Fetal survival in pregnancy complicated by massive subchorionic thrombohaematoma

Abstract

This case involves a pregnant patient in her late 20s whose pregnancy was complicated by placentamegaly and early-onset, severe fetal growth restriction (FGR). Investigations ruled out genetic and infectious aetiologies. The pregnancy eventually was further complicated by abnormal umbilical artery blood flow. Shared decision-making with the patient and obstetrical team led to delivery by caesarean section at 28 weeks and 4 days. The baby was admitted to the neonatal intensive care unit but, overall, did well. Placental pathology revealed a massive subchorionic thrombohaematoma (MST). This case highlights the importance of early detection, evaluation and management of pregnancies complicated by severe FGR as well as the significance of shared decision-making with patients. We aim to increase the awareness of MST in the differential diagnosis of placentamegaly, as this finding in combination with early and severe FGR has been shown to be a poor prognostic factor for the fetus.

Background

Massive subchorionic thrombohaematoma (MST), formerly described as Breus’ mole, is a maternal thrombus greater than 1 cm in thickness that develops between the chorionic plate and villous chorion of the placenta. The thrombus bulges above the chorionic plate often resulting in the compression of umbilical vasculature.^1–5 According to the Atlas of Placental Pathology, the thrombus involves at least 25% of the chorionic plate.⁶ MSTs are uncommon, occurring in approximately 1 in 3000 pregnancies.^{3 7 8} While the underlying aetiology of MST is unclear, several maternal comorbidities have been associated with an increased risk of MSTs including thrombophilia, cardiovascular disease, hypertension, diabetes mellitus and pre-eclampsia.1 2 4 5 Pregnant patients who have received thrombolytic therapy or anticoagulation are also predisposed to MSTs.^{1 5} Small and asymptomatic subchorionic thrombohaematomas are frequently found incidentally and have little clinical significance. Alternatively, massive subchorionic thrombohaematomas are often associated with poor clinical outcomes, likely due to their impact on placental function.^{5 9} Reported complications of MSTs include oligohydramnios, intrauterine haemorrhage, intrauterine growth restriction, fetal pulmonary hypoplasia, placental insufficiency, preterm delivery and fetal demise.1 2 7 9 The site and size of an MST impact the severity of subsequent outcomes. Decreased fetal perfusion secondary to cord compression may be observed if the thrombohaematoma is present near the umbilical cord insertion site.1 4 7 9 Placentamegaly, while rarely seen in association with MSTs, has been identified as a poor prognostic factor when present.^{5 7} To our knowledge, few cases of MSTs complicated by placentamegaly have been reported with the exclusion of associated malformations and aneuploidies. All pregnancies in these cases with abnormal umbilical artery (UA) Dopplers resulted in spontaneous abortion or fetal demise.1 3 5 9 Here, we report a case of MST presenting with abnormal UA Dopplers complicated by placentamegaly and fetal growth restriction (FGR), resulting in a viable pregnancy at 28 weeks and 4 days gestation.

Case presentation

The patient is in her late 20s. She is a G2P1001. She presented to initiate prenatal care in the first trimester of pregnancy. A transvaginal ultrasound was done that showed a fetal crown-rump length of 7 weeks and 1 day. Fetal heartbeat and amniotic fluid were normal. Our patient had the usual prenatal laboratory evaluations which were all normal. Routine ultrasound for anatomy was done at 19 weeks and 6 days. This showed a fetus with normal anatomy but with an estimated fetal weight in the second percentile for gestational age, consistent with early-onset FGR. Significant placental thickening was present on ultrasound at this time, as shown in figure 1. The placenta measured 6.0 cm in thickness, with echogenic areas noted in the placenta thought to be from haemorrhage or inflammation. Due to the early-onset FGR, there was concern for both genetic and infectious complications of pregnancy, as these are known to be common aetiologies when growth restriction presents before 24 weeks gestation.

Figure 1.

