that penetrate deeply into the myometrium to reach the endometrium as approximately 200 convoluted spiral arteries. The radial arteries also give rise to the basal arteries, which are subjacent to the endometrium but do not reach the luminal surface. In early gestation, trophoblastic invasion into the lumens of the spiral arteries results in loss of vessel smooth muscle and contractile ability, producing vasodilation, decreased resistance, and increased blood flow. Abnormal or inadequate trophoblastic invasion is a hallmark of the histopathology of the uteroplacental circulation in preeclampsia (see Chapter 35 ).

Oxygenated maternal blood enters the intervillous space from the terminal openings of the spiral arteries that emanate from the basal plate, or decidua basalis, which is the junction of the chorioallantoic placenta with endometrium of pregnancy, or decidua ( Fig. 3.2 ). The branching chorioallantoic villi occupy the intervillous space of the placenta, with maternal blood bathing the villous surfaces. These villi are covered by a trophoblast bilayer: an outer, terminally differentiated, multinucleated mass called syncytiotrophoblast, and a subjacent, proliferative, mononucleated stem cell population called cytotrophoblast. The syncytiotrophoblast is the primary site for exchange of oxygen, nutrients, and wastes between maternal and fetal blood. Maternal blood passively exits the intervillous space through multiple collecting veins in the decidua basalis that empty into uterine veins that drain via the internal iliac veins and also via the ovarian veins into the inferior vena cava on the right, and into the renal vein on the left.

A developmental diagram shows progressive stages of chorionic villus formation from implantation to embryonic vessel development over days 4 to 17. — Fig. 3.2

Up to 90% of uterine blood perfuses the chorioallantoic placenta at term, with the remainder supplying the myometrium and nonplacental endometrium. Notably, the placental and nonplacental vasculatures are anatomically and functionally distinct. Moreover, regulation of perfusion through these vascular beds differs, which highlights the importance of distinguishing studies that measure total uteroplacental blood flow versus placental blood flow.

Changes During Pregnancy

Uterine blood flow increases markedly during pregnancy, from less than 100 mL/min before pregnancy to 700 to 900 mL/min at term, depending on the method of measurement ( Fig. 3.3 ). Uterine blood flow at term represents a greater proportion of cardiac output than in early pregnancy (12% versus 3.5%). Sheep studies indicate that increases in uterine blood flow can be divided into three phases. An initial phase likely controlled by ovarian secretion of estrogen and progesterone occurs before and during implantation and early placentation. A second phase results from the growth and remodeling of the uteroplacental vasculature to support placental development. The third phase results from progressive uterine artery vasodilation to meet the markedly increased nutrient requirements of the rapidly growing fetus. Expressed in terms of uterine weight, uterine flow per gram of tissue is particularly high in early gestation, and this ratio decreases as pregnancy progresses. In comparison, umbilical blood flow, as a function of fetal weight, is relatively constant during pregnancy at 110 to 120 mL/min/kg, although some studies showed a decrease in umbilical venous blood flow per kilogram fetal weight throughout gestation. Uterine blood flow is higher in twin than in singleton pregnancy, but the flow per unit of estimated fetal weight is similar.

A scatter plot shows an upward trend in uterine artery blood flow from 16 to 40 weeks of gestation with a best-fit line and equation. — Fig. 3.3

Distribution of Blood Flow

The increase in uterine blood flow results from increases in uterine artery diameter and flow velocity. The uterine artery diameter doubles from early pregnancy until week 21, is static until week 30, and then increases until at least week 36. The mean flow velocity in the uterine artery increases eightfold over the course of gestation. This increase in uterine and common iliac artery blood flow is associated with a decrease in external iliac artery flow, redistributing blood to the uterus ( Fig. 3.4 ).

A line graph shows changes in blood flow through common iliac, external iliac, and uterine arteries from nonpregnant to 36 weeks of gestation. — Fig. 3.4

Autoregulation

Vasoconstriction or vasodilation in response to changes in systemic arterial pressure maintains steady transcapillary fluid exchange. In sheep, the nonpregnant uterine circulation and the nonplacental uterine circulation in pregnancy exhibit autoregulation, but autoregulation is limited in the uteroplacental circulation. This occurs because the uteroplacental circulation is a dilated, low-resistance system with largely pressure-dependent perfusion, with limited ability to dilate or constrict. Importantly, the spiral arteries that supply the intervillous space lack the metaarterioles and precapillary sphincters that are essential for autoregulation. However, studies are conflicting because of variation in the animal models and experimental conditions used; for example, uteroplacental autoregulation has been demonstrated in guinea pigs, rabbits, and sheep. These discrepancies may be explained by the activity of the nonplacental uterine vasculature, which accounts for a small fraction of total uteroplacental blood flow but exhibits similar autoregulatory responses in pregnancy and nonpregnancy. In contrast, limited autoregulatory ability exists in the placental circulation, which means that placental blood flow may diminish with reductions in maternal blood pressure (e.g., during hemorrhage or neuraxial anesthesia).

