Presentation: Pregnancy
Title:        Mother and Child
Date & Time:  Monday, April 12, 2010 at 10 AM
Lecturer:     Dr. Garcia and Team

QUIZBANK: "Fetus and Pregnancy"

{47859} pregnant
{08434} normal pregnant uterus, gross
{09780} normal pregnant uterus; baby below match-stick
{24666} normal placenta
{21104} normal pregnancy
{38995} normal pregnancy
{08928} normal placental villi in ectopic pregnancy
{08930} normal placental villi in ectopic pregnancy
{11024} placental infarct, gross; these are common and usually harmless

{49415} hydrops fetalis
{49416} fetal death, cord around neck

Parvo B-19 hydrops fetalis

Yutaka Tsutsumi MD

WebPath Case of the Week

EXAMINING THE PLACENTA (stil good: Am. Fam. Phys. 57(5), March 1998)


    Around 1 known pregnancy in 6 ends with miscarriage (i.e., loss of the child before 20 weeks). The true number of lost conceptions is undoubtedly higher as they are very early (i.e., "the period is late").

      Loss of the child in the second trimester is uncommon; as with earlier loss, finding the cause is seldom easy (Am. Fam. Phys. 76: 1341, 2007). However, it's now fairly clear that just as in preterm birth, histologic chorioamnionitis, bacterial infection, and viruses are important causes (Am. J. Ob. Gyn. 195: 797, 2006) -- and of course "intimate partner violence" (Lancet 373: 278, 2009).

    About half of miscarriages supposedly have a chromosomal abnormality. You'll go crazy trying to sort out what's known (and what's not) about the other causes, which include "failure to implant" (nobody knows how common this is), disappearance of the corpus luteum "because of other endocrine disease", "incompetent cervix", low folic acid/B6 (i.e., poor diet -- does this run with some other lifestyle-related risk factor? JAMA 288: 1867, 2002; Ob. Gyn. 100: 107, 2002), and of course antiphospholipid antibody and (especially later in the course of the pregnancy) congenitally hypercoagulable blood (NEJM 343: 1015, 2000; Ann. Int. Med. 130: 736, 1999; Factor V-Leiden is now infamous and generally the thrombophilias are well-established causes of loss of pregnancies -- "prothrombin G20210A" is evidently an exception Ob. Gyn. 115: 14, 2010). Contrary to older ideas, nowadays assisted reproductive technology probably isn't a risk for loss later in pregnancy (Ob. Gyn. 114: 818, 2009).

    If the amniotic sac ruptures early in pregnancy (perhaps from amniotic band syndrome), an astute pathologist can spot vernix (desquamated cells from the baby) in granulomas in the lost tissue.

    BLIGHTED OVUM / ANEMBRYONIC PREGNANCY features a good placenta and membranes but no baby (due to a known or unknown genetic defect -- some of these are triploid and this fades into moles). It is common and now easily recognized on ultrasound; often this is a sad surprise for a woman who think she has a normal pregnancy. The pathologist will eventually see the villi; unlike hydatidiform mole, there's atrophy rather than proliferation of trophoblast, and the edema of the villi isn't impressive.

    You already know that donated ova have a higher rate of miscarriage (about a third) even if the ovum is known to have implanted.

    Previous elective abortion (either surgical or by the increasingly-popular methods involving taking medication) do not seem to place a woman at risk for future miscarriage or ectopic pregnancy (NEJM 357: 648, 2007).

    Today there is some interest in bacterial vaginosis and chlamydia as causes of loss of the unborn child before viability (Am. J. Ob. Gyn. 183: 431, 2000; others).

    After a miscarriage, curettage of the endometrium yields necrotic tissue, often intensely inflamed with neutrophils. There will of course always be decidua, and often villi if they have not been passed.

    * Lancet 371: 290, 2008 reports that 68,000 women die yearly from unsafe abortions in countries where the procedure is illegal. Obviously, this is an estimate, and I don't understand how it was reached.


    We have already talked about problems with the baby (hydrops fetalis, infections) that can be lethal. Disease of the placenta can obviously be fatal or damaging as well.

    No one really knows how often problems with the cord cause the child's death, but it must be fairly common.

    Often the dead child remains in the amniotic fluid for days or weeks, and pathologists can estimate the time since death of these "macerated" babies. (The unborn child is in a sterile environment and thus autolyzes rather than putrefies.) A "papyraceus" fetus is a twin who died and whose body was flattened by the other child's.