Ultrasound of placenta at 19 weeks and 6 days

Non-invasive prenatal testing was done and revealed normal male fetal chromosomes. Amniocentesis for further diagnosis of possible chromosomal mosaicism was offered but declined by the patient. Testing for cytomegalovirus (CMV), parvovirus B19, HIV and syphilis were all negative. The patient returned for a repeat ultrasound at 22 weeks and 5 days gestation. Again, there was marked placentamegaly with areas of echolucency and hyperechoic areas which were suggestive of intraparenchymal haemorrhage. UA Dopplers showed absent end-diastolic flow. The patient was offered treatment with betamethasone for fetal lung maturity, but after a detailed discussion of her options and likelihood of neonatal survival, she decided to wait until 24 weeks gestation to proceed with this steroid treatment. She was given a course of 12 mg intramuscular betamethasone at 24 weeks. At 27 weeks and 4 days, an obstetrical ultrasound showed an estimated fetal weight of 596 g, which was <1% for her gestational age (see figure 2). The modified biophysical profile was 8/8. UA Dopplers showed intermittent absent and intermittent reversed blood flow.

Figure 2.

Ultrasounds of thickened placenta at 28 weeks and 4 days

The patient was sent to the labour and delivery unit for admission and closer surveillance along with repeat dosing of antenatal corticosteroids for fetal lung maturity. A lupus anticoagulant panel was drawn and showed the possible presence of weak lupus anticoagulant but recommended repeat labs in 3 months for further diagnosis. Beta 2 glycoprotein IgG and IgM were negative as were cardiolipin antibodies. Prothrombin time, partial thromboplastin time, liver and kidney function and international normalised ratio (INR) were normal. The patient remained normotensive throughout pregnancy.

Ultrasound at 28 weeks and 4 days again showed a thickened placenta measuring 5.1 cm (see figure 3). The fetal position was breech. Persistent reversed end-diastolic blood flow was now noted in the UAs. Fetal ductus venosus Doppler studies were normal. Due to the reversed UA blood flow, a recommendation for delivery was made. Intravenous magnesium sulfate infusion for fetal neuroprotection was started with plans for delivery later that day. The patient underwent a primary lower segment transverse caesarean delivery at 28 weeks and 4 days. The infant was male with Apgar scores of 7/9 and weight of 660 g. Arterial cord pH was normal at 7.30. Venous cord pH was normal at 7.34. The placenta was grey in colour on the maternal side, and there was nodularity present as illustrated in figures 4 and 5. The amniotic fluid was noted to have a dark brown colour consistent with chorioamniotic haemosiderosis or diffuse iron-stain pigment deposition within the chorioamniotic layers and membranes from chronic placental bleeding. The baby went to the neonatal intensive care unit for treatment of respiratory depression, prematurity and FGR. Placental pathology showed a placental disc in the 95th percentile of weight for gestational age with marked distal villous hypoplasia and large intervillous blood collections consistent with a massive subchorionic haematoma, previously called a Breus’ mole (see figures 6 and 7). The fetal membranes had diffuse laminar necrosis.

Figure 3.

Maternal surface of placenta shows thickening and nodularity.

Figure 4.

Fetal surface of placenta.

Figure 5.

Microscopy showing indwelling, non-viable villi that are spread apart.

Figure 6.

Microscopy showing placental membranes with only laminar necrosis and no haemosiderosis.

Figure 7.

Fetal growth chart by Karen Carlson, MD

Differential diagnosis

The differential diagnosis of early-onset FGR and placental abnormalities include placental insufficiency from antiphospholipid syndrome or other autoimmune disorders, maternal hypertension and pre-eclampsia, intrauterine infection, genetic disorders affecting placental and fetal development and severe maternal malnutrition. The intraparenchymal haemorrhage on the placenta causing significant thickening could be caused by placental abruption, haematoma or vascular malformations.

