Recommendations of the AGG (Obstetrics and Prenatal Medicine Working Group, Section Maternal Diseases) on Maternal Thrombocytopenia in Pregnancy

Abstract

Thrombocytopenia is a common hematologic disorder characterized by reduced platelet count in peripheral blood. Acquired and chronic thrombocytopenia is very important in obstetrics. A decreased platelet count of 15–20% is normal in uncomplicated pregnancies; platelet count decreases continuously from 1st trimester on, however usually remains within the normal ranges of between 150 and 450 G/L. The occurrence of mild thrombocytopenia (100–149 G/L) in pregnancy is usually due to gestational thrombocytopenia and does not require further evaluation. But a differential diagnostic examination should be carried out if the platelet count drops to < 100 G/L. Other forms of thrombocytopenia may also occur or become activated in pregnancy and they require special attention. This recommendation presents the diagnostic workup, differential diagnoses, and possible consequences of different thrombocytopenia conditions in pregnancy. The recommendations are based on current international recommendations (George 2023, Bussel 2023) and a search of the literature using the search terms “thrombocytopenia” and “pregnancy”.

Keywords

thrombocytopenia - pregnancy - autoimmune thrombocytopenia - gestational thrombocytopenia

Introduction

Thrombocytopenia is a common hematological disorder characterized by decreased numbers of thrombocytes in peripheral blood. Acquired and chronic thrombocytopenia is very important in obstetrics. A decrease in the number of thrombocytes by 15–20% is normal in uncomplicated pregnancies; such a decrease is continuous and starts in the 1st trimester of pregnancy, however platelet counts usually remain within the normal ranges of between 150 and 450 G/L. Thrombocyte counts are lower in twin pregnancies compared to singleton pregnancies [1]. The occurrence of mild thrombocytopenia (100–149 G/L) in pregnancy is usually due to gestational thrombocytopenia and does not require further evaluation. The precise etiology of gestational thrombocytopenia is not fully understood. It is assumed that it is the result of a combination of factors which include increased placental perfusion, increased thrombocyte destruction, and decreased thrombocyte production.

A differential diagnostic workup should be carried out if the platelet count drops to < 100 G/L. Other forms of thrombocytopenia may also occur or be activated in pregnancy and require special attention. Symptoms may range from mild to severe and vary depending on the severity of the disorder: petechiae, nose bleeds, bleeding of the gums and postpartum bleeding are common. In rare cases, thrombocytopenia in pregnancy can lead to life-threatening bleeding. Early diagnosis and appropriate treatment are crucial to prevent possible complications. This recommendation presents the diagnostic workup, differential diagnoses, and possible consequences of different thrombocytopenia conditions in pregnancy.

Methods

The recommendations are based on current international recommendations [2] [3] and a search of the literature in PubMed using the search terms “thrombocytopenia” and “pregnancy” and included articles in German or English published up until 4/2024. Primary articles published within the last 10 years were considered.

Thrombocytopenia

Definition

Platelet count < 150 G/L

Epidemiology

Thrombocytopenia of < 150 G/L is present in the 3rd trimester of pregnancy in 7–12% of pregnant women [4]. A platelet count of < 100 G/L only occurs in 1% of pregnancies. Thrombocytopenia with a platelet count of 100–150 G/L is, in all probability, related to the gestation and does not require further investigation.

Etiology

Platelet counts decrease during the entire pregnancy in uncomplicated singleton pregnancies and increase again after the birth of the child. Thrombocyte counts are already significantly lower in the 1st trimester of pregnancy compared to non-pregnant women [1].

The risk of bleeding for mother and child and the risk of severe maternal complications differs depending on the etiology and the required therapy differs accordingly.

The risk of severe maternal blood loss caused by thrombocytopenia only increases strongly if thrombocyte levels are between 10 and 20 G/L. Strong bleeding may occur if the platelet count is between 20 and 100 G/L and an invasive procedure is carried out but does not occur spontaneously.

Diagnosis

Every thrombocytopenia should be investigated

• if the platelet count decreases to less than 100 G/L

• if it already existed prior to pregnancy or was known since childhood

• if it manifests in the 1st or 2nd trimester of pregnancy

• if the patient or members of her family have a history of bleeding.

