Complications during pregnancy: Pathology review

26 year-old Effie is brought to the emergency department with severe lower abdominal pain and bloody vaginal discharge that began a few hours ago. Her last menstrual period was 7 weeks ago. She has been sexually active with multiple partners and uses condoms on occasion. Her past medical history is significant for pelvic inflammatory disease. On examination, her blood pressure is 80/40 mmHg and her pulse is 130 beats per minute. She is pale and her extremities are cold and clammy. Next to her, there’s also 37-year-old Kate who came in noting an abrupt onset of abdominal pain and continuous vaginal bleeding. She is going through week 28 of her fourth pregnancy and was involved in a car crash a couple of hours ago, but did not immediately seek medical care. On presentation, fetal heart rate and movement are significantly diminished. Laboratory studies reveal low platelets, prolonged PT and PTT and elevated d-dimers. Peripheral blood smear shows schistocytes.

Based on their initial presentation, both Effie and Kate have a form of pregnancy complication.

Now, the most common medical complication of pregnancy is hypertensive disorders of pregnancy. These are diseases that cause high blood pressure during pregnancy, either a systolic blood pressure higher than 140 mmHg, or a diastolic blood pressure higher than 90 mmHg, or both. So, when hypertension is diagnosed before 20 weeks gestation, it’s usually chronic hypertension, meaning that it’s not due to pregnancy.

After 20 weeks gestation, new onset hypertension without proteinuria or damage to other organs is gestational hypertension. Now if hypertension gets severe, meaning systolic blood pressure of 160 mmHg or greater and/or diastolic blood pressure of 110 mmHg or greater, it can often lead to organ damage. One key thing to look out for is the presence of proteinuria, or excessive amounts of protein in the urine, which is a marker of kidney damage. Other affected organs include the brain and liver.

Now, if the hypertension coexists with proteinuria or other organ dysfunction, then it’s called preeclampsia. Preeclampsia is more common during a person’s first pregnancy, in pregnancies with multiple gestations, or in mothers 35 years or older. Other risk factors include having pre-existing hypertension, diabetes, chronic kidney disease or autoimmune disorders like the antiphospholipid syndrome. The exact reason why preeclampsia develops is unclear, but a high yield pathophysiologic feature though is the development of an abnormal placenta. Normally, during pregnancy, the spiral arteries dilate to 5-10 times their normal size and develop into large uteroplacental arteries that can deliver large quantities of blood to the developing fetus. In preeclampsia, these uteroplacental arteries undergo fibrosis, causing them to narrow, which means less blood gets to the placenta. This hypoperfused placenta starts releasing proinflammatory proteins. These then get into the mother’s circulation and cause the endothelial cells that line her blood vessels to become dysfunctional. Endothelial cell dysfunction causes vasoconstriction or narrowing of the blood vessels and also affects the kidneys in a way that makes them retain more salt, both of which result in hypertension. Vasoconstriction will also lead to reduced blood flow to the kidneys, which are particularly susceptible to ischemia and can cause glomerular damage leading to proteinuria.

The high blood pressure can also cause placental abruption, where the placenta detaches prematurely from the uterine wall. Next, the increased pressure inside blood vessels can cause endothelial injury which leads to the formation of lots of tiny thrombi in the microvasculature. This process uses up massive amounts of platelets so there’s an increased risk of bleeding. To make things worse, these tiny blood clots are like large rocks in a river and damages the red blood cells trying to move past them, so there’s extrinsic hemolytic anemia. Specifically, red blood cells get split into smaller fragments called schistocytes. And bare in mind that these schistocytes are visible on peripheral blood smear. If all this wasn’t bad enough, the thrombi can block blood flow to the liver, causing severe liver injury which can cause an elevation in liver enzymes.