Outcome and follow-up

The patient did well postoperatively and postpartum. She returned to normal daily activities shortly after discharge from the hospital. The infant received routine newborn screening for genetic and metabolic disorders, which was within normal limits. Chromosomal studies were not obtained on the baby. Ultrasound of the fetal head was performed and was normal. Congenital heart disease as screened with echocardiogram was negative. Serial exams for retinopathy of prematurity remained normal. The fetus was noted to have hypospadias with a plan for urology follow-up.

Discussion

This report describes a case of MST with early-onset and severe FGR, ultimately resulting in a viable pregnancy outcome. Previous cases have also described FGR in association with MST, but most resulted in poor fetal outcomes, specifically fetal demise. Uteroplacental insufficiency due to MST likely plays a role in the mechanism of FGR in these cases.⁴ A study by Alanjari et al described 14 cases of MST with a 50% survival rate. Five of seven non-surviving subjects in this study had abnormal UA Dopplers in the form of absent or reversed end-diastolic flow velocity and were also diagnosed with FGR. None of the neonates that survived had a diagnosis of FGR.¹⁰ Another case by El-Agwany described a dichorionic diamniotic pregnancy, with MST complicating the course for one of the two fetuses. The fetus whose placenta was directly affected by MST was also diagnosed with FGR. The ultimate outcome of the FGR fetus was fetal death.⁴ These studies, like ours, support the concept that the presence of a thickened placenta, abnormal UA Dopplers and an FGR fetus should raise concerns for MST.

FGR <3% before 24 weeks gestation with an otherwise normal appearing fetus or FGR <3% before 32 weeks gestation with minor fetal anomalies noted may be associated with chromosomal abnormalities. Therefore, chromosomal analysis with karyotype or chromosomal microarray should be recommended.¹¹ Fetal or neonatal genetic testing is important in pregnancies complicated by FGR. Genetic disorders account for up to 19% of fetuses with FGR, and the incidence of chromosomal abnormalities in these pregnancies is even higher with early-onset FGR. With FGR occurring before 26 weeks gestation, triploidies are most commonly seen. The severity of FGR has been shown to be related to an associated chromosomal abnormality, with an incidence of 18% when the EFW is below the third percentile versus 7.8% of fetuses that have chromosomal abnormalities when the EFW falls below the tenth percentile. The chromosomal abnormality is sometimes found only in the placenta, termed confined placental mosaicism, with fetal chromosomes being normal. Amniotic fluid testing by amniocentesis is recommended to discern fetal mosaicism from confined placental mosaicism, as the prognosis for each of these conditions is different. Confined placental mosaicism may be a cause for a false-positive cell-free DNA test on the mother. With mosaicism that is confined to the placenta, the incidence of FGR is 6.5%–25%. When infarcts are present in the placenta of an FGR fetus, confined placental mosaicism is present almost 1/3 of the time.¹⁰ Specific chromosomes that are altered in the placenta and are associated with poor perinatal outcomes include chromosomes 2, 7–10, 13–18 and 21–22. These are the chromosomes that are responsible for placental growth and function. When comparing placentas from growth-restricted fetuses, placentas with mosaicism were associated with many more infarcts and areas of vasculopathy as compared with placentas with normal chromosomes. Additionally, the portion of the placenta affected by the abnormal trisomic tissue impacts the placental function. When trisomy 16, specifically, is confined to the placenta, 43%–58% of fetuses will be small for gestational age. Conversely, with small for gestational age newborns, 16% have associated placental mosaicism. Fortunately, newborns with minimal malformations at birth tend to catch up with growth when the placenta contains a trisomy 16.¹¹