Changes During Parturition

Labor causes marked changes in uteroplacental perfusion. Uterine contractions decrease perfusion inversely proportional to the strength of the contraction and the increase in intrauterine pressure. The uterine blood flow is limited when the intrauterine pressure exceeds 30 mm Hg, end-diastolic flow in the uterine artery ceases when the intrauterine pressure exceeds 35 mm Hg, and blood flow totally ceases when intrauterine pressure exceeds 60 mm Hg. The strength of a normal uterine contraction in labor is 40 to 100 mm Hg. During uterine relaxation, there is a period of increased perfusion above baseline. The decrease in perfusion during a contraction causes autotransfusion into the central circulation of 300 to 500 mL, increasing the maternal stroke volume and cardiac output through increased cardiac preload. This phenomenon can be significant for patients with maternal cardiac disease, who may poorly tolerate the autotransfusion associated with each contraction.

Hemodynamics

Uterine blood flow like other organs is determined by perfusion pressure and vascular resistance:

Uterine blood flow = \frac{Uterine perfusion pressure}{Uterine vascular resistance} = \frac{Mean uterine arterial pressure - Mean uterine venous pressure}{Uterine vascular resistance}

There are several ways that uteroplacental blood flow may decrease ( Box 3.1 ).

Box 3.1

Common Causes of Decreased Uteroplacental Blood Flow

Decreased Uterine Perfusion Pressure

•
Decreased Uterine Arterial Pressure
- •
  Obstetric hemorrhage
- •
  Neuraxial anesthesia–induced sympatholysis
- •
  Systemic vasodilators
- •
  Supine position (arterial compression component)
•
Increased Uterine Venous Pressure
- •
  Supine position (vena caval compression component)
- •
  Valsalva maneuver
•
Increased Uterine Vascular Resistance
- •
  Uterine contraction (especially uterine tachysystole and uterine tetany)
- •
  Endogenous vasoconstrictors (catecholamines in stress or hypovolemia)
- •
  Exogenous vasoconstrictors (epinephrine, phenylephrine, norepinephrine, ephedrine)

Decreased uterine arterial pressure may occur with: (1) hypovolemic or obstructive shock with reduced cardiac preload; (2) cardiogenic shock with reduced myocardial contractility; (3) distributive shock with reduced cardiac afterload (e.g., anaphylaxis, neurogenic shock, neuraxial anesthesia–induced sympatholysis); and (4) major cardiac arrhythmias.

Supine positioning with aortocaval compression may decrease uterine arterial pressure by reducing cardiac preload, mainly via impaired venous return from vena caval compression. Aortocaval compression also directly increases uterine venous pressure, further reducing uterine perfusion pressure. The Valsalva maneuver (while pushing during the second stage of labor) also increases uterine venous pressure.

As the uterus is a hollow muscular viscus, with the uterine artery on the outside and the placenta and fetus on the inside, uterine vascular resistance greatly increases during uterine contractions, leading to diminished or abolished uteroplacental perfusion. This is particularly relevant during long or obstructed labor and excessive oxytocin administration resulting in tachysystole or uterine tetany. Uterine vascular resistance also increases in response to endogenous vasoconstrictors released in response to stress, dehydration or hypovolemia, and exogenous vasoconstrictors (e.g.,phenylephrine, norepinephrine [noradrenaline], ephedrine, or epinephrine [adrenaline]) administered during labor or cesarean delivery.

The hemodynamics of uteroplacental blood flow are uniquely associated with the coiled uterine spiral arteries, which in humans extend from the distal ends of the radial arteries in the myometrium into the decidua, terminating at the intervillous space ( Fig. 3.5 ). The spiral geometry of these vessels provides a reserve of high resistance to flow when the requirement for uteroplacental blood supply is low, and the ability to purge this reserve in pregnancy when the requirement for uteroplacental blood supply is high.

A three-dimensional reconstruction shows a uterine spiral artery passing through the myometrium, endometrium, and basal plate into the intervillous space. — Fig. 3.5

The nonpregnant spiral artery has low flow and high resistance, with muscular walls under sympathetic neurovascular control. During normal human pregnancy, the uteroplacental circulation undergoes marked geometric and hemodynamic transformations from the influence of invading trophoblasts. Spiral arteries are remodeled to become vessels with high flow and low resistance, no longer under sympathetic control, with distal segments transformed into inverted funnels opening into the intervillous space. The degree of spiral artery remodeling is quite nuanced. Using mathematical modeling of flow and resistance for the full range of spiral artery remodeling ( Fig. 3.6 ), Zamir et al. calculated that a conversion fraction, defined as the depth of remodeled vessel/total depth of tissue traversed by the spiral artery, of more than 80% was required to provide the uteroplacental perfusion needed for normal pregnancy. This mathematical and rheological approach complements pathologic observations that the depth of trophoblast invasion correlates with the adequacy or inadequacy of uteroplacental blood flow; failure of adequate remodeling in the first trimester has been associated with preeclampsia with severe features, fetal growth restriction (FGR), and prematurity.