ECTOPIC PREGNANCY (Am. Fam. Phys. 72: 1707, 2005)

    This occurs whenever the embryo implants someplace other than the normal intrauterine location. (Contrary to some textbooks, you're not a officially a fetus until you're eight weeks.)

    The usual location is the oviduct, though ovary, peritoneum, and uterine cornua are other known sites. Rarely an intraperitoneal pregnancy goes to term.

      Old cesarean scars are also noteworthy as sites for ectopic pregnancies (BJOG 113: 1035, 2006). In the liver: Ob. Gyn. 109: 544, 2007.

    The best-known cause is old pelvic inflammatory disease, less often scarring from endometriosis. But about half of cases in the US happen "for no reason." In countries where there is much more gonorrhea, there are many more ectopic pregnancies.

    No matter where the pregnancy is, the local cells decidualize and the child develops for a while. In a tubal pregnancy, disaster strikes at about 6 weeks after the missed period (about 8 weeks after conception). One of the following happens:

    • The placenta has invaded far enough through the wall of the tube to make it rupture, with massive internal bleeding.
    • The expanding mass passes back out through the fimbriated end of the oviduct ("tubal abortion").
    • The placenta comes off the wall of the tube, causing heavy bleeding.
    • Or the baby can simply die, and the whole gestation gets reabsorbed. Rarely the baby calcifies (a "lithopedion", or stone child).
    The pathologist can help make the diagnosis in a woman who may be bleeding, by finding decidualized endometrial tissue with no villi.

    Treatment is surgical. Or if an ectopic pregnancy is known to be present but has not ruptured, methotrexate can end it.

{00102} tubal pregnancy, gross
{40140} ectopic pregnancy, gross
{40365} ectopic pregnancy, gross

Ectopic pregnancy


Ectopic pregnancy

KU Collection

Ectopic pregnancy
GIF animation

Ectopic pregnancy, ruptured


Ectopic pregnancy, ruptured


Ectopic pregnancy


Ruptured Ectopic Pregnancy
Text and photomicrographs. Nice.
Human Pathology Digital Image Gallery

Ectopic pregnancy
Wikimedia Commons

9 week fetus
Ectopic pregnancy
Wikimedia Commons

    * Click here for the bizarre way in which ectopic pregnancies must be handled in El Salvador, where it is illegal to end the life of an unborn child EVEN to save the mother's life and even though the child's chances of being born are zero.


    You will learn about the problems in advanced pregnancy while you are on "OB".

    Many of the problems that develop toward the end are caused by problems with the umbilical cord. Of course, if the cord is compressed enough to occlude the veins, the child is in grave danger. This includes slip knots, cord around neck, or cord being compressed by the child's head against the cervix.

      These are among the causes of "late decelerations" and so forth observed on fetal monitoring. If you, the child, are not getting enough oxygenated blood after a contraction has been going on for a while, your heart may slow.

    Infections (strep, gonorrhea, listeria, others) can involve the membranes, causing them to rupture early. Sexual intercourse late in pregnancy can promote these infections. Or a leak may "just happen", producing oligohydramnios sequence and/or fetal loss depending on the timing.

    Infections can pass through a ruptured membrane and produce inflammation of the amnion (amnionitis) and cord (funisitis). Common bacteria (a pathologist can spot fusobaterium using a silver stain) can infect the placenta (villitis, chorioamnionitis), as can syphilis, toxoplasmosis, and TB. If you see granulomas, think of listeria. A chlamydia infection is likely to produce red eyes in the newborn. The one established fungal culprit is candida (look for classic "thrush" on the umbilical cord). In malaria zones, involvement of placenta often permanently damages the baby (Hum. Path. 32: 1022, 2001). Thankfully there's not much brucellosis in the US any more.

    ABRUPTION OF THE PLACENTA is a huge bleed between the placenta and the wall. It is among the most dreaded obstetrical complications.

    PLACENTA PREVIA occurs when the placenta covers the lower uterine segment over the cervical outlet. This can cause premature labor by affecting the placenta. As the cervix dilates, bleeding occurs.

