Placental Insufficiency

Etiology

The major etiologies that may lead to placental insufficiency are poorly understood and are still being studied. There are known associated maternal risk factors, which include pre-eclampsia or other maternal hypertensive disorders, maternal cigarette use, maternal drug use including cocaine or heroin, maternal alcohol consumption, primiparity, advanced maternal age, and prior history of delivery of IUGR neonate.[2][6] Studies analyzing Doppler waveforms in various placental vessels of mothers who smoked cigarettes during pregnancy demonstrated reductions in the blood flow velocity waveforms, thus indicating that nicotine exposure can lead to altered placental vasculature.[6] Any maternal condition that can lead to a compromise in fetal circulation puts the fetus at risk for placental insufficiency. Certain medications such as antineoplastic, anticonvulsants, or anti-coagulants can also interfere with fetal growth. Extremes of maternal body mass index, including maternal malnutrition, have also been associated with the development of IUGR neonates.[7] Studies of complicated IUGR pregnancies have demonstrated that there was an incomplete transformation of the placental vasculature early in the pregnancies that Doppler ultrasound studies can detect.[5][8]

Epidemiology

Prematurity is the leading cause of perinatal death, followed by intrauterine fetal growth restriction, which complicates approximately 4% to 6% of known pregnancies. Placental insufficiency is a potential cause of preterm labor, pre-eclampsia, IUGR, and stillbirth, which can affect 10 to 15% of pregnancies. For an IUGR fetus, the risk of spontaneous preterm labor is 3-fold greater when compared to a non-growth-restricted fetus, and there is also a 5 to 6 times higher risk for the development of perinatal death.[2] Unfortunately, approximately 50% of newborns with IUGR are only detected following delivery.

Pathophysiology

Although the underlying etiology of placental insufficiency is unknown, there are proposed mechanisms. Placental insufficiency is associated with reduced blood flow across the umbilicus to the fetus, which can be secondary to increased umbilical-placental vascular resistance. This increased resistance can be visualized as abnormal umbilical artery Doppler flow velocity waveforms. It can be secondary to an abnormality of villi insertion into the placental membrane, a perfusion abnormality between the umbilicus and placenta, or a reduction in uteroplacental blood flow.[2] Studies of umbilical artery Doppler have illustrated that the degree of placental injury is directly related to the degree of fetal injury during pregnancy.[9]

The main role of the placenta is to serve as the interface between fetal and maternal circulations. For this to occur, placental adherence and uterine arterial remodeling must be established to ensure nutrients can be delivered to the growing fetus. The hallmark of successful placentation is the remodeling of the uterine arteries. Following fertilization, the blastocyst forms, composed of an inner cell mass that eventually becomes the fetus and an outer shell called the trophoblast that becomes the fetal portion of the placenta. To aid with placental adherence, the cytotrophoblast, which is the inner layer of the trophoblast, secretes matrix metalloproteinases that breakdown the zona pellucida, and adherence is facilitated by the formation of anchoring villi and expression of adhesion molecules.[10] This invasion of the uteroplacental arteries allows for remodeling into dilated, low-resistance, inelastic vessels that lack maternal vasomotor control, leading to increased uteroplacental perfusion such that the requirements of the fetus can be met.[5] Any disturbance in the remodeling process can lead to an increase in uteroplacental vascular resistance, leading to hypoperfusion of the placenta and its downstream effects, including coagulation activation, endothelial cell dysfunction, placental thrombosis, and fibrin deposits, which are associated with the development of IUGR.[5][3] Furthermore, if there is a loss of focal adhesion of the endovascular trophoblasts, a reduction in placental surface area can be seen associated with placental insufficiency. This reduction in the placental surface area, along with an increase in the thickness of the placenta, creates a globular appearance to the placenta, which is postulated to act as a compensatory mechanism for placental insufficiency. 

The intrauterine environment is a low-oxygen environment; as such, fetal circulation needs to be flexible to adapt to any changes that occur with uteroplacental function.[9] This hypoxic environment stimulates angiogenesis, whereby vascular connections are made between the maternal circulation and the intervillous space. Now that a vascular and nutritional support network has been established, the villous trophoblast, which consists of maternal microvilli and a fetal basal layer, is formed.[10] Maintaining placental function requires large amounts of energy, indicated by the fact that in a regular physiologic state, the placenta consumes approximately 70% of the glucose and 40% of the oxygen normally supplied to the uterus. Therefore, to achieve optimal fetal growth and development, nutrient delivery to the uterus must exceed the placental demand such that there are residual nutrients for fetal utilization.[10] Therefore, any compromise of nutrient delivery to the uterus impacts nutrient delivery to the fetus. 