A schematic shows spiral artery structure in nonpregnancy, preeclamptic pregnancy, and normal pregnancy, with varying trophoblast invasion and funnel size. — Fig. 3.6

Mechanisms of Vascular Remodeling andRegulation

The increase in uteroplacental blood flow occurs primarily from a substantial decrease in uterine vascular resistance ( Fig. 3.7 ) together with an increase in cardiac output and intravascular volume. Although the mechanisms are incompletely understood, three main factors contribute to the decrease in vascular resistance: (1) vascular remodeling, (2) changes in vascular reactivity, and (3) the development of the widely dilated spiral arteries.

A line graph shows a decrease in uterine vascular resistance from the nonpregnant state to early and mid gestation, with error bars at each point. — Fig. 3.7

Vascular remodeling of uterine arteries during pregnancy includes lengthening and straightening of coiled vessels and vessel dilation. There is no change in the diameter of the common iliac or external iliac arteries, but the uterine artery diameter doubles by 21 weeks’ gestation, and by 40 weeks, there is an eightfold increase in mean flow velocity. The arcuate and radial arteries also dilate by 22% to 220%, depending on the species studied ; in rats and mice this is associated with an increase in distensibility and a decrease in elastin content. Processes contributing to vascular remodeling include placentation with endovascular trophoblast invasion, increased shear stress, venoarterial exchange, and humoral factors. A decrease in blood viscosity during pregnancy also has a minor effect on reducing uterine vascular resistance.

A change in vascular reactivity during pregnancy is mediated by endothelial and vascular smooth muscle levels with an overall tendency for reduced tone, limited vasoconstriction, and increased vasodilation. The growth of the placenta creates a low-resistance vascular pathway by the significant reduction of the intramyometrial microcirculation and the creation of an intervillous space.

Effect of Endogenous Steroid Hormones

The endogenous steroid hormones are fundamental in short- and long-term uterine vascular changes during pregnancy, with estrogen as the primary driver of angiogenesis and vasodilation. Plasma concentration of estrogen, initially derived from the ovaries and later predominantly from the placenta, rises concomitantly with the increase in uterine blood flow during pregnancy. Angiogenic and vasodilatory effects of estrogen are mediated via estrogen receptors ER-α and ER-β. Most of these receptors are located in the nucleus and mediate genomic effects by regulating the transcription of genes that are responsible for the longer-term uterine angiogenic responses. There are also membrane receptors that mediate nongenomic effects by upregulating endothelial production of nitric oxide through the activation of endothelial nitric oxide synthase (eNOS) and the augmentation of eNOS protein expression. Progesterone modulates the effect of estrogen on uterine blood flow by downregulating the expression of estrogen receptors; however, the exact effects of progesterone on uterine blood flow remain incompletely understood.

Cortisol, the plasma level of which doubles during pregnancy, has both systemic and local effects on uterine blood flow. Systemically, cortisol contributes to regulation of uterine blood flow by increasing plasma volume. Although cortisol decreases eNOS protein expression and nitric oxide release, it potentiates the response to vasoconstrictor agents, including angiotensin II, vasopressin, and norepinephrine. Attenuation of these effects occurs during pregnancy.

Measurement of Uteroplacental Blood Flow

Techniques used to measure uteroplacental blood flow in animals and humans have varied according to the experimental question, available technology, and ethical considerations. All methods have inherent potential for error. Many early studies measured flow in only one uterine artery, which may not reflect total flow, depending on the location of the placenta. Although placental perfusion is of greatest clinical interest, it is not always differentiated from total uterine blood flow, and the two uterine artery circulations vary independently. However, usually the measurement of intervillous blood flow provides a reasonable surrogate of placental blood flow.

The most common method of clinically assessing uterine artery flow is Doppler ultrasonography. The uterine artery can be identified transabdominally or transvaginally; color flow aids vessel identification. Blood flow can be quantified by measuring the mean flow velocity and vessel cross-sectional area. Flow velocity measured by Doppler ultrasonography is angle-dependent and can be difficult to obtain correctly. An estimation of the volume of blood flow (Q) can be made by multiplying mean velocity (V) and vessel cross-sectional area (A), which is estimated with two-dimensional (B-mode) ultrasonography, that is, Q = V × A. Measurement of absolute flow using this technique is difficult and prone to error, from inaccuracies in the measurement of vessel cross-sectional area (e.g., as arteries pulsate during the cardiac cycle) and velocity. Therefore, for diagnostic purposes, indices related to vascular impedance are derived from the flow velocity waveform that is independent of the angle of insonation. These rely on the uterine vascular bed normally having low resistance, with flow continuing during diastole. If distal resistance is increased, diastolic velocity decreases relative to systolic velocity, resulting in a waveform showing greater pulsatility. Commonly derived indices include the following:

Systolic / diastolic (S / D) ratio = \frac{Systolic (\max) velocity}{Diastolic (\min) velocity}

Pulatility index (PI) = \frac{Systolic (\max) velocity - diastolic (\min) velocity}{Mean velocity}

Resistance index (RI) = \frac{Systolic (\max) velocity - Diastolic (\min) velocity}{Systolic (\max) velocity}

In early pregnancy, uterine artery flow is very pulsatile with high systolic flow and low diastolic flow. As gestation progresses, resistance gradually decreases. Abnormal patterns, including persistence of high resistance, diastolic notching, and the absence of end-diastolic flow or reversal of diastolic flow, are predictive of the development of abnormalities such as preeclampsia or FGR ( Fig. 3.8 ). Doppler velocimetry is also applied to the umbilical vessels for antepartum fetal assessment (see Chapter 6 ). Other methods of evaluation include the use of two-dimensional and three-dimensional Doppler, power Doppler, contrast-enhanced ultrasonography, and functional magnetic resonance imaging (MRI). Blood oxygen level–dependent functional MRI (BOLD MRI), which does not require administration of contrast media, has been used to evaluate placental and fetal perfusion following hypoxia in pregnant sheep and hyperoxia in pregnant humans. Emerging functional MRI assessments of placental perfusion by the exchange of magnetically labeled water protons, including arterial spin labeling and intravoxel incoherent motion (IVIM) echo planar imaging (EPI), offer the benefit of avoiding radiation but suffer from low signal-to-noise ratios and long scan times.

A Doppler ultrasound panel shows a normal uterine artery waveform without notching and an abnormal waveform with notching and increased pulsatility. — Fig. 3.8

Clinical Associations

The “Great Obstetric Syndromes”

Preeclampsia

Of many competing theories of the underlying pathophysiology of preeclampsia (see Chapter 35 ), one implicates an imbalance of angiogenic and antiangiogenic factors. An increase in serum levels of soluble fms-like tyrosine kinase receptor-1 (sFlt-1), which is an antagonist of vascular endothelial growth factor and placental growth factor (PlGF), reduces angiogenesis. Moreover, there is deficient remodeling of the uterine spiral arteries. In normal pregnancy, the uterine spiral artery remodeling enhances vasodilation and decreases uterine vascular resistance. However, in pregnancies complicated by preeclampsia, there is insufficient or shallow trophoblast invasion of the myometrial spiral arteries. This failure of spiral artery remodeling predisposes to hypoperfusion and chronic hypoxia. Alternatively, flow volume in the placenta may be unaffected, but the pathologic spiral artery remodeling may lead to pulsatile, higher pressure flow within the placenta that is thought to cause damage to villi that mediate maternal-fetal transfer. In normal remodeling of spiral arteries, there is a loss of smooth muscle cells from the arterial walls; however, in the presence of insufficient remodeling, the vasoreactive muscle cells are not obliterated and contribute to increased vascular tone and contractility. The abnormal flow thus contributes to ischemia-reperfusion injury and oxidative stress.

Clinically, the ratio of sFlt-1 to PlGF is used by some to predict the onset of preeclampsia in patients with clinical risk factors. Additionally, the uterine artery Doppler pulsatility index (PI) is elevated in early pregnancy in patients who will subsequently develop preeclampsia. Abnormal uterine artery Doppler PI is associated with abnormal spiral artery remodeling and thus is a surrogate for placental vascular insufficiency. The administration of low doses of aspirin to patients at high risk of preeclampsia, based on early screening with uterine artery Doppler PI and biomarkers such as pregnancy-associated plasma protein A and PlGF, reduces the development of preterm preeclampsia.

Fetal Growth Restriction

Etiologies for FGR include genetic, constitutional, infectious, maternal, and placental origins. Abnormal placental architecture is common, especially vascular abnormalities in villi, basal plate, or both. Placental hypoperfusion yields relative hypoxia and increased vascular resistance. Cases of severe, early gestational onset of FGR commonly exhibit placental pathology with features of abnormal uteroplacental perfusion and defective extravillous trophoblast invasion. There is a direct correlation between abnormal uterine artery Doppler measurements and defective spiral artery remodeling. Importantly, FGR with abnormal uterine artery Doppler measurements is associated with lesions of the fetal stem arteries. High resistance in the placenta evolves into deterioration of the Doppler pattern in the umbilical arteries. Normally, there is high flow in the umbilical arteries during diastole. With increased placental vascular resistance, there is diminished end-diastolic flow, resulting in an elevated umbilical artery PI. As resistance builds, there is absent, and ultimately reversal of, end-diastolic flow. The latter is a poor prognostic factor that increases the risk for intrauterine fetal demise and requires iatrogenic delivery as early as 30 weeks’ gestation, depending on the clinical scenario.

