Introduction

Pruritic urticarial papules and plaques of pregnancy (PUPPP), otherwise known as polymorphic eruption of pregnancy (PEP), is the most frequently occurring gestational skin abnormality. It is an inflammatory rash that is characteristically benign and pruritic (itchy), beginning on the abdomen in stretch marks before spreading to other areas.¹ Intrahepatic cholestasis of pregnancy (ICP), also known as obstetric cholestasis (OC), on the other hand, is the most common liver disorder that happens during pregnancy. ICP is characterised by pruritus (itchy skin) and elevated serum bile acids. Also, there is an increased risk of adverse fetal outcomes as maternal bile acids are passed through the placenta to the fetus and accumulate in the amniotic fluid.²

Each condition has distinct causes, features, and risks, which will be explored throughout this article.

Aetiology & pathophysiology

Pruritic urticarial papules and plaques of pregnancy (PUPPP) 

PUPPP is a benign inflammatory skin condition that typically affects first-time birth parents in their third trimester but can occur following birth. It is known to happen more with multiple pregnancies (twins or triplets). Recurrence in successive pregnancies is less than 7%, and if it does occur, it is milder.³

The exact cause of PUPPP remains unknown, but several theories have been suggested, such as abdominal distension, hormonal changes, placental factors, and the role of fetal DNA in skin lesions of PUPP patients.^1,3

A previous study postulated that stretching of the abdominal skin, especially in multiple pregnancies, can cause damage to connective tissue within stretch marks (striae) and the exposure of antigens within collagen, which then stimulates an allergic-type reaction as the PUPP rash. The deposition of fetal DNA (similar to skin with increased vascularity and damaged collagen) during the third trimester may be the target of immune reactivity, and an immune response is generated from cross-reactivity to collagen in otherwise normal-appearing skin. High levels of progesterone, particularly in cases of multiple pregnancies, and increased progesterone receptor immunoreactivity have been documented in birth parents with PUPPP. Another idea implies that a placental hormone-type substance may induce fibroblast proliferation in the maternal skin.¹

Intrahepatic cholestasis of pregnancy (ICP)

ICP is a liver disorder occurring in the late second and early third trimester of pregnancy. It involves pruritus (feeling itchy), increased levels of serum bile acids, and other liver function tests. Notably, the symptoms and biochemical anomaly. The aetiology of ICP is poorly understood and is considered to be influenced by multiple factors such as genetics, hormones, and environment. Some persons assigned female at birth (AFAB) may be genetically susceptible, as ICP has been recognised in familial clusters and first-degree relatives, and there is a higher risk of the condition recurring in successive pregnancies. Studies showed evidence of mutation in genes (ABCB4) encoding hepatobiliary canalicular translocator proteins called multidrug resistance 3 (MDR3) via a sex-limited, dominant inheritance pattern. Other genes linked to the development of ICP are ATP8B1(FIC1), ABCB11 (BSEP), ABCC2, and NR1H4 (FXR).² 

Previous studies have also shown an association between high levels of estrogen states, such as multiple pregnancy, ovarian hyperstimulation, and late second-trimester presentation of ICP. Similar ICP characteristics can be seen in persons AFAB taking contraceptive pills high in estrogen, and in those genetically predisposed women, high blood estrogen levels can induce ICP. The role of progesterone has also been investigated, and studies demonstrated that progesterone-sulfated metabolites can partially activate farnesoid X receptor FXR (bile acid receptor) and impair the functioning of the main hepatic bile acid receptor.²

ICP is more common in persons AFAB with a low level of selenium and vitamin D, and is also prevalent in some countries in winter when selenium and vitamin D levels are usually low. Chronic underlying liver disease is correlated with ICP, but it is unknown if liver diseases contribute to the development of ICP or are revealed by pregnancy.²

Epidemiology

Clinical presentation:

• Onset
  • PUPPP – typically late third trimester^1,3
  • ICP - often late second to early third trimester²
• Pruritus
  • PUPPP – intense, starts on the abdomen and extends to the trunk, lower abdomen, under the breasts, and limbs^1,3
  • ICP – intense and generalised, affecting the palms and soles, often worsening at night²
• Rash appearance
  • PUPPP – red, hive-like raised papules and inflamed plaques presenting in abdominal stretch marks (striae) sparing the belly button before affecting other areas; small blisters which can leak straw-coloured fluid and form crusts when scratched may also be present^1,3
  • ICP – no rash, only marks from scratching²
• Other symptoms
  • PUPPP – no other symptoms^1,3
  • ICP – nausea, anorexia, fatigue, right upper quadrant pain, dark urine, pale stool, secondary insomnia, and rarely clinical jaundice²
• Duration
  • PUPPP – ameliorates towards the end of gestation or resolves immediately (or days to weeks) following birth; there is no post-inflammatory pigment change or scarring of the skin^1,3
  • ICP – abnormal liver biochemistry usually returns to normal quickly following delivery; for some individuals, the irregular liver function tests may remain, and there may be an increased risk of developing hepatobiliary disorders later in life² 