The diagnostic investigation into the many different causes of thrombocytopenia, which should be done in early pregnancy if possible, is decisive for obstetric management and the impact on the neonate.

Common clinical symptoms and laboratory results make it difficult to obtain a differential diagnosis, and an interdisciplinary approach (involving the obstetrician, laboratory medical specialist, hematologist) is necessary.

Medical history

• Personal and familial history of excessive bleeding, hematomas, complications of pregnancy

• Known disorders such as thrombotic microangiopathic syndrome (TMA), systemic lupus erythematosus (SLE) or other autoimmune diseases as well as liver diseases

• Thrombocytopenia in a previous pregnancy: time of the decrease in thrombocytes (which trimester of pregnancy, dynamics of the decrease); the extent of the thrombocytopenia, its clinical manifestation, and the gestational age are significant.

• Medication history, e.g., new long-term medication in the last three weeks or sporadic intake of medication

• Eating habits

• Signs of hematomas, petechiae

• Signs of infection (fever, shivering fits)

• Prior pregnancy including the presence or absence of complications

Laboratory tests

• Parallel platelet counts in EDTA and citrated blood samples because of potential false-low results to exclude EDTA-induced pseudothrombocytopenia (< 1%)

• Visual assessment of blood smear during the initial diagnostic workup

Gestational Thrombocytopenia

Definition

Gestational thrombocytopenia is a physiological condition which does not need to be evaluated or treated. It is the most common cause of thrombocytopenia in pregnancy and the most probably diagnosis if platelets counts are between 100 and 149 G/L and there are no symptoms of bleeding [5].

Typical characteristics of gestational thrombocytopenia:

• usually present at delivery but can occur at any time during pregnancy

• mild presentation in 99% of cases (> 100 G/L)

• no severe bleeding or hematomas

• no abnormalities detected in blood smear

• no fetal or neonatal thrombocytopenia

Epidemiology

• Affects 5–10% of all pregnant women

• The most common cause of thrombocytopenia in pregnancy (75%)

• In 75% of cases, the platelet count is between 130–150 G/L, in 1% of cases it is less than 100 G/L.

• Usually occurs in the 3rd trimester of pregnancy

Etiology

Pregnancy-induced hemodilution and increased thrombocyte turnover are the causes of gestational thrombocytopenia (platelet sequestration and consumption in the placenta) [6].

Diagnosis

• Platelet count should be determined in EDTA and citrated blood samples.

• HELLP syndrome must be excluded.

• Progress should be monitored as needed.

• Hematological investigation is recommended if the platelet count drops to less than 100 G/L.

• Depending on the findings, thrombocyte count should be checked every 2–4 weeks to record further decreases.

Therapy/Management

• No specific therapy required

• Obstetric management:

  • Gestational thrombocytopenia does not affect the mode of delivery.

  • Epidural anesthesia/spinal anesthesia may be administered if platelet count is > 80 G/L.

Prognosis

• Asymptomatic, no increased risk of bleeding for the mother or child

• Normalization of maternal platelet counts within 6 weeks post partum, usually already in the first week postpartum [7]

• Neonatal platelet count is normal.

• Women who are status post gestational thrombocytopenia have a 14 times higher risk of recurrence in a subsequent pregnancy [6].

Immune Thrombocytopenia

Definition

Primary immune thrombocytopenia (ITP) is an isolated thrombocytopenia of < 100 G/L without clinically apparent comorbidities or causes. It can also be a secondary feature of an autoimmune disease [8]. ITP can occur in every trimester of pregnancy as well as postpartum.

Epidemiology

• 1–3/10000 pregnancies [3]

• 10× higher than in the general population

• 1–4% of all cases of thrombocytopenia in pregnancy

• ⅔ of cases are known due to typical history of bleeding prior to the start of pregnancy.

Etiology

Formation of specific antibodies against different glycoprotein complexes of the thrombocyte membrane with consequent sequestration of circulating platelets, especially in the spleen. The increased incidence of ITP diagnosed in pregnancy compared to the general population is assumed to be due to the increased number of blood count tests done in pregnancy, the examinations carried out in cases with gestational thrombocytopenia, and the greater prevalence of autoimmune diseases in women compared to men [9].

