Classically, the American College of Obstetrics and Gynecology (ACOG) defines preeclampsia as the presence of hypertension and proteinuria occurring after 20 weeks of gestation in a previously normotensive patient. However, pregnant women frequently also show other biochemical changes, leading up to the development of proteinuria, such as low platelets and/or elevated liver enzymes.
Preeclampsia is a common pregnancy disease, since between 6% and 10% of all pregnancies develop this complication(1,2). This highly variable disorder represents a leading cause of maternal and fetal morbidity and mortality(3-10). The high mortality is also caused by the need for premature delivery in many cases, especially in those where preeclampsia sets in early during the pregnancy.
There are two variants of preeclampsia, depending on the onset of the disease: early-onset preeclampsia (before 34 weeks of gestation) and late-onset preeclampsia (after 34 weeks of gestation). While the first subtype is less common, it has much stronger effects on the pregnant woman and the fetus, and it also has a much higher risk of perinatal and maternal death(11,12).
There are two stages required for the onset of preeclampsia, abnormal placentation in the first trimester, followed by an accumulation of maternal manifestations in the second and third trimesters, based on excess angiogenic factors(12).
The exact pathophysiological mechanism leading to the development of preeclampsia remains controversial and unclear. However, the main common belief is that uteroplacental ischemia, due to oxidative stress, abnormal natural killer cells and transformation of the spiral arteries, drives the hypertensive, multiorgan failure response(13,14). This endometrial dysfunction and inflammation lead to hypoperfusion of the fetoplacental unit.
Another possibility is the alteration of both innate and adaptive immune processes due to a genetic predisposition to preeclampsia. The polymorphism of genes encoding inflammatory factors, activated by placental insufficiency or hypoxia, may explain the aberrant immune response specific to this pathology(15).
Nevertheless, it is unanimously accepted that preeclampsia consists in a status of imbalance between circulating angiogenic and antiangiogenic factors. Preeclampsia is characterized by decreased concentrations of the proangiogenic vascular endothelial growth factor and placental growth factor and increased concentrations of antiangiogenic proteins such as soluble fms-like tyrosine kinase-1 and soluble endoglin(16,17).
The diagnosis of preeclampsia is generally made after 20 weeks, being classified as mild, moderate or severe preeclampsia(18).
Mild preeclampsia involves an elevated blood pressure less than 160 mmHg (systolic) and/or 120 mmHg (diastolic) and proteinuria with higher values than 300 mg, but less than 5 g per day.
Severe preeclampsia is characterized by an elevated blood pressure higher than 160 mmHg (systolic) and/or 110 mmHg (diastolic) and proteinuria equal or higher than 5 grams per day(19). Severe preeclampsia is sometimes associated with thrombocytopenia (less than 100,000/uL), oliguria (less than 500 mL per day) or with pulmonary edema.
The only effective cure for preeclampsia is delivery, and until delivery the main important target is to control the blood pressure. Although it does not cure the pathology, blood pressure control leads to a decrease in the risk of associated maternal cerebrovascular events and to an extension of the gestation period as close as possible to the term.
However, the administration of antihypertensives is often delayed due to their well-known effect of decreasing uteroplacental irrigation, leading to intrauterine growth restriction or fetal bradycardia(20).
Antihypertensives such as methyldopa, labetalol or nifedipine are most commonly used. Each antihypertensive drug comes with its own pregnancy-associated risks(21,22).
For example, atenolol has been associated with fetal growth restriction, while labetalol is associated with neonatal hypoglycemia and bradycardia(23).
Nifedipine and methyldopa are considered the safest antihypertensives for use during pregnancy.
5. Effects of preeclampsia on newborn
5.1. Fetal growth restriction
Preeclampsia, characterized by decreased uteroplacental blood flow and ischemia, is the most common cause of intrauterine growth restriction. Severe preeclampsia is a well-known factor associated with reduced birth size, while mild preeclampsia is less frequently associated with this condition(24,25).
It is well known how the circulation responds to hypoxia, by centralizing the circulation to protect the noble tissues (“brain sparing”). The fetal circulation performs the same process and, thus, during control ultrasounds, a cranial circumference can be observed which increases accordingly, while in the case of femoral length or abdominal circumference, a stagnation of the parameters is noted, due to the existing vasoconstriction at that level.
When preeclampsia develops early, by considering fetal biometrics and gestational age, the woman’s counselor must be realistic, in accordance with the chances of survival of the fetus. Thus, if in the case of a pregnancy under 24 weeks, with an estimated fetal weight less than 500 grams, diagnosed with preeclampsia and requiring delivery, the prognosis of the newborn is unfavorable.
