Introduction

The placenta is the medium through which material passes from the maternal circulation to the fetal circulation by passive diffusion or active transport.[1]

Development

After fertilization of the sperm and ovum, four cell division leads to a morula (16 cells). Around the fourth day after fertilization, the morula enters the uterus as a blastocyst. The blastocyst divides into trophoblast and embryoblast. About 6 to 7 days later, the differentiating blastocyst implants into the uterine decidua. Then, the trophoblast further divides into the syncytiotrophoblast and cytotrophoblast; together, these compose the fetal component of the placenta. These two cell types lay on either side of villi. The cytotrophoblast resides on the inner layer of the chorionic villi. Syncytiotrophoblasts are multinucleated cells that are located on the outer layer of the chorionic villi. In between the syncytiotrophoblast layer, lacunae form to serve as a direct connection to the maternal blood. The remaining cells surrounding the lacunae, called trabeculae, penetrate deep into the uterine wall and, later, develop into the villous trees of the placenta. The maternal blood supply lies in the decidua basalis of the endometrium, which constitutes the maternal component of the placenta.

As the pregnancy progresses, the villous cytotrophoblast slowly disappears from the chorionic villi. Additionally, the villi structure develops to reduce the distance between the maternal blood and fetal vessels — this change benefits maternal-fetal-exchanges. By the end of a pregnancy, five types of villi comprise the placenta: mesenchymal villi, immature intermediate villi, stem villi, mature intermediate villi, and terminal villi. From the mesenchymal villi and immature intermediate villi, about three to five mature intermediate villi grow from the stem villous, and ten to twelve branches of the terminal villi grow from the mature intermediate villi. These villi help communication between the chorionic plate and decidua. Most of the villi float freely in the intervillous space while other villi attach to the decidua as structural stability for the placenta.

• Mesenchymal villi play a significant role early in the first trimester as the most primitive type of villi. The villi are mostly filled with mesenchymal cells and with poorly developed villi. Mesenchymal cells will later differentiate into a variety of other cells including the following: endothelial cells, blood cells, macrophages, myofibroblasts, smooth muscle cells, and fibroblasts.
• Immature intermediate villi are prevalent in the mid-first trimester. These reticular structures contain fluid as well as macrophages called Hofbauer cells. Between the stroma, small arterioles and venules start to develop.
• Stem villi appear condensed with collagen fibers during the mid-first trimester. Additionally, there are few fibroblasts and macrophages as well as muscularized arteries and veins in the villi.
• Mature intermediate villi, in mid-gestation, are bundles of connective tissue with numerous peripheral capillaries as well as some small terminal arterioles and collecting venules.
• Terminal villi mainly function during the late second trimester through the early third trimester. These villi have no stroma and predominantly contain sinusoidal capillaries.[2][3][4][5]

Function

The placenta plays a vital role in maternal-fetal physiology. The placenta has numerous responsibilities:

• Implantation: The syncytiotrophoblast, which later grows as part of the placenta, facilitates implantation by directly invading the wall of the endometrium in the uterus.[1]
• Maternal recognition of pregnancy: Human chorionic gonadotropin (hCG) is synthesized and released from the syncytiotrophoblast to stimulate luteal progesterone production to maintain the pregnancy. Without hCG production, the absence of progesterone would trigger menses and, therefore, the sloughing of the endometrium with the implanted zygote.[6]
• Nutrient and gas exchange: Terminal villi are the functional unit at which maternal-fetal exchange of nutrients and gases occur. Mother's blood provides oxygen, water with electrolytes, hormones, and other nutrients. In exchange, the fetus excretes carbon dioxide, water, urea, hormones, and other waste products. The maternal and fetal circulation do not mix. Instead, blood flow moderates the passive or active transport of nutrients and gases between vasculature.[7][8]
• Fetal protection from any immunologic attack: The placenta holds the ability to metabolize numerous substances and protect against microbial infection. Macrophage in the stroma of the chorionic villi and syncytiotrophoblast play a critical role in the protection of the fetus. Additionally, many leukocytes reside in the decidua of the endometrium to support a successful pregnancy.[9][10]
• Prepare environment: Many hormones are released from the placenta to uphold a pregnancy. The placental growth factor is released from the placenta to prepare the mother’s body for pregnancy in terms of cardiovascular adaption. Additionally, the placental growth factor promotes fetal development and maturity. Human chorionic somatomammotropin (HCS), also known as human placental lactogen (HPL) promotes breast development and alters the metabolism of the mother. It decreases maternal insulin sensitivity so that more glucose is available for the fetus.[1][11]

Abnormalities in the placenta’s function can lead to poor pregnancy outcomes.