{15876} abruption of the placenta, sectioned in situ

    PLACENTA ACCRETA is a portion of placenta that lacks decidua, adhering instead directly to the myometrium. This is mostly a problem because after birth, the placenta will separate only with difficulty and there will be bleeding. One known cause is an old cesarean scar.

      PLACENTA INCRETA is deep into the myometrium. PLACENA PERCRETA is through the myometrium.

    Placenta accreta


    You remember the mnemonic for the infections of the unborn child:

      T: Toxoplasmosis
      O: Other (syphilis, TB, listeria)
      R: Rubella
      C: Cytomegalovirus
      H: Herpes simplex II

    * Pathologists are just now starting to examine placenta changes in children with cerebral palsy, and the results are not very surprising: clots, partial abruption, inflammation, widespread infarction (Arch. Path. Lab. Med. 124: 1785, 2000).

    * Fun to know: Cesarean section means "to cut". It has nothing to do with Julius Caesar or laws that he passed. Even in ancient times, it was routine to take the child by C-section when it was obvious the mother would die.

    * The old rule was, "Once a cesarean, always a cesarean." In the early 1990's, politics for some reason dictated that "every women deserves a trial of vaginal delivery no matter how many cesarean sections she's had previously". This became a "cause for women's advocates" who distributed "informational literature", and then became a mandate by practice groups and third-party payers. And as any reasonable person would expect, it led to a great many catastrophic deaths (uterine rupture, placenta accreta, amniotic fluid embolization). For an account of the fiasco, see ACOG Practice Bulletin 104: 203, July 2004. Today, the practice recmmendation is that as long as there's been only one cesarean section, and it was with a low-transverse incision (or maybe a lower-segment vertical incision), and resuscitation is available in case of disaster, the woman should be given a CHOICE of a trial of vaginal delivery. DON'T try vaginal delivery if there was a classical incision used for the cesarean section.

Rubella of the placenta
Advanced students
Yutaka Tsutsumi MD

CMV of the placenta

Yutaka Tsutsumi MD


    Think about it.

      One chorion, one amnion: No membrane separates the children. They must be monozygotic (identical) twins.

      One chorion, two amnions: A membrane separates the children, but it contains only an amniotic layer, not a chorionic layer. They must be monozygotic twins. Okay, there was one reported exception: NEJM 349: 154, 2003 (in vitro fertilization, donor oocytes).

      Two chorions: A membrane or two separates the children, and contains both chorion and amnion. They may be monozygotic or dizygotic (fraternal) twins. Dichorionic placentas can be separate or fused.

    The major hazard is a one-way channel between the twins' umbilical cords. This causes twin-twin transfusion syndrome. The twin who gets the blood will be big and can die of circulatory overload. The twin who loses the blood will be small and can die of anemia. Repairing it in-utero: Am. J. Ob. Gyn. 198: e4, 2008.

    An "acardius" is a very malformed fetus with no heart. It can survive if it is anastomosed to a normal twin.

{15651} twin placenta
{39022} twin placenta, gross
{39989} monochorionic monoamniotic twin
{15709} in utero death of a twin

Stillborn twin

TOXEMIA OF PREGNANCY (Am. Fam. Phys. 70: 2317, 2004)

    Somewhere in the world, a women dies every three minutes from causes related to toxemia of pregnancy (Curr. Op. OB-Gyn, 14: 119, 2002). Long a major mystery of medicine, the mystery of toxemia of pregnancy is just now being clarified.

    The key molecule is sFlt1 (now "soluble vascular endothelial growth factor receptor-1, sVEGFR-1), a tyrosine kinase that binds to VEGF and other factors. This ends up having a variety of actions on blood vessels, including inhibiting their growth and causing them to leak (J. Clin. Inv. 111: 600, 649, & 707, 2003; NEJM 350: 672, 2004; Hypertension 55: 689, 2010). Ordinarily, this is the "brakes" on vascular proliferation late in pregnancy. In toxemia of pregnancy, it appears too soon.

    The process begins when the placenta becomes ischemic. Poor trophoblastic invasion, insufficiency of the uterine arteries, or goodness-knows-what sets it up. Once begun, a vicious cycle starts. Something (evidently sFlt1) is released by the ischemic placenta that causes endothelial swelling (raising blood pressure) and leakage (proteinuria and edema), and damage sufficient to produce DIC. All of this is pre-eclampsia.