Together all these make up HELLP syndrome, H for hemolysis, EL for elevated liver enzymes, and LP for low platelets. The damaged liver swells up and in some cases, as the condition worsens, the liver capsule may rupture leading to a subcapsular hematoma. This can present as right upper quadrant or epigastric pain. But if a lot of blood is lost, it can also lead to severe hypotension. Now, in other cases, HELLP syndrome can develop into disseminated intravascular coagulation, or DIC. That’s because damage to the endothelium can lead to the release of tissue factor, which triggers the coagulation cascade. And this, except for platelets which are already low, also depletes coagulation factors, making it even harder to establish hemostasis. This may present as bleeding from mucosal surfaces, intravenous lines or incision sites, if there are any. Now, what’s high-yield is that in terms of lab work, remember there’s decreased coagulation factors which means a prolonged prothrombin time, or PT, and prolonged partial thromboplastin time, or PTT. Another important hint is elevated d-dimer levels which come from clot lysis. So an individual with ΗΕLLP plus prolonged PT and PTT and elevated d-dimers is having DIC!

Finally, endothelial injury in preeclampsia increases vascular permeability, which is when water is allowed to slip out of blood vessels between neighboring endothelial cells and get into the tissues. Because there’s also a loss of protein from the blood due to the proteinuria, even more fluid moves from the blood vessels into the tissues. And this causes generalized edema which is often seen in the legs, face and hands; pulmonary edema which can cause cough and shortness of breath; and cerebral edema which can cause headache, confusion, and seizures. For your exams, what’s high-yield to remember is that when a female with preeclampsia develops seizures, we call it eclampsia.

Alright, now, let’s discuss treatment. The antihypertensive medications that can be used for chronic hypertension in pregnancy or gestational hypertension are hydralazine, methyldopa, labetalol, or nifedipine. To remember this, you can use the mnemonic Hypertensive Moms Love Newborns. In preeclampsia and eclampsia, in addition to antihypertensives, IV magnesium sulfate is also given to prevent or treat seizures. But since all of the problems of preeclampsia and eclampsia stem from placental dysfunction, it’s important to know that the definitive treatment is delivery of the fetus and placenta. Especially in the case of eclampsia or HELLP syndrome, delivery has to be immediate.

Okay, next, there is gestational trophoblastic disease, which includes both benign and malignant proliferations of placental or trophoblast cells. At the benign end of the spectrum, there’s molar pregnancy, which is also called hydatidiform moles. At the malignant end, there’s invasive moles, which can arise from benign moles and choriocarcinoma, which is placental cancer that most frequently occurs in the absence of a molar pregnancy.

Now, moles result from errors in normal fertilization. Normally, at fertilization, a single egg with 23 chromosomes fuses with a single sperm with 23 chromosomes, resulting in a new cell with 46 chromosomes. This can go wrong in two ways, so we have two kinds of moles: complete, or classic, and incomplete, or partial mole. Both lead to an abnormal proliferation of placental or trophoblast cells. The difference is that a complete mole appears when a chromosomally empty egg fuses with a normal sperm, and the sperm genetic material duplicates to form a 46 chromosome cell. However, it doesn’t have both maternal and paternal chromosomes, so the mole develops into a mass rather than developing into a fetus. An incomplete mole, on the other hand, appears when a normal egg is fertilized by two sperm - which forms an organism with 69 chromosomes, that usually develops into non-viable fetal parts.