Lateralization can negatively affect successful placentation when the placental invasion favors 1 side, and the placenta is not implanted centrally. If the placenta remains asymmetric until term, Doppler ultrasound demonstrates persistent notching on the non-implanted side, leading to a relative placental insufficiency. Placental lateralization has also been associated with increased risk for the development of maternal pre-eclampsia and, thus, downstream placental insufficiency.[9][11]

History and Physical

As IUGR is 1 of the primary outcomes associated with placental insufficiency, most neonates that survive present either prematurely and are known as extremely low birth weight neonates or depending on when the insult to the vascular supply occurred, they may present with altered body proportions at birth.[10] If there is a failure of placentation, downstream effects such as IUGR are clinically evident in Doppler studies at approximately 26 weeks gestation.[9]

When there is a concern for IUGR, whether secondary to placental insufficiency or another etiology, the fetus benefits from frequent combined monitoring using Doppler and biophysical profile screens. This combination of screening techniques allows for recognizing the declining performance observed when IUGR is related to placental problems. Utilizing Doppler studies, failed placentation can be visualized by presenting notching in the uterine arteries and increased resistance in the umbilical artery with progression to either absent or reversed end-diastolic volumes. Non-reactive fetal heart rate tracing is 1 of the first signs seen on a biophysical profile when there is a concern for fetal compromise. The following may be seen: poor or loss of fetal body movements, breathing, and tone. These features of declining Doppler status and poor biophysical profiles are typical when there is fetal distress, which is common when there is placental insufficiency and may indicate that delivery is required.

Evaluation

Currently, the criteria to diagnose placental insufficiency are lacking as there are also no standardized methods for diagnosis. Part of the problem is due to the wide variety of terminology used to describe what is known as placental insufficiency.[1] However, as technology has improved, Doppler ultrasound has proven to be useful for evaluating fetal and placental circulations in both healthy and diseased states. Four Doppler techniques are fundamental in providing useful information regarding fetal-maternal circulation, including umbilical artery studies, uterine artery studies, middle cerebral artery studies, and ductus venosus studies.[9] As a fetus matures during gestation towards term, many circulatory changes occur that can be evaluated by Doppler ultrasound. 

Before the onset of pregnancy, uterine arteries show low diastolic flow, high resistance, and elastic recoil noted in early diastolic notches. Successful placentation involves removing the intimal muscle from the vasculature so that the blood vessels have a vigorous diastolic flow, minimal resistance, and no elastic properties. When placentation is successful, Doppler ultrasound demonstrates that the remodeling occurs rapidly, such that by 12 weeks gestation, there is a loss of notching. Resistance is low by 20 weeks gestation or earlier. When there is a failure of placentation, notching persists, and resistance remains high, which is correlated with maternal-hypertensive-related fetal complications, including IUGR, pre-eclampsia, and fetal demise.[9] Using the uterine artery for Doppler screening to evaluate for notching and resistance to help identify these high-risk situations is approximately 85% sensitive for detecting severe IUGR and pre-eclampsia. 

As resistance in the placenta increases, Doppler studies of the umbilical artery can demonstrate normal, reduced, absent, or reversed end-diastolic velocities.[12][8] It is normal for placental resistance to be high in the early stages of pregnancy. Therefore, it can be expected that end-diastolic velocity is absent in Doppler studies up to 12 to 14 weeks of gestation. When the placental successfully invades, resistance drops and Doppler studies of the umbilical artery should demonstrate continuous flow by 14 to 18 weeks of gestation.[9] Persistent umbilical artery resistance throughout pregnancy indicates an increased risk of placental insufficiency.

While umbilical artery Doppler studies provide important information about possible placental compromise, a valuable adjunct is using the middle cerebral artery (MCA) Doppler. The MCA provides information regarding systemic circulatory responses in the developing fetus, representing downstream resistance in the cerebral microcirculation. The normal MCA Doppler displays high resistance throughout pregnancy; however, the placental disease can be identified with increased diastolic flow and a declining pulsatility index. Therefore, MCA Doppler studies can provide important additional information when there is a concern for severe IUGR, indicating that there may be fetal compromise and intervention may be required. 

Another form of Doppler that provides insight into placental and fetal health is the venous Doppler, which relays information about cardiac data when the fetal circulation is experiencing stress. The venous waveform shown to provide the best clinical data is the ductus venosus. There are many benefits of using the ductus venosus over other venous waveforms, which include its responsiveness to oxygenation changes, it is 1 of the primary regulators of venous return in abnormal and normal fetal circulations, it is independent of cardiac function, it serves as a direct conduit to view right atrial retrograde pulse waves, and lastly, because it has elevated and focal velocity color Doppler signal from as early as 12 weeks gestation up to 40 weeks gestation, it is very easily imaged.[9] Suppose an abnormal ductus venosus or retrograde atrial wave is visualized on Doppler at around 12 to 14 weeks gestation. In that case, there is an increased risk for fetal cardiac abnormalities, and it also serves as a possible precursor indicating severe placental-based IUGR. 

MRI imaging has been found to provide additional information to detect and diagnose placental insufficiency. Flow voids occur when there is a loss of MRI signal observed in a blood vessel where blood flows vigorously. When using T2-weighted Rapid Acquisition with Relaxation Enhancement imaging, placental insufficiency can be detected when decreased flow voids are observed between the placenta and the uterus, as this can be considered to reflect a reduction in uteroplacental perfusion.[5] An additional advantage of MRI imaging is that it provides high soft-tissue contrast. Therefore, placental vascular abnormalities, including hemorrhages and infarctions, can be detected on placental MRI, indicating a high risk for placental insufficiency and downstream IUGR.