Preterm Delivery

Abnormalities in uteroplacental blood flow may contribute to the pathophysiology of spontaneous preterm birth. There is a higher risk of abnormal placentation, including abnormal transformation of the spiral arteries, in patients with spontaneous preterm birth. The uterine artery Doppler pattern may be abnormal in patients who eventually will deliver preterm. Further work is needed to understand the pathways underlying the abnormal uteroplacental blood flow seen in patients with preterm labor and delivery. Collectively, a common pathway underlying the “Great Obstetric Syndromes” implicates abnormal spiral artery remodeling and consequent abnormal uteroplacental perfusion.

Effects of Labor and Disorders of Labor

Uterine Contractions

The placenta and fetus are located inside a hollow viscus with a muscular wall. Uterine contraction strength, timing, pulsatile nature, and uterine diastolic filling time during active labor markedly affect placental perfusion.

There are similarities between coronary artery blood flow to the subendocardial region of the contracting heart and uterine artery blood flow to the placenta ( Fig. 3.9 ). In both cases, the arterial blood supply comes from the outer surface of a hollow organ and must cross a contracting muscular wall to perfuse a target on the inside of the wall (e.g., the subendocardium in the heart and the intervillous space of the placenta within the uterus). Importantly, perfusion is either completely occluded, as in the heart, or greatly reduced, as in the uteroplacental circulation, during the muscular contraction of systole. Flow only resumes during the muscular relaxation of diastole.

A cross-sectional diagram compares subendocardial and placental perfusion, with areas marking tissue at risk and lines indicating blood supply. — Fig. 3.9

In active labor, a typical uterine contraction (systole) lasts from 40 to 60 seconds, and uterine relaxation (diastole) is typically 2 to 5 minutes in duration. Most fetuses tolerate the periodic cessation in placental perfusion during contraction; however, fetuses with underlying placental insufficiency may not tolerate labor. Excessive uterine contractions may be associated with oxytocin administration and may cause tachysystole with more than 5 contractions in 10 minutes or uterine tetany with a sustained contraction. There is a substantial reduction in uterine diastolic filling time with each condition. Even normal fetuses, with normal baseline placental function and perfusion, may suffer hypoxia from acute hypoperfusion. The risk of prolonged uterine contractions with short uteroplacental diastolic filling time is increased in cases of obstructed labor. A consequence of placental hypoperfusion with resulting hypoxia is fetal autonomic stimulation, which may result in fetal heart rate (FHR) decelerations or fetal bradycardia during or shortly after uterine contractions. Intrauterine resuscitative measures include reducing uterine tone, either by stopping oxytocin infusion and/or administering tocolytic medication (see Chapter 8 ).

Umbilical Cord Prolapse

Prolapse of the umbilical cord in labor may cause fetal hypoxia via cord occlusion and vasospasm and is an obstetric emergency requiring expedited delivery (see Chapter 8 ).

Antepartum Hemorrhage

Antepartum hemorrhage has many causes and may compromise blood flow and oxygen delivery to the fetus (see Chapter 37 ).

Dystocia and Oxytocin Augmentation

Uterine tachysystole caused by oxytocin labor augmentation may acutely reduce placental perfusion. Evidence from monkeys, dogs, rabbits, and humans suggests that oxytocin-induced contractions cause a greater reduction in placental blood flow than spontaneous contractions. Recovery of blood flow after uterine relaxation is slower in augmented versus spontaneous contractions.

Poor Placentation and Fetal Intolerance to Labor

Placental dysfunction, manifesting as FGR or preeclampsia, is associated with an increased risk of fetal intolerance to labor. A chronically hypoxic fetus poorly tolerates the superimposed hypoxia caused by uterine contractions, predisposing to fetal hypoxia and acidosis. The fetus may manifest an abnormal FHR tracing, which is associated with a loss of end-diastolic flow in the umbilical artery.

Fetal Consequences of Inadequate Uteroplacental Blood Flow

Inadequate uteroplacental blood flow, whether acute and prolonged or chronic and persistent, can result in fetal acidosis, asphyxia, hypoxic-ischemic encephalopathy, and fetal death. The FHR tracing may show decelerations, loss of normal variability, bradycardia, or a combination of these abnormalities. The risk for fetal acidosis increases with the increasing deceleration area from baseline FHR, regardless of the shape of the decelerations. There are three gradations in the hypoxic process: hypoxemia, hypoxia, and asphyxia. Of interest, studies in monkeys have shown that hypoxic-ischemic encephalopathy evolves if cord occlusion persists for 15 to 18 minutes. Notably, normal outcomes in human fetuses have been reported after even 25 minutes of acute bradycardia, while some neonates had neurologic findings after as little as 10 minutes of acute bradycardia.

A common misconception is that most cases of cerebral palsy result from inadequate intrapartum uteroplacental blood flow. In actuality, 90% of cerebral palsy cases cannot be linked to intrapartum hypoxia (see Chapter 10 ).