      * This seems pretty well established; a United Nations panel has accepted it as the best direction for further study: Ob. Gyn. 109: 168, 2007).

    When the woman has had a seizure, it's "eclampsia" and the mother and baby are both at grave risk.

    Risk factors include hydatidiform mole, twins, diabetes, obesity, malnutrition (selenium deficiency? Am. J. Ob. Gyn. 189: 1343, 2003), high blood pressure, kidney disease, and the thrombophilias (for the last, see Am. J. Ob. Gyn. 200: 46.e1, 2009). Newly-recognized is (maybe!) vitamin D deficiency (J. Clin. Endo. Metab. 92: 3517, 2007). Most often it happens during the first pregnancy.

      The placenta &/or unborn child's physiology probably contributes something, since if Dad is the product of a pregnancy with pre-eclampsia, the risk is double (NEJM 355: 867, 2001).

      Further, lethal disease in one twin is likely to cause pre-eclampsia that can be cured by destroying the affected twin to permit safe continuation of the remaining twin's gestation to term (Am. J. Ob. Gyn. 191: 477, 2004).

      * Perhaps the reason that it occurs most often in the first pregnancy is the finding (awaiting confirmation) that women who have had very little (<4 months) exposure to semen are at much greater risk (Am. J. Ob. Gyn. 188: 1241, 2003). Can you think of why this makes sense? Remember that half of the placental antigens are contributed by Dad. If you are not prudish, see J. Repro. Imm. 46: 155, 2000 for a correlation between a popular practice between husband and wife and how it seems to protect from pre-eclampsia.

    Pre-eclampsia is considered non-preventable, but restricting sodium, resting, and maybe prescribing antihypertensive medications can stave off eclampsia.

    Don't worry about "the usual suspects" produced by the ischemic placenta -- thromboxanes, angiotensin, endothelium, and so forth.

The morphology is distinctive.

  • There are bleeds in the liver and under its capsule. The portal capillaries contain fibrin thrombi and there are patches of necrosis, mostly adjacent to the portal areas.
  • The glomeruli display spectacular swelling of the endothelial cells, and scuz composed of fibrin and platelets between the endothelial cells and the basement membrane.
  • The walls of the uterine arteries fill with lipid ("atherosis") and may undergo extensive fibrinoid necrosis.
  • Infarcts in the placenta are likely to be large and/or numerous.
  • In the worst cases, you can see microthrombi throughout the vascular system.
  • Update on the histopathology: The clincial correlation with the pathology is so-so (Am. J. Ob. Gyn. 194: 1050, 2006).

      * A Dutch group that does a lot of sampling of chorionic villi has reported that first-trimester pregnancies where the vessels are close to the intervillous space are more likely to go onto toxemia (Am. J. Ob. Gyn. 202: 88e, 2010).

Delivery is curative.

When there is also hemolysis, elevated liver enzymes, and low platelet count (findings that typically run together), we make the additional diagnosis of HELLP SYNDROME. I've predicted that the placenta produces some toxic factor that remains to be discovered; there is now a report that it is CD95, the fas ligand (Gastroent. 126: 849, 2004) and/or endothelin-1 (J. Clin. Endo. Metab. 90: 4205, 2005). There are more players as well, and the process is obviously a complex mix of problems (Am. J. Ob. Gyn. 194: 317, 2006).


    This dread, thankfully rare illness seems to be caused by carrying a child with recessively-inherited mitochondrial disease of fat metabolism (JAMA 288: 2163, 2002), also possibly etiologic in HELLP syndrome.


    This is the most common of the diseases of trophoblast of pregnancy ("gestational trophoblastic disease").

    About one pregnancy in 1000 in the US is a mole. It's much more common in China and Southeast Asia.

    A hydatidiform mole looks like a mass of grapes, as each villus swells up. The pathologist will see villi with very poor or absent blood vessels (i.e., mostly just myxoid stuff; after all, there is no fetal heart to perfuse the chorionic vessels) and a lot of edema. The amount of trophoblast on the surfaces is variable and probably means nothing.

      "Complete" or "classic" moles have no associated baby, and the villi are uniformly swollen. The surrounding trophoblast is hyperplastic, growing in sheets. They have all the chromosomes from the father ("diandrogenetic"; "daddy's girl"), and are 46XX (usually, two sperms or a duplicated set from one sperm) or (much less often) 46XY (two sperms).