Diagnosis

A platelet count of < 100 G/L in the 1st trimester of pregnancy followed by a further drop (rarely increase) in platelet numbers over the course of pregnancy are indicative for the diagnosis.

• Evidence of antibodies against platelet membrane glycoprotein complexes

• The absence of evidence of antibodies does not exclude a diagnosis of ITP

• Platelet counts should be checked every four weeks in the 1st and 2nd trimesters of pregnancy and then every two weeks until delivery [3]

Clinical course

Maternal course

• Usually asymptomatic or uncomplicated course

• In rare cases, clinically apparent bleeding complications: there is an increased risk of bleeding if the count drops to 20–30 G/L.

• A slight decrease in platelet counts occurs similar to that in uncomplicated pregnancies and is not an indication of the severity of ITP.

Fetal/neonatal complications

• Autoantibodies may enter the fetal circulation through the placenta, leading to increased platelet reduction in the fetus.

• Thrombocytopenia-related fetal or neonatal bleeding complications are very rare (0.014, 95% CI: 0.008–0.025 for intracerebral hemorrhage; 0.122 [0.095–0.157] for neonatal thrombocytopenia < 50 G/L). There are no reliable predictors of severe neonatal thrombocytopenia. There is no close correlation between maternal and neonatal platelet counts with ITP [10] [11].

• The risk of thrombocytopenia of < 50 G/L in infants born to mothers with ITP is estimated to be 10–15 % [12].

• Risk factors for neonatal thrombocytopenia are status post neonatal thrombocytopenia with severe thrombocytopenia (< 50 G/L) at the same gestational age and maternal thrombocytopenia < 100 G/L at the time of delivery; status post splenectomy.

• Neonatal platelet counts may decrease even further post partum; the typical nadir occurs between days 2–5 post partum [4] which is why daily checks are useful.

• Differential diagnosis: when evaluating the fetus/neonate it is important to be aware of rare severe fetal/neonatal alloimmune thrombocytopenia (FNAIT) which is acquired in pregnancy [13].

Therapy

Treatment of ITP depends on what is required over the course of the pregnancy; administration of corticosteroids or intravenous immunoglobulin are considered the first-choice drugs, especially if bleeding is present [14] [15]. There is no evidence that maternal ITP therapy increases fetal platelet counts. Most female patients do not require treatment [16]. When platlet counts drop < 50 G/l around delivery date it is recommended to check if platelets increase after adminstration of 20–30 mg prednisislon orally.

Glucocorticoids or immunoglobulins (IVIG) are indicated for patients with no bleeding if the platelet count drops to < 30 G/L just prior to the delivery date and a planned birth or if the platelet count drops to < 50 G/L and an invasive procedure such as a planned caesarean section is required ([Table 1]). Treatment should start one week prior to the delivery date. If the count decreases to < 20–30 G/L during the birth, additional platelet concentrates should be transfused. To administer epidural/spinal anesthesia the platelet count should be > 80 G/L.

Table 1 Expected effect and response times.

Therapy	Initial response (days)	Peak response (days)
IVIG	1–3	2–7
Dexamethasone	2–14	4–28
Prednisone	4–14	7–28

Delivery

The mode of delivery should be based on obstetric criteria. The maternal obstetric history and current platelet count should also be considered when planning the mode of delivery. A platelet count of > 50 G/L is considered sufficient for delivery by caesarean section and a platelet count of > 80 G/L is considered necessary prior to the administration of an epidural or spinal anesthetic.

Although the risk of severe fetal bleeding complications is rare, operative vaginal deliveries (forceps, vacuum extraction), placement of a scalp electrode, and fetal blood analysis should be avoided if possible. As fetal thrombocyte counts do not correlate with maternal counts, it is not possible to provide a cut-off figure for maternal platelet counts below which these measures should not be carried out.

It is important to determine the neonatal platelet count using umbilical cord blood immediately after delivery.

Maternal care in any subsequent pregnancy

With ITP there is a risk of recurrence in subsequent pregnancies (Guilett 2023). Regular blood count tests in any subsequent pregnancy are advised but prophylactic treatment is not.