Chronic Fetal Hypoperfusion and Diseases Presenting in Adult Life

Chronic placental hypoperfusion can affect the future health of both the mother and child. For example, evidence suggests that women with preeclampsia have a higher risk for developing cardiovascular disease and possibly breast or ovarian cancer in later life. Furthermore, the fetus has a higher lifetime risk of death from cardiovascular disease, metabolic syndrome, type 2 diabetes, and breast cancer. The concept of developmental origins of health and disease holds that an adverse intrauterine environment (e.g., impaired placental perfusion or dysfunction) can induce altered fetal and/or maternal phenotypes via placental epigenetic and nutrient transport abnormalities.

Effects of Anesthesia and Analgesia on Uteroplacental Blood Flow

Anesthesia and analgesia can have direct and indirect effects on the fetus. General anesthesia may exert a direct effect (resulting in transient neonatal respiratory depression), whereas neuraxial analgesia and anesthesia exert predominantly indirect effects, of which the most important is alteration of uteroplacental blood flow. Nonanesthesia interventions that may impact the fetus via changes in uteroplacental blood flow include maternal supine posture, supplemental oxygen, and a prolonged uterine incision–delivery interval (see Chapter 26 ).

General Anesthesia

Direct Effects of General Anesthetic Drugs

Available data suggest that commonly used induction agents have minimal or no direct adverse effect on uteroplacental blood flow. Allen et al. found that thiopental (thiopentone) inhibited the response of human myometrial arteries to contractile agents in vitro but had no effect on relaxation induced by prostacyclin. Alon et al. reported that uterine blood flow did not change significantly during induction and maintenance of propofol anesthesia in pregnant sheep. Craft et al. reported that uterine tone increased but uterine blood flow remained constant after an intravenous bolus of ketamine in pregnant sheep. Similarly, Strümper et al. reported that neither racemic nor S ⁺-ketamine affected uterine perfusion in pregnant sheep. Few data are available on the direct effects of etomidate on uteroplacental blood flow. Collectively, these data show relative safety, yet caution is warranted as many of the studies were conducted in sheep.

Indirect Effects of General Anesthetic Agents

During intravenous induction, uteroplacental perfusion may be affected by indirect mechanisms, such as the sympathetic response to laryngoscopy and tracheal intubation. Jouppila et al. reported that intervillous blood flow decreased by 22% to 50% during the induction of anesthesia with thiopental 4 mg/kg, succinylcholine 1 mg/kg, and tracheal intubation. Gin et al. compared thiopental 4 mg/kg and propofol 2 mg/kg in patients undergoing elective cesarean delivery and found that venous plasma concentrations of epinephrine and norepinephrine increased after tracheal intubation in both groups, but the maximum norepinephrine concentration was lower in the propofol group. No differences in neonatal outcomes were observed. Levinson et al. found that intravenous ketamine increased blood pressure with a concomitant rise in uterine blood flow in pregnant sheep. The addition of a rapid-acting opioid (e.g., alfentanil , remifentanil ) may minimize the increase in circulating catecholamines.

Studies in pregnant sheep have shown that usual clinical doses (i.e., 0.5 to 1.5 minimum alveolar concentration [MAC]) of volatile anesthetic agents, including isoflurane , desflurane , and sevoflurane ) have little or no effect on uterine blood flow, although deeper planes of anesthesia are associated with reductions in maternal cardiac output, blood pressure, and uterine blood flow. Nonetheless, high concentrations (approximately 2 MAC) of inhalational anesthetic agents have been used during ex utero intrapartum treatment procedures without evidence of impaired fetal gas exchange. A dose-dependent reduction in uterine tone caused by inhalational anesthetic agents would be expected to increase uterine blood flow in clinical circumstances in which tone is increased (e.g., hyperstimulation with oxytocin, cocaine overdose, placental abruption). Overall, there is little reason to choose a particular inhalational agent on the basis of uterine blood flow effects.

Vasoactive drugs have little direct effect on spiral artery tone owing to the trophoblast remodeling of the vessel walls in normal pregnancy. However, placental blood flow depends on maternal cardiac output, which is reduced by most anesthetic drugs, with the exceptions of ketamine and etomidate . The impact of anesthetic drugs may be augmented in the presence of maternal dehydration, obstetric hemorrhage, or conversion to general anesthesia from neuraxial anesthesia. The unresponsiveness of remodeled spiral arteries allows the use of vasoactive drugs to enhance maternal cardiac output without influencing placental blood flow directly, with some drugs shunting blood toward the uteroplacental circulation, as competing vascular beds vasoconstrict.

Effects of Ventilation

Conflicting experimental data exist in animals regarding the effects of maternal hypercapnia on uteroplacental blood flow, ranging from hypoperfusion or no change in pregnant sheep to hyperperfusion in pregnant pigs. BOLD MRI functional studies in pregnant rats showed that maternal exposure to 5% inspired CO ₂ and 20% F io ₂ elicited an 80% reduction in placental perfusion. With fetal asphyxia, functional MRI and Doppler ultrasound studies have demonstrated an increased perfusion index and fetal bradycardia in pregnant rats. Hypercapnia induced direct vasodilation in the cerebral circulation in pregnant rats, with the predominant hemodynamic effect due to an increase in sympathetic tone and levels of circulating catecholamines, epinephrine and norepinephrine.