Diagnostic clues

Laboratory findings

• PUPPP
  • Labs are typically normal^1,3
  • Diagnosis is clinically based on symptoms^1,3
• ICP
  • Elevated total serum bile acids - greater than 10 micromol/L²
  • Possibly increased liver enzymes - alanine aminotransferase (ALT) and aspartate aminotransferase (AST), not surpassing two times the upper normal pregnancy limit² 
  • Elevated bilirubin in less than 50% of cases at less than 6 mg/dL²
  • High prothrombin time²

Response to treatment

PUPPP

Treatment for PUPP is mainly to alleviate itching and reduce inflammation and redness. Topical corticosteroids and oral antihistamines are utilised and are effective. In severe cases, oral steroids can be beneficial. Measures such as soothing, cool baths, wet soaks, wearing cotton clothes, and using bath emollients and soap substitutes, followed by emollient creams or ointments, also help.^1,3

ICP

Immediate treatment is required following ICP diagnosis with the primary aim of reducing the risk of perinatal morbidity and mortality and relieving maternal symptoms. Ursodeoxycholic acid (UDCA) improves maternal symptoms in around two weeks and improves bile acid levels in two to three weeks. For birth parents who show no improvement in ICP, unresponsive to UDCA, other medications like rifampin, cholestyramine, and S-adenosyl-L-methionine can be used.²

Maternal and fetal implications

PUPPP

In PUPPP, as the condition normally self-resolves postpartum, there is no increased risk to fetuses or birth parents. Importantly, PUPPP is not an indication of early delivery.^1,3

ICP

ICP is linked to severe fetal complications such as preterm labour, sudden fetal demise (stillbirth), preterm birth, fetal distress, meconium-stained amniotic fluid, and neonatal morbidity. Delivery is often done between 36 to 37 weeks to avoid fetal complications for birth parents with extremely high bile acid levels (greater than 100 micromol/L) and risk factors like jaundice (not improving with medications) and a history of fetal demise by 37 weeks (secondary to ICP).² 

FAQs

What is the difference between PUPPP and PG?

PUPPP, which means pruritic urticarial papules and plaques of pregnancy, is a common skin condition that typically appears in the third trimester of pregnancy. It presents as intensely itchy red bumps and raised areas, usually starting within stretch marks on the abdomen and sometimes spreading to the thighs, buttocks, and arms, but it spares the area around the belly button. It's considered harmless to both the birth parent and fetus and is more common in first-time pregnancies or birth parents carrying multiple fetuses.

In contrast, PG, or pemphigoid gestationis, is a rare autoimmune blistering disorder that also causes itching and rash during pregnancy, but it often starts in the second or third trimester and often starts around the navel. PG may progress to form blisters and carries some risks for the baby, such as preterm birth or low birth weight. Unlike PUPPP, PG requires confirmation through skin biopsy and immunofluorescence studies.^1,4

What is the difference between cholestasis and itching?

Cholestasis of pregnancy, or intrahepatic cholestasis of pregnancy (ICP), is a liver condition that causes intense itching without a rash, especially on the palms of the hands and soles of the feet, and often worsens at night. This itching results from the accumulation of bile acids in the bloodstream that impair bile flow in the liver. In contrast, general itching during pregnancy can be caused by benign factors like dry skin, skin stretching, or conditions like PUPPP, and is typically less severe or accompanied by a rash. The key difference is that cholestasis involves liver dysfunction and poses risks to the baby, whereas common pregnancy-related itching is usually harmless.^2,5

How do you identify PUPPP?

To identify PUPPP, a clinician looks at the characteristic appearance and distribution of the rash. It usually begins with stretch marks on the abdomen in late pregnancy and spreads outward, but does not involve the belly button. Itching is a major symptom, and the diagnosis is made clinically, meaning based on symptoms and physical appearance alone, without the need for lab tests or imaging. The condition resolves after delivery.¹

How do you diagnose cholestasis in pregnancy?

Cholestasis in pregnancy is diagnosed through a combination of symptoms and lab tests. A birth parent normally presents with intense, unexplained itching, especially on the palms and feet, with no visible rash