      "Partial" moles (twice as common as classic moles) have unevenly swollen villi, trophoblastic proliferation is minimal, they may have a non-viable baby with them, and they are 69,XXY or 69,XXX. The extra set can come from either parent.

      The two lesions can't always be distinguished histologically. A triploid mole is much less likely than a diploid mole to go on gestational trophoblastic disease (Cancer 100: 1411, 2004). Update on the clinical features: BJOG 114: 1273, 2007.

      * You can be a good doctor without knowing the karyotypes of hydatidiform moles, but it's a triumph of science and a favorite trivia question. Future truly hardcore pathologists: You can tell a partial mole from a complete mole because the former stains with a p57 that is only expressed from the maternal chromosomes (Am. J. Surg. Path. 25: 1225, 2001).

    Usually the uterus is larger than it should be, and bleeding and loss occurs in the fifth month. If the serum hCG levels have been monitored, they are higher than normal.

    Once delivered, the only risk is that an invasive mole or choriocarcinoma may develop. This will be announced by persistent elevations of hCG after the mole is gone.

      Around 10% of complete moles go on to cause gestational trophoblastic disease (i.e., invasive mole or choriocarcinoma), but only about 1% of partial moles.

{27062} hydatidiform mole, histology
{08921} hydatidiform mole, histology
{08922} hydatidiform mole, histology
{18785} hydatidiform mole

Partial mole


Parital mole


Big uterus with mole










Partial mole


Partial mole


INVASIVE MOLE ("chorioadenoma destruens")

    This is hypertrophic trophoblast with at least some villi, penetrating deep into, and maybe through, the uterine wall, following a hydatidiform mole. Villi may embolize but not metastasize (i.e., they won't grow into tumors at remote sites). This lesion is benign and will regress, and is now easily cured by chemotherapy. The major danger is uterine hemorrhage while the disease is active.


    This is vicious cancer of the trophoblast. The greatest risk is following a hydatidiform mole, but any pregnancy (term, ectopic, miscarriage, abortion) can rarely give rise to "chorio".

    Grossly, the tumor is mushy and ultra-bloody (since trophoblast by its nature invades blood vessels). The tumor has always disseminated widely by the time it is diagnosed.

    Microscopically, there will be no villi. The pathologist will see cytotrophoblast and syncytiotrophoblast, usually in alternating layers.

    Formerly, this was uniformly lethal. Today, the large majority are cured with chemotherapy.

{25185} choriocarcinoma, gross (looks like ketchup)
{49378} choriocarcinoma with right ovary, gross
{49379} choriocarcinoma, gross
{25186} choriocarcinoma, histology
{25187} choriocarcinoma, histology
{27056} choriocarcinoma, uterus, histology
{27059} choriocarcinoma, uterus, histology
{40660} choriocarcinoma, histology

Classic drawing
Adami & McCrae, 1914




Tom Demark's Site

    * There are several other lesions involving gestational trophoblast. Leave their diagnosis to us. "Exaggerated placental site" is a non-problem. "Syncytial endometritis" / "placental site nodule" calls for serial hCG measurements but usually causes no trouble. "Placental site trophoblastic tumor" is composed of variant trophoblastic cells and produce human placental lactogen (and maybe don't produce hCG). It usually follows a normal birth, lacks the anaplasia of a real choriocarcinoma, and produces a distinctive glomerular lesion with fibrin and IgM in the loops (Ob. Gyn. 114: 465, 2009) Some choriocarcinomas take the forms of other familiar carcinomas, especially squamous.

{47859} pregnant

* Acupuncture and other "alternative" medicines (with the exception of black cohosh and phytoestrogens) completely fail for relief of menopausal syndromes (Ann. Int. Med. 137: 805, 2002).

* Politics

One does not have to be any kind of militant to be concened with "women's issues", both nationally and on a global scale. The facts are appalling. Today, the brave resistance illustrated in Goya's famous picture is being re-enacted with some success. We can hope for a better tomorrow, but in the meantime, we can help make the changes.

For more on violence, estrogen replacement, the bendictin fiasco, female genital mutilation, the pap smear faisco, fetal monitoring, emergency contraception, trafficking, and forced marriage, see the online version of these notes.

Physicians are natural leaders in helping us look for solutions, and in setting good examples.

Goya The Disasters of War