Treatment / Management

Currently, there is no known treatment for placental insufficiency other than delivering the fetus if it is at a viable time point. Low-dose aspirin and antioxidant therapies, including vitamins C and E, have been shown to promote improved placentation in cases of uncertainty for successful placentation.[9] Studies have demonstrated that there is an approximate 38% reduction in perinatal mortality when early Doppler ultrasound is used for cases of suspected IUGR during pregnancy.[12][13] High-risk women, such as those with chronic hypertension, coagulopathies, or a history of pre-eclampsia, can benefit from having Doppler ultrasound screening at 12 to 14 weeks gestation because if bilateral notching is evident, then low-dose aspirin therapy should be initiated.(A1)

In vitro studies have demonstrated that heparin can stimulate neo-angiogenesis and improve placental perfusion. Heparin’s anticoagulant properties are exhibited by its ability to mobilize tissue inhibition factor into circulation and by its ability to enhance antithrombin activity. Additional benefits of heparin when considering placental insufficiency and its downstream consequences are that it promotes trophoblastic proliferation, reduces inflammation by downregulating the complement cascade, reduces apoptosis, and acts indirectly as a growth factor.[3] Heparin has also been shown to upregulate certain proteins involved in placental angiogenesis and development. These include angiopoietin-2, which is responsible for chorionic villi vascular remodeling; leptin, which is responsible for the regulation of nutrient transfer; and vascular endothelial growth factor receptor-3, tissue inhibitor matrix metalloprotease-1, tumor necrosis factor-alpha, and angiostatin. Based on its properties and preliminary data, some studies have demonstrated that heparin may play a role as a preventive treatment for placental disease.(A1)

Differential Diagnosis

Many factors can contribute to placental insufficiency, and it is known that IUGR is a major downstream complication; however, it can be difficult at times to differentiate a small-for-gestational-age (SGA) neonate from an IUGR neonate. One of the major benefits of Doppler studies, especially of the umbilical artery, is that abnormal umbilical artery Dopplers can be used to differentiate between pathologic IUGR and a small-for-gestational-age neonate, thus guiding which pregnancy would require high-level surveillance versus routine monitoring.[9][14] When the mean estimated fetal weight is below the 10th percentile for a specific gestational age, the fetus is SGA. Conversely, an IUGR fetus may not be able to achieve normal growth, usually secondary to placental insufficiency, a genetic disorder, or infection.[14] Therefore, an SGA neonate is physically small but healthy versus an IUGR neonate, who may also be physically small but may have compromised health. In considering differential diagnoses that contribute to placental insufficiency, there are known associated diseases, including but not limited to preeclampsia and maternal hypertensive disorders, as these both interfere with placental resistance and uteroplacental blood flow. Other illnesses to consider include oligohydramnios and maternal malnutrition or calorie restriction.

Prognosis

Suppose a neonate suffers from IUGR as a consequence of placental insufficiency and survives the perinatal period. In that case, they are at higher risk compared to a non-growth-restricted neonate for developing cognitive deficits in childhood, including cerebral palsy and seizure disorders. Patients with placental insufficiency often have abnormal umbilical artery Doppler flow velocity waveforms (DFVWs). When 1 study compared DFVWs of infants who experienced placental insufficiency in-utero versus those who did not, they found that the infants who had had abnormal DFVWs also had lower IQs when they were 5 years old. There is also evidence that suffering from IUGR as an infant predisposes to chronic illness as an adult, including increased risk for developing coronary artery disease, hypertension, and diabetes.[2] To lead to a better prognosis for the neonate, the priority should be to focus on interventions that allow for maximizing gestational age at birth. It is estimated that for each week pregnancy is prolonged for fetuses between 24- and 28 weeks gestation, survival without associated sequelae is increased by approximately 10% to 15%.[3]

Complications

The downstream effects of placental insufficiency on the developing fetus are complex and multifactorial; however, the major effects tend to be placental respiratory failure and fetal hypoxemia, both of which contribute to IUGR and its associated effects, including prematurity.[10][14] The most detrimental complication is a complete lack of placentation and, thus, miscarriage. For the developing fetus, the degree of umbilical artery abnormalities seen on Doppler is correlated with acidosis, resuscitation requirements, pressor support, ventilatory support, as well as multisystem organ failure, which tends to occur when there is hypoxemia as this triggers a redistribution of blood flow in the developing fetus to essential organs such the as the brain and heart at the expense of other pertinent organs, such as the bowels and kidneys.[14] Furthermore, when Doppler studies demonstrate absent or reversed end-diastolic flow, the neonate has an increased frequency of intraventricular hemorrhage.[9] With increasing placental resistance during pregnancy, the already IUGR fetus is at further risk for hypoglycemia, hypoxic-ischemic encephalopathy, thrombocytopenia, leukopenia, and anemia.[8] Furthermore, there is evidence indicating that infants are at risk for developing cognitive deficits in childhood and later developing chronic illness as an adult.