Related Testing

The chorionic villus sampling test (CVS) is a diagnostic, ambulatory procedure testing for chromosomal abnormalities. This test is recommended at the time of conception for women above the age of 35 if a parent is a carrier of a genetic disorder, women with abnormal ultrasound results, or women with previous children with chromosome abnormalities. Performance of the test may be transcervically or transabdominally; during the test, a small cell sample is taken from the fetal part of the placenta chorion between the 10th and 13 weeks of pregnancy. The fetus’ chromosomes are karyotyped to diagnose chromosomal abnormalities. There is a risk of miscarriage and, in some literature, limb defects when performing placenta chorion testing before the suggested testing period (before the tenth week). Other complications include vaginal bleeding, infection, rupture of membranes, and fetomaternal hemorrhage. In some cases, results can be inconclusive so that other tests may be necessary. Amniocentesis is an alternative to CVS as both are used to analyze genetic information.[12][13][14]

The combined test is a screening tool used to primarily detect Down syndrome in the first trimester with a low false positive rate. This test is also known to detect trisomy 18 and 13 as well as monosomy X and triploidies at lower accuracy rates. It is comprised of ultrasound to determine nuchal translucency, pregnancy-associated plasma protein-A (PAPP-A) which correlates with aneuploidy, and free beta or total human chorionic gonadotropin (hCG). Ultrasound imaging is performed between 11 and 13 weeks while the collection of serum sample ranges from 9 to 13 weeks. If screening with the combined test suggests chromosomal abnormalities, CVS or amniocentesis should be offered for definitive prenatal diagnosis.[15][16][17]

• Ultrasound is a safe, effective, and easily used imaging study as it functions with no radiation can be used as a diagnostic tool and can be applied bedside. This tool can detect fetal death, diagnose dysmorphologies, and localization of the placenta.[18][19]
• HCG is a hormone synthesized by the syncytiotrophoblast cells in the fetal component of the placenta. The production of hCG in the first trimester is necessary to maintain pregnancy by promoting progesterone secretion by the corpus luteum. hCG levels peak between weeks 8 and 10. After the tenth week, hCG levels plateau and the placenta takes responsibility to produce progesterone. Blood hCG can be detected during the first week after fertilization while at-home urine pregnancy tests can detect hCG two weeks after fertilization. It has several functions including the following: promotion of progesterone production by the corpus luteal cells, angiogenesis in the uterus, growth of uterus and fetus, cell differentiation to increase syncytiotrophoblast cells, suppress immunologic attack by mother on fetus, suppress myometrial contractions during pregnancy, development of umbilical cord, and affects maternal brainstem causing morning sickness.[20][21][22][23]
• PAPP-A is a hormone produced by the fetus and the placenta in pregnancy. This hormone promotes placental growth and function through the facilitation of the insulin-like growth factor (IGF). Therefore, PAPP-A levels increase with time of pregnancy. In some studies, the thickness of placenta also correlates with higher blood levels of PAPP-A. Chromosomal abnormalities, like trisomy 21, are significantly correlated with low blood PAPP-A.[24][25]

Placental growth factor (PIGF) is a potent angiogenic protein factor produced by the syncytiotrophoblast. The purpose of PIGF is to facilitate the development and maturation of the placental vasculature. Low PIGF suggests placental dysfunction associated with pre-eclampsia and intrauterine growth restriction.[26][27]

Human chorionic somatomammotropin (HCS), also known as human placental lactogen (HPL) is produced by the syncytiotrophoblast starting in week 6. HCS functions to promote breast development and decrease maternal insulin sensitivity and increases glucose availability for the fetus. Literature indicates the measurement of HCS is clinically relevant during the third trimester as blood HCS results can predict the outcome by indicating functionality of the placenta and, indirectly, fetal growth.[28][29]

Pathophysiology

Intrauterine growth restriction (IUGR) is a condition in which fetal growth is less than the tenth percentile of the predicted weight for gestational age. IUGR can lead to fetal morbidity and mortality. The restriction of growth can be the result of maternal, fetal, and placental causes. Most fetuses develop IUGR secondary to maternal causes like preeclampsia, poor nutrition, drug addiction, alcohol use, and tobacco use. Retardation occurs symmetrically in all organs with fetal causes like chromosomal abnormalities, congenital malformations, and congenital infections. Additionally, abruptio placentae, placental infarction, and a single umbilical artery (instead of two) cause asymmetric growth retardation, which is also known as “head sparing.” The common factor among these risk factors is that blood flow to the fetus is compromised either through vasoconstriction or loss of blood. Diagnoses of IUGR is difficult in utero. Therefore, the detection of highly associated conditions like unexplained oligohydramnios (about 85% of IUGR infants also have oligohydramnios) should warrant further evaluation. Assessment for IUGR includes doppler sonography as well as analysis of estimated fetal weight, the volume of amniotic fluid, and mother’s blood pressure status.[30][31][32][33][34]