More recent findings suggest that tetraploid mosaicism is more common in the placentas of pregnancies associated with FGR, but the mechanism that causes this is not yet evident. Severe FGR has also been associated with a single gene mutation (monogenetic) syndrome. Newborns from these pregnancies typically go on to become short in adulthood, and half may have intellectual difficulties. There are two such known groups of monogenetic disorders. One group has all small fetal biometrics and may also have genital or hand abnormalities. Included in this group are Fanconi anaemia, Seckel, Bloom and Nijmegen breakage syndromes, all of which are autosomal recessive chromosomal instability syndromes.¹¹ The second group associated with a single gene mutation syndrome has extremely short fetal long bones due to a dysfunction of growth hormone and the insulin growing factor 1 axis. Some of these syndromes are associated with hearing deficits, microcephaly and delayed development.¹¹

Pregnancies complicated by thickened placentas should be considered at-risk pregnancies. Abnormalities in the placenta can affect not only the fetus but the mother and the newborn. Conversely, maternal and fetal conditions can affect the placenta. When placental thickening is noted on ultrasound, a complete and thorough fetal anatomic survey should be completed. Blood testing with complete blood count (CBC), TORCH titers (toxoplasmosis, rubella, cytomegalovirus, and herpes simplex), HIV and syphilis should be tested. Abruption should be suspected if there is abdominal pain. Chorioangioma, subamniotic haematomas and cord angiomyxoma should be considered in the differential diagnosis of a thickened placenta.¹²

Complex pathophysiological processes are involved in the development of FGR caused by placental abnormalities. A healthy placenta needs to have significant remodelling of spiral arteries. Non-infectious and non-genetic FGR is caused by abnormal remodelling of the spiral arteries. When oxidative stress occurs to an extensive degree and is widespread throughout the placenta, miscarriage frequently results. However, when less extensive arterial remodelling occurs, FGR may arise from the compromised circulation of blood to the placenta in the early stages of formation of the placenta. This begins at the end of the first trimester. Abnormal interactions of natural killer cells cause a decreased release of proteases, inadequate histotrophic nutrition and a decrease in extravillous trophoblast cells. These changes cause abnormal maternal arterial remodelling in the junctional zone of the radial arteries which results in increased velocity and pulsatile flow of maternal blood into the placenta. These jet-like streams of blood flow cause mechanical damage to the placenta by forming channels and lacunas in the villous trees. This is likely the underlying pathophysiological cause of FGR. Higher resistance to blood flow in the placenta is frequently noted beginning in the second trimester. This lack of remodelling in the junctional zone and retention of vascular smooth muscle also allow for recurrent reperfusion injuries of the placenta. Narrowing of the lumens from sclerotic changes in the spiral arteries further restricts blood flow to the placenta. The resulting increased resistance within the umbilical cord circulation impairs nutrient and oxygen transport to the fetus, after which FGR ensues.¹³

Thromboses and infarcts are the most common findings in placentas associated with FGR. Thromboses occur due to maternal blood clotting in intervillous spaces. As fibrin is repeatedly deposited around the periphery of the thrombus, the result is a large echogenic lesion located under the maternofetal plate. When complete obstruction occurs in an artery, an infarct results. This causes an interruption of fetal circulation in the associated cotyledons. Small placental thromboses and infarcts are commonly found in uncomplicated pregnancies, but large infarcts and extensive fibrin deposition are associated with uteroplacental insufficiency and a jelly-like placenta with resulting FGR. This malperfusion of the placenta causes further oxidative stress, which then causes abnormal cell function and even death of cells. Suppression of placental growth and function follows.¹³

A thickened placenta has been found to occur in between 0.6% and 7.6% of pregnancies. The criteria for the diagnosis of a thickened placenta vary based on the gestational age of the pregnancy. The normal placenta measures between 2 and 4 cm in thickness by ultrasound.^{14 15} Placentamegaly has commonly been defined as an ultrasound measurement of placental thickness of over 4 cm at any time during pregnancy. Some authors have used a definition of >4 cm in the second trimester and >6 cm in the third trimester.¹⁶ The thickened placenta is not associated with any specific pathological condition but may be the result of inflammation, compensatory hypertrophy or oedema. The pathophysiology causing the thickening of the placenta remains an enigma. It is rarely an intrinsic abnormality but rather a result of abnormal maternal or fetal blood flow through the placenta.¹⁷ With anaemia, the placenta may compensate for decreased oxygen diffusion by increasing the surface area.