Thrombotic Thrombocytopenic Purpura (TTP)

Definition

TTP is a very rare disease with a prevalence of 5 per 1 million people. The disease usually occurs between the ages of 30 to 40 years. Thrombotic thrombocytopenic purpura is caused by greatly reduced ADAMTS13 activity [17].

There are two forms of TTP:

• congenital thrombotic thrombocytopenic purpura (= hereditary form, Upshaw-Schulman syndrome) due to mutation of the ADAMTS13 gene

• acquired autoimmune TTP mediated by inactivating anti-ADAMTS13 autoantibodies

Etiology

TTP is caused by a deficiency of the zinc-protease ADAMTS13. This metalloprotease cleaves von Willebrand factor (vWF), which is responsible for the cross-linking and adhesion of platelets to damaged blood vessel walls. A decrease of ADAMTS13 activity to under 10% leads to thrombus formation in the smallest blood vessels with generalized platelet aggregation with disseminated thrombosis of the microcirculation, ischemia of downstream tissue and subsequent end-organ failure. Erythrocytes similarly undergo mechanical damage from vascular occlusion, leading to hemolysis.

Pregnancy can be a trigger for acute congenital TTP or the acquired form caused by a pregnancy-induced increase of von Willebrand factor (vWF) and an absolute increase in uncleaved high molecular weight vWF multimers. Physiologically, ADAMTS13 activity drops in pregnancy to a maximum of 50%. Hereditary TTP often becomes apparent for the first time in pregnancy. Acquired TTP is more common and more likely to occur in patients with no familial history of TTP. Acquired TTP occurs with a similar distribution in all trimesters of pregnancy as well as post partum.

Diagnosis

The diagnosis is based on the extent of ADAMTS13 activity, a von Willebrand factor-cleaving protease; activity levels of < 10% confirm the diagnosis of TTP.

Therapy

This is a very rare and acutely life-threatening pathology which always requires treatment in an appropriately equipped maximum-care hospital. Plasmapheresis therapy should be rapidly initiated in consultation with the hematology, nephrology and transfusion medicine departments and started, where possible, within 4–8 h after manifestation of microangiopathic hemolytic anemia and thrombocytopenia. Treatment can decrease maternal mortality from 90% to 10–20% [18]. With acquired TTP it is urgent to start plasmapheresis as this removes anti-ADAMTS13 autoantibodies and supports active ADAMTS13 in the reinfused plasma. For patients with congenital TTP, treatment with plasma infusions is sufficient because this supports ADAMTS13; plasma infusions are started from weeks 5–10 of gestation and continued with increasing frequency in the 2nd and 3rd trimesters of pregnancy and for 6 weeks post partum. Recombinant ADAMTS13 is now available for substitution therapy in persons with hereditary ADAMTS13 deficiency. The first case reports of successful substitution therapies in pregnancy have been published [19]. It is assumed that the ability to cross the placenta is limited because of the relatively high molecular weight of 190000 Da. Administration of this factor is now also possible in Germany in the context of the expanded access to TAK-755 program which provides access on compassionate grounds and is registered with the Paul Ehrlich Institute.

Treatment with Caplacizumab (Cablivi) may also be considered in cases with acquired TTP.

Pregnancy-specific Differential Diagnoses Associated with Thrombocytopenia

HELLP syndrome

Definition

A typical constellation of laboratory findings occurring in pregnancy consisting of hemolysis, elevated transaminases and thrombocytes < 100 G/L. HELLP stands for Hemolysis, Elevated Liver enzymes, Low Platelets. It is a serious disorder of pregnancy but is not necessarily accompanied by hypertension or preeclampsia ([Table 2]).

Table 2 Differential diagnosis of gestational and immune thrombocytopenia in pregnancy.