The effect of hypocapnia on uteroplacental blood flow is controversial. Some investigators have noted that hyperventilation with hypocapnia causes fetal hypoxia and metabolic acidosis in animals, whereas others have found no effect. Levinson et al. observed that positive pressure ventilation decreased uterine blood flow in pregnant sheep; however, because the addition of inhaled carbon dioxide did not improve uterine blood flow, the reduction in blood flow was attributed to the effects of mechanical hyperventilation.

Positive pressure ventilation can reduce venous return and cardiac output, particularly at high ventilatory pressures and in the presence of high levels of positive end-expiratory pressure. In pregnancy, this may be more marked for several reasons: (1) ventilation potentiates the hemodynamic compromise resulting from aortocaval compression, particularly in the hypovolemic parturient; and (2) respiratory compliance is reduced owing to raised intraabdominal pressure from the gravid uterus.

Neuraxial Anesthesia and Analgesia

Direct Effects of Neuraxial Anesthesia and Analgesia

Studies using Doppler ultrasound measurements, among other techniques, have shown that epidural and spinal analgesia do not normally have a significant direct affect on uteroplacental blood flow or fetal oxygenation.

Indirect Effects of Neuraxial Anesthesia and Analgesia

Uteroplacental blood flow may decrease after neuraxial anesthesia because of (1) maternal hypotension, (2) effects of vasopressors, or (3) decreased uteroplacental blood flow from anesthesia-related increases in uterine tone.

Maternal hypotension and vasopressors

Neuraxial anesthesia causes dose-dependent sympathectomy and vasodilation. In the absence of hypotension or reduced cardiac output, the effect on uteroplacental blood flow is minimal. However, the extensive neural blockade required for cesarean delivery may cause marked hypotension, which may be exacerbated by aortocaval compression and hypovolemia (see Chapter 26 ).

Limited data are available assessing vasopressors in the presence of fetal compromise or placental insufficiency. Erkinaro et al. developed a sheep model to compare the effects of phenylephrine and ephedrine after a period of experimental fetal hypoxia. Hypotension was induced by epidural anesthesia and then corrected with either phenylephrine or ephedrine. In an initial study, ephedrine was associated with better restoration of uterine artery blood flow, but with no differences in fetal acid-base measurements or lactate concentration. However, in a second study in which the placenta was embolized with microspheres to model placental insufficiency, phenylephrine and ephedrine had similar effects on uterine blood flow, fetal pH, and base excess, as found in the initial study, but fetal lactate concentration was greater in the phenylephrine group. Although the investigators speculated that this might reflect impaired fetal clearance of lactate, the placental embolization may have narrowed the margin of safety for uteroplacental blood flow and increased fetal lactate production in the phenylephrine group.

In two studies, women with preeclampsia undergoing cesarean delivery with spinal anesthesia were randomized to receive phenylephrine or ephedrine for the prevention or treatment of spinal anesthesia–induced hypotension. Neither study identified differences between the two drugs in the acid-base status of the neonates, suggesting that either drug is appropriate for use in women with preeclampsia with potentially compromised uteroplacental circulation.

Ephedrine and phenylephrine both continue to be used clinically for maintaining maternal blood pressure during the administration of neuraxial anesthesia (see Chapter 26 ). Although most early experimental data in animals suggested that uteroplacental perfusion is better maintained with ephedrine than with alpha-adrenergic agonists, the applicability of those results to human pregnancy is unclear. Further, placental transfer of ephedrine may increase fetal myocardial oxygen consumption, increase fetal basal metabolic rate, and cause mild fetal metabolic acidosis, although the clinical significance of this is unclear.

Pregnancy is associated with a reduced response to endogenous and exogenous vasoconstrictors, including angiotensin II, endothelin, thromboxane, epinephrine, norepinephrine, phenylephrine, serotonin, and arginine vasopressin. The relative refractoriness of the systemic and uterine circulations varies for different agents.

Concentrations of angiotensin II in maternal blood are increased twofold to threefold ; however, the vasopressor response to angiotensin II is attenuated. This refractoriness is diminished in patients in whom preeclampsia develops. The uterine circulation is less responsive to angiotensin II than the systemic circulation. Thus, the infusion of physiologic doses of angiotensin II has minimal effects on uteroplacental blood flow, while increasing systemic blood pressure. The difference in sensitivity of the uterine and systemic circulations to angiotensin II is an important physiologic adaptation during pregnancy. This response contributes to the redistribution of cardiac output, the increase in uterine blood flow, and possibly the maintenance of uterine blood flow during normal fluctuations in blood pressure.