Infectious agents, diabetes, pre-eclampsia and multiple other complications of pregnancy may result in a thickened placenta. Infections such as syphilis, COVID-19, malaria, Zika, CMV and Toxoplasma gondii have been associated with thickened placentas.¹⁶ The infectious process may cause fibrosis and inflammation within the placenta. In a pregnancy complicated by diabetes, increased oxidative stress on the placenta may damage blood vessels during their formation. Moreover, elevated insulin levels have a mitogenic effect on placental cells. Increased vascular resistance in the placenta may lead to the proliferation of villi and capillaries as they compensate for fetal hypoxaemia. The endothelial dysfunction associated with pre-eclampsia may also play a role in the thickened placenta. Thickened placentas have been associated with placental insufficiency as measured by a reduction in UA Doppler flow.¹⁶ Thickened placentas have also been associated with abnormally invasive placental pathology, placental mesenchymal dysplasia, infarction, inflammation, thrombosis, fibrin deposits, compensatory hyperplasia and fetal hydrops. Fetal and maternal anaemia, sacrococcygeal teratomas, fetal chromosomal abnormalities, high prepregnancy BMI, diabetes, assisted-reproductive technologies, excessive pregnancy weight gain, pre-eclampsia, Beckwith-Wiedemann syndrome and fetal heart failure have all been described in association with thickened placentas.¹⁷

While most cases of pregnancies complicated by MST and FGR have proven poor prognoses, a case reported by Nishida et al had a more positive outcome. In contrast to our case, the FGR fetus had normal UA Dopplers throughout pregnancy. Despite the diagnosis of FGR in association with MST in this subject, the fetus was ultimately delivered at 33 weeks gestation without complications.¹⁸ This case describes a similar outcome to ours, with a viable, uncomplicated birth in the setting of FGR with an MST. However, the UA Doppler findings were different than in our case. Early identification of FGR is critical in the management of these pregnancies, as further investigations should be considered to identify aetiologies and comorbid conditions. While UA Dopplers have shown utility in monitoring fetal status in the setting of FGR, normal Dopplers should not halt further workup, as MST is still possible when a thickened placenta is present. A broad differential including MST should be considered for early-onset FGR with a concomitant placental abnormality.¹³

Our case described a fetus with FGR and placental thickening concerning for haemorrhage or inflammation at 19 weeks and 6 days gestation. Fetal demise in cases like ours occurred as early as 22 weeks gestation.¹⁰ Our decision to closely monitor with antenatal ultrasounds and UA Dopplers was critical in assessing fetal status and optimising time of delivery. While intraparenchymal haemorrhage of the placenta was identified on antenatal ultrasound in our case, MST was not definitively diagnosed until pathological examination after birth. Evaluating placental structure and function antenatally helped us anticipate a potential diagnosis of MST, which influenced the delivery plan and other components of management. We support placental examination both antenatally with imaging and postnatally to identify the underlying causes of pregnancy complications.

Learning points.

• Early identification and monitoring of fetal growth restriction are critical in management of affected pregnancies, to provide further investigations and interventions to maximise maternal and fetal outcomes by opportune timing of delivery.

• Patient education and shared decision-making with effective communication are crucial throughout pregnancy, especially when considering abnormalities, interventions and treatment options at previable and periviable gestational ages.

• Placental examination both with ultrasound antenatally and grossly after delivery can provide valuable insights into the potential underlying causes of complications during pregnancy.

• The differential diagnosis for early-onset fetal growth restriction includes placental insufficiency, maternal hypertensive disorders, genetic factors and intrauterine infections. Amniocentesis should be considered as fetal triploidies and confined placental mosaicisms are associated with early and severe fetal growth restriction.

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