Parameter	Preeclampsia 2nd–3rd trim.	HELLP 3rd trim.	TTP 1st–3rd trim.	aHUS 3rd trim. postpart.	Acute fatty liver of pregnancy 3rd trim.	Antiphospholipid syndrome 3rd trim.	System. Lupus erythematodes 1.–3. trim.
aHUS = atypical hemolytic uremic syndrome; DIC = disseminated intravascular coagulation; TTP = thrombotic thrombocytopenic purpura
Hypertension	+++	+++	+	++	+	+/–	++
Proteinuria	+++	+++	+/–	+++	+/–	+/–	+++
Upper abdominal pain	+/–	+++	+/–	+/–	++	+/–	+/–
Neurology	+	+	++	+/–	+	+	+
Thrombocytopenia	+	+++	+++	+++	+	+	+
Hemolysis	+/–	+++	+++	+++	+	+/–	+
Reduction of renal function	+/–	+	+	+++	++	+/–	++
ATP/AST >	+	+++	+/–	+/–	+++	+/–	+
DIC	+/–	+	+/–	+/–	+++	+/–	+/–
Approach	Antihypertensives	Rapid delivery of infant	Plasma exchange	Plasma exchange/ecuzulimab	Supportive, rapid delivery of infant	ASS, NMH	Hydrochloroquin, Cortison, Immunsuppressiva

Epidemiology

Together, preeclampsia (2–3%) and HELLP (0.5–0.9%) make up 15–22% of all thrombocytopenias in pregnancy [20]. 93% of cases occur at or after 30 weeks of gestation and 75% at or after 35 weeks of gestation, but they can also manifest for the first time in the postpartum period (up to 30%). The platelet count drops to < 100 G/L in only 7% of cases; it drops to < 60 G/L in just 3% of cases (Perez 2021).

Etiology of thrombocytopenia

Thrombocytopenia is caused by cytokine-mediated endothelial dysfunction with systemic clotting activation and intravascular consumption of platelets and clotting factors. The nadir is reached around 23–29 h after diagnosis. The fetus does not have thrombocytopenia.

Differential diagnosis

For the differential diagnosis, differentiating HELLP syndrome from thrombotic thrombocytopenic purpura (TTP) and complement-mediated thrombotic microangiopathy (TMA) or atypical hemolytic uremic syndrome (= aHUS) is essential. It is particularly important between weeks 25–30 of gestation when the symptoms of neurological ischemia are most obvious or if symptoms do not improve after the birth of the child. Microangiopathic hemolytic anemia and thrombocytopenia occur with TTP and aHUS. The determination of ADAMTS13 activity is indicative for diagnosing TTP.

Clinical symptoms

Upper abdominal pain, hypertension, proteinuria, cephalgias, elevated transaminases, clotting is usually normal, persistence of symptoms for > 72 h after delivery.

Prognosis

The severity of thrombocytopenia correlates with maternal morbidity and perinatal mortality.

Therapy

From week ≥ 34 + 0 of gestation, rapid delivery of the infant is indicated in cases with a severe course [20].

Thrombotic microangiopathy (TMA) – aHUS

Definition

Thrombotic microangiopathy (TMA) is the formation of thrombi in very small blood vessels (arterioles, venoles, capillaries) accompanied by damage to the endothelial cells of these vessels ([Table 2]). TMA leads to ischemia with serious organ dysfunction and may become acutely life-threatening.

Etiology

Complement-mediated thrombotic microangiopathy (CM-TMA) or atypical hemolytic uremic syndrome (= aHUS) are induced by increased complement activation on the endothelial cells. This can lead to the development of microthrombi in the microcirculation of the entire vasculature. The kidneys are most commonly affected. Complications of pregnancy may trigger TMA in the absence of genetic or acquired complement dysregulation.

Non-diarrhea-associated (atypical) hemolytic uremic syndrome is the result of uncontrolled activation of the complement system and can occur in pregnancy or post partum, especially after delivery by caesarean section. The highest risk of developing this disorder is in the postpartum period, and it can occur up to 10 weeks after birth. It is a diagnosis of exclusion although the complement level is not indicative for the diagnosis. In patients with hereditary CM-TMA the first manifestation occurs either in pregnancy or post partum. The symptoms may be similar to those associated with HELLP syndrome or TTP. Obtaining the correct differential diagnosis is a challenge as complement factor C3a levels may be up to 10 times higher in a normal pregnancy (or 20 times higher in cases with preeclampsia or HELLP syndrome). Hemolytic anemia, thrombocytopenia and a rise in serum creatinine levels are diagnostically indicative for TMA.