What’s extremely high-yield is that with a complete mole, the placenta secretes a huge amount of hCG. So affected females initially present with signs of pregnancy, like missed periods. Vaginal bleeding is another sign, which may range from light spotting to heavy bleeding, and parts of the mole may even be eliminated, and they look like grapes, or cherry-like clusters. Additionally, for unclear reasons, this huge amount of hCG can lead to early preeclampsia, meaning hypertension and proteinuria before 20 weeks of gestation. Don’t confuse that with chronic hypertension, which is hypertension without proteinuria before 20 weeks of gestation. At the same time, excess hCG can lead to hyperemesis gravidarum, which is extreme nausea and vomiting which can lead to severe dehydration. Interestingly, hCG has a subunit that’s similar to TSH, so it can cause symptoms of hyperthyroidism, like insomnia, anxiety, tachycardia, and palpitations. Too much hCG can also result in the growth of theca lutein cysts in the ovaries, which can cause symptoms like pelvic pain or pressure on the affected side. Finally, since the mole grows much faster than a normal pregnancy would, a physical examination shows a uterus that’s too big for gestational age. Histologically, we’ll see fingerlike projections called chorionic villi which contain tiny arterioles and venules. Now, most villi will be hydropic, meaning swollen and edematous. And all around the villi, there’ll be diffuse and circumferential proliferation of large trophoblast cells. These can be either cytotrophoblasts with central nuclei and pale cytoplasm, or syncytiotrophoblasts that have multiple nuclei and darker cytoplasm. Another thing we can do is stain for the p57 protein. This is produced by a gene that’s only expressed on maternal cells. So a complete mole will stain negative for p57. Now, a very high yield test result you must remember is that a transvaginal ultrasound will show no fetal parts. Instead, there will be a diffuse echogenic pattern, called a “snowstorm” pattern, sometimes described as looking like a "clusters of grapes". This results from the presence of abnormal placental villi and blood clots that accumulate in the uterus. An incomplete mole also secretes more hCG than normal, but not quite as much as a complete mole. So while missed periods and vaginal bleeding are present, the uterus is not larger than expected for gestational age, and there are no symptoms of hCG hyperstimulation like early preeclampsia, hyperemesis gravidarum, hyperthyroidism, or ovarian cysts. On histological examination, we’ll also see villi, but, unlike complete moles, only some of them will be hydropic. Another key distinction is that p57 staining will be positive. On a transvaginal ultrasound, fetal parts will be visible.

Treatment for both complete and incomplete moles is uterine evacuation through suction curettage and methotrexate. Methotrexate is very frequently tested, so it’s important to know that it is an antimetabolite medication that is structurally similar to folic acid and is toxic to the rapidly dividing cells of the embryo. For your test, remember that it’s essential to monitor the hCG levels afterwards until they go back to normal. If that doesn’t happen, we can suspect an invasive mole or choriocarcinoma.

Okay, so, a high-yield fact is that both complete and incomplete moles are benign conditions, but can develop into malignant tumors, like invasive moles or, in rare cases, choriocarcinomas. In invasive moles, the villi invade deeper into the myometrium, which is the muscular wall of the uterus. In fact complete moles have a 15-20% risk of developing into invasive moles, whereas with incomplete moles, the risk is under 5%. However, it’s high-yield to know that most choriocarcinomas develop during or after a non-molar pregnancy. Broadly speaking, choriocarcinomas are usually quite small but if they get large enough, they can present with lower abdominal pain or pressure. They are also extremely aggressive, so they have a high chance of spreading via the circulation. A high-yield fact is that a very common location for metastasis is the lungs, causing shortness of breath and hemoptysis. On a chest x-ray, this shows up with the characteristic “cannonball metastases”. These are multiple, large, well-circumscribed, and round metastatic masses. Metastatic disease to the brain may also cause headache, dizziness, nausea, slurred speech or visual disturbances. Just like benign moles, choriocarcinomas also secrete hCG and this can cause symptoms of hyperthyroidism, as well as bilateral, multiple theca-lutein ovarian cysts. For your test, remember that under the microscope, choriocarcinomas look very similar to moles, so they have cytotrophoblasts and syncytiotrophoblasts. But the key distinction is that there are no villi. The main treatment is methotrexate. Alright, now let’s look at ectopic pregnancy. Normally, a fertilized egg travels through the fallopian tube and implants in the uterus, but in an ectopic pregnancy, the fertilized egg ends up implanting somewhere else. For your exams, remember that the most common site is the ampulla of the fallopian tube, but it can also occur on various surfaces, like the ovaries. The cause of an ectopic pregnancy is often unknown, but there are well known risk factors. A very high-yield one is pelvic inflammatory disease, since the inflammation results in scarring and adhesions, particularly in the fallopian tubes, thus, blocking the fertilized egg from traveling down into the uterus. Scar tissue can also build up in the fallopian tubes as a result of previous surgery involving the fallopian tubes, endometriosis, advanced age, and smoking, which is thought to damage the epithelium lining the fallopian tubes. The individual will frequently also have a history of prior ectopic pregnancy or infertility, which may indicate some anatomical abnormality of the fallopian tubes.