Choriocarcinoma is a germ cell malignant tumor of the cytotrophoblast and syncytiotrophoblast cells. The tumor cells mimic placental tissue; however, there are no villi to exchange nutrients. Choriocarcinoma can develop into a small hemorrhagic tumor and can easily invade maternal blood vessels leading to early hematogenous spread throughout the circulation. Patients usually present with a uterus larger than expected for gestational age. The evaluation includes ultrasound which shows a “snowstorm appearance.” Blood tests typically show elevated beta hCG, which is produced by syncytiotrophoblast. High levels of hCG can lead to thecal cysts in the ovary. Treatment is dilation and curettage with follow-up monitoring with beta-hCG levels. This germ cell tumor usually responds poorly to chemotherapy; however, there are some cases in which chemotherapy after resection may result in a successful outcome.[35][36][37][38]

Preeclampsia, usually arising in the third trimester, is pregnancy-induced hypertension by increased total peripheral resistance but the pathogenesis is poorly understood. Literature provides evidence for an imbalance of angiogenic and anti-antigenic factors as well as defective spiral artery remodeling, which eventually leads to the former hypothesis. This disproportion favors anti-angiogenic factors leading to endothelial dysfunction in the maternal organs. In terms of diagnosing pre-eclampsia, hypertension couples with one of the following: elevated liver enzymes, reduced liver or kidney function, or pulmonary or cerebral edema. Preeclampsia resolves with delivery and removal of the maternal-fetal vascular interface. Methyldopa and magnesium sulfate are the recommendations for control of hypertension.[39][40][41]

• HELLP syndrome refers to preeclampsia with thrombotic microangiopathy concerning the liver by hemolysis, elevated liver enzymes, and low platelets. Like eclampsia, this warrants immediate delivery.[42]
• Eclampsia is preeclampsia with seizures. Like HELLP, this warrants immediate delivery.[43]

Clinical Significance

Placenta previa is the implantation of the placenta over the cervical os, which usually presents as painless vaginal bleeding in the third trimester. Additionally, the uterus is soft and non-tender on physical exam. The fetus is usually not in distress. Risk factors include a history of cesarean section or multiple vaginal births. A transabdominal ultrasound localizes the placenta, but placenta previa diagnosis is by transvaginal ultrasound. In these cases, mother and fetus must undergo careful monitoring and delivery is often by cesarean section.[44][45][46]

Placental abruption (abruptio placentae), complete or partial, is the premature separation of the placenta from the decidua basalis, which is the number one cause of vaginal bleeding late in pregnancy. Unlike placenta previa, uterine bleeding is painful with uterine contractions and fetal distress is usually present. Commonly, bleeding is due to rupture of maternal vessels, but fetal-placental vessels can also cause the separation. Ultrasound is the preferred diagnostic tool. Conditions affecting circulation act as risk factors and include hypertension, tobacco, cocaine, trauma, and premature rupture of membranes. Treatment includes the delivery of the baby. However, placental abruption frequently results in stillbirth.[47][48][49]

Placenta accreta spectrum (PAS), formally known as morbidly adherent placenta, describes the improper attachment and separation of the placenta to a defective decidual layer of the endometrium. Women with maternal age, multiparity, or history of C-section or uterine surgery are at high risk for abnormal placenta adherence. Discovery of this condition is on ultrasound before delivery; however, there is difficulty with placental separation after birth which causes postpartum bleeding. Therefore, prenatal diagnosis is important to prepare for difficult labor, which may involve surgery. If findings are unclear with ultrasound, magnetic resonance imaging (MRI) can clarify the diagnosis. There are three types of morbidly adherent placenta ranging from various depths of infiltration.[50][51][52]

• Placenta accrete, the most common type is the implantation of placenta onto the myometrium rather than the decidua.[52]
• Placenta increta describes the placenta intervening the myometrium but avoiding invasion outside the uterus.[52]
• Placenta percreta is the deepest penetrating of the three types as the placenta pushes through the myometrium and into the uterine wall. In some cases, the placental cells can reach out of the uterus and invade the rectum or bladder.[52]