Congenital complement dysregulation with mutations in CFH, CFHR1, C3 or CF1 are the most common genetic changes associated with aHUS (66%). Genetic dysregulation of the complement system due to mutations in the CFH gene or anti-CFH antibodies is associated with a poor renal prognosis whereas mutations in MVP and C3 (complement factor 3) have a better prognosis (especially in children). MCPC = CD46, DAF = CD55 + CD59, DAF = CD55 + CD59 are complement-regulating factors which protect against excessive complement activation. A temporary imbalance may occur post partum.

Clinical symptoms

The primary symptom is renal function impairment (oliguria, anuria) which can range from acute renal failure potentially requiring dialysis to terminal renal failure in 76% of affected female patients. This type of kidney damage rarely occurs with preeclampsia/HELLP syndrome and TTP. There is also less reduction of ADAMTS13 activity (activity > 10%) and stool samples are typically Shiga toxin-negative (Shigella).

HELLP syndrome may be wrongly diagnosed in female patients with CM-TMA, and this misdiagnosis may only become clinically apparent when the renal function has deteriorated or does not improve after delivery of the infant.

Fetal complications

Fetal complications are rare with aHUS. However, IUFD may occur in the context of thrombosis-related placental infarction affecting decidual vessels of the placenta.

Therapy

Eculizumab: this monoclonal antibody is a terminal complement inhibitor. It blocks uncontrolled terminal complement activation which causes complement-mediated thrombotic microangiopathy and thereby decreases terminal complement activity.

Acute fatty liver of pregnancy

Definition

Acute fatty live of pregnancy (AFLP) is a life-threatening hepatic function disorder which only occurs in the 3rd trimester of pregnancy. It is associated with significant fatty infiltration and a high mortality risk for mother and child (maternal lethality of 10%) ([Table 2]). The incidence is 1 : 5000–10000 births.

Etiology

Disorders of β-oxidation in hepatic mitochondria lead to lipid accumulation. The precise pathophysiological mechanism is still not known. What is known is that fetal defects of the long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) enzyme lead to flooding of the maternal organism with fatty acids or their metabolites.

Clinical symptoms

Uncharacteristic symptoms include loss of appetite, itching, nausea and vomiting with acute deterioration of the mother’s general condition within a few hours to a few days. Development of hypertension caused by the vasoconstrictive effect of free bilirubin is common, along with jaundice, cephalgia and encephalopathy. This combination of clinical symptoms can be an indication of acute fatty liver of pregnancy. Complications include coagulopathy, electrolyte disorders, and multiple organ failure including hepatic and renal failure as well as acute pancreatitis. Maternal mortality (up to 10%) and infant mortality (up to 20%) is high.

The Swansea criteria can be useful for diagnosis, with hypoglycemia an indicative symptom [21].

Therapy

Therapy is supportive (volume and glucose replacement, correction of the coagulopathy; immediate delivery of the infant).

Secondary thrombocytopenias of other origin

Secondary thrombocytopenias can occur in the context of lupus erythematosus or antiphospholipid syndrome [22] [23] ([Table 2]).

Drug-induced thrombopathies

• Thrombocytopenia due to ASS is the result of increased thrombocyte turnover. Bleeding may occur more frequently with ASS. Treatment consists of administering desmopressin.

• Heparin-induced thrombocytopenia (HIT) is very rare in pregnancy. Bleeding occurs in 2% of cases and thrombocytopenia occurs in 0.11%. Bleeding complications and clotting disorders only occur if the doses are incorrect.

• Thrombocytopenia may be associated with taking analgesics (indometacin, ibuprofen, diclofenac), antibiotics, diuretics, antiepileptic agents/sedatives, or antacids.

Infections

HIV, cytomegalovirus, rubella, and parvovirus B19 may cause thrombocytopenia and should also be considered.

Conflict of Interest

The authors declare that they have no conflict of interest.

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Publication History

Received: 21 October 2024

Accepted after revision: 07 December 2024

Article published online:
11 March 2025