Sensitivity to vasoconstrictors, such as epinephrine , norepinephrine , and phenylephrine , is attenuated during pregnancy. Larger doses of vasoconstrictors are typically required to maintain blood pressure during spinal anesthesia for cesarean delivery. In contrast to the responses to angiotensin II, the uterine circulation is more responsive to the above agents compared with the response of the systemic circulation. Importantly, during hemorrhage or other major stressors that result in large catecholamine release, uteroplacental perfusion is unlikely to be preferentially preserved above essential maternal perfusion.

The mechanism underlying the difference in vascular sensitivity between the uterine and systemic circulations is unclear, but the distribution of receptor subtypes is believed to be important. For example, there are two distinct subtypes of angiotensin II receptors: AT1R and AT2R. In most tissues, including systemic vascular smooth muscle, AT1R receptors are predominant and mediate vasoconstriction. However, AT2R receptors, which do not mediate smooth muscle contraction, account for 75% to 90% of angiotensin II binding in uterine artery and myometrium.

Effects of anesthesia-related increases in uterine tone

Catecholamine levels increase during labor. Epinephrine antagonizes the uterotonic effect of endogenous and exogenous oxytocin via direct tocolytic effects. Effective pain relief from neuraxial analgesia decreases circulating catecholamine levels, which may result in stronger, more frequent, or sustained contractions; this may reduce uteroplacental blood flow and predispose to fetal bradycardia (see Chapter 24 ).

Beneficial Effects of Neuraxial Analgesia and Anesthesia

Neuraxial analgesia has been used to improve fetal well-being in preeclampsia and FGR. With preeclampsia, the trophoblast invasion of the uterine decidua is impaired, causing spiral arteries to retain their nonpregnant smooth muscle, which makes them susceptible to vasoconstriction. Clinical studies have observed that sympathetic deafferentation induced by neuraxial anesthesia improved uteroplacental blood flow in women with preeclampsia. In patients with preeclampsia and FGR, epidural ropivacaine caused a dose-dependent improvement in uterine artery blood flow, which was reversed by saline placebo. Women with preeclampsia remote from term, who were treated with continuous antepartum epidural analgesia therapy, had longer enrollment-delivery intervals, some evidence of increased fetal growth, and reduced severity of preeclampsia, with less hypertension and a higher platelet count. Although these studies were small, nonrandomized, and unblinded or partially blinded, the observed benefit of epidural analgesia is likely more than a consequence of vasodilation. Whereas systemic vasodilators (e.g., nifedipine ) do not reliably improve placental blood flow, probably because of simultaneous vasodilation of the uteroplacental vessels and competing vascular beds, neuraxial analgesia and anesthesia induce segmental vasodilation, reflex vasoconstriction in unanesthetized regions, and redistribution of cardiac output toward vascular beds with sympathetic blockade, including the uteroplacental circulation.

Neuraxial Anesthesia for Cesarean Delivery

Elective cesarean delivery

With appropriate management of hemodynamic changes, neuraxial anesthesia has minimal impact on placental perfusion and fetal oxygenation during elective cesarean delivery. However, severe hypotension may decrease uteroplacental blood flow via reduction in perfusion pressure, reflex release of endogenous vasoconstrictors, diversion of blood to the lower limbs, and response to vasopressors. The rapid and extensive sympathetic blockade during spinal anesthesia, and some methods used to treat hypotension, may account for the observation that umbilical arterial blood pH is lower with spinal anesthesia than with epidural or general anesthesia for cesarean delivery.

Studies of the effect of bolus intravenous fluid administration have had mixed results. Most Doppler studies have shown that fluid preload before the initiation of neuraxial analgesia does not change vascular resistance indices, although a decrease has been reported.

Emergency cesarean delivery

For emergency cesarean delivery, in situations involving alteration in uterine activity, hemorrhage, or preeclampsia, the effects of epidural and spinal anesthesia on uteroplacental blood flow are of particular concern. Studies have reported conflicting results. In the setting of severe maternal hypotension, compromised uterine perfusion, or prior or partial anesthesia administration, neuraxial techniques may result in decreased uteroplacental blood flow; prompt interventions, such as administration of fluids, vasopressors, or blood, can help mitigate these effects.

Effects of Nonanesthetic Agents

Alpha- and Beta-Adrenergic Receptor Antagonists

In patients with chronic or gestational hypertension, the effects of antihypertensive drugs on uteroplacental perfusion depend on the interaction of their effects on uterine vascular resistance and systemic blood pressure. Although studies of the response of uteroplacental blood flow to labetalol have had varying results in different animal species, showing an increase, a decrease, and no change, studies in humans have generally demonstrated no significant change. Studies of methyldopa in patients with preeclampsia have found either a reduction or no change in indices of uterine and placental vascular resistance. A multicenter trial showed that treating chronic hypertension with a blood pressure goal of less than 140/90 mm Hg was associated with improved maternal outcomes and no increased risk for small-for-gestational-age neonates. This suggests that antihypertensive agents can effectively reduce maternal blood pressure with minimal impact on placental perfusion.

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