In addition to biometrics, the Doppler velocimetry of three fetal vessels – middle cerebral and umbilical arteries and ductus venosus – is also recommended in order to provide information on the downstream peripheral vascular impedance of the placenta. It has been shown that absent or reversed end-diastolic flow in the umbilical artery is correlated with poor perinatal outcomes(26).
When brain sparing is present, a reduction in cerebral flow resistance can be observed, which can be characterized as a decrease in the Doppler indices of the middle cerebral arteries. The normalization of these parameters occurs in severe and terminal cases of fetal growth restriction.
Fetal growth restriction is common especially in early-onset preeclampsia. The associated risk of intrauterine death is 15 times higher(27), in direct correlation with the severity of the Doppler velocimetry abnormalities(28) and independent of the gestational age(29).
Guidelines suggest that fetuses with late-preterm intrauterine growth restriction should be delivered when there is any evidence of maternal hypertension(30).
5.2. Bronchopulmonary dysplasia (BPD)
There are several hypotheses for preeclampsia being a risk factor for BPD. Preeclampsia is also a predisposing condition for a restriction in fetal angiogenesis, due to the reduced blood flow to the fetoplacental level, through hypoxia and ischemia(31).
The “vascular hypothesis of BPD” suggests that preeclampsia can alter critical lung-vessel interactions necessary for normal lung development, even after adjusting for birth weight and gestational age(32-34). This is due to an imbalance between pro- and antiangiogenic factors that could also impair the vascular and alveolar development of the fetal lungs(35-40).
Since delivery is the only effective treatment, preeclampsia often leads to small for gestational age and premature birth.
As with intrauterine growth restriction, cases of BPD have generally been reported in severe preeclampsia and in newborns less than 28 weeks of age(41).
5.3. Hematological effects
The proinflammatory immune state can disrupt fetal hematopoiesis, so that the hematological profile of the newborn can be badly altered. Neonatal thrombocytopenia, with a platelet count less than 150,000/uL, neutropenia, reduction in T regulatory cells and an increased cytotoxic natural killer profile were all observed in neonates born from pregnant women with preeclampsia.
Thrombocytopenia is usually identified at birth or in the first third days after delivery, in most cases with rapid resolution of no more than two weeks(42). Rarely, neonates develop severe or clinically significant thrombocytopenia (<50,000/uL)(43,44). Unfortunately, the pathophysiological process through which they develop thrombocytopenia is still unknown(45). The only mechanism indicated so far is that fetal hypoxia is a depressant status for megakaryocyte proliferation(46). These newborns have been shown to have significant megakaryocytopoiesis defects without any evidence of increased platelet destruction, thus supporting this hypothesis(47).
The incidence of neutropenia (neutrophil count less than 500) is 50% in neonates delivered to women with preeclampsia and it is usually associated with reduced numbers of circulating colony-forming unit-granulocyte macrophage (CFU-GM)(48,49). The fetal bone marrow production of the myeloid lineage is inhibited by uteroplacental insufficiency(50).
This is why an early neonatal hematological screening should be performed in these cases, in order to decrease mortality and improve the growth and development of the baby.
5.4. Neurodevelopmental spectrum diseases
Children exposed to preeclampsia have highly variable neurodevelopmental outcomes. It was shown that maternal preeclampsia has a protective effect on the brain, with a lower risk of cerebral palsy(51).
Lower risk of intraventricular hemorrhage was also suggested among infants born between 26 and 30 weeks from pregnancies diagnosed with preeclampsia(52).
When comparing through three sets of neuropsychomotor development tests – Bayley Scales of Infant Development, second edition (BSDI-II), Mental Developmental Index (MDI) and Psychomotor Developmental Index (PDI) – children of the same age, from normal pregnancies, versus children from mothers with preeclampsia, both groups were shown to have similar neuropsychological and intellectual development at 12 months and at 18 months, with the group undergoing preeclampsia having higher scores, therefore better intellectual development(53).
The early diagnosis and treatment of preeclampsia are a necessity for both the pregnant woman and the newborn. The effects of this condition on the woman are described in detail, while those on the newborn remain in the study stage.
Preeclampsia leads to a much higher risk of death in utero, as well as to the restriction of intrauterine growth, bronchopulmonary dysplasia, thrombocytopenia, or neutropenia. The medium- and long-term consequences on the development of the newborn still remain to be studied, as this specific uteroplacental insufficiency and the hypoxic status in which the conception product develops can have effects not only in the perinatal period, but also repercussions in the adult life.
Conflict of interests: The authors declare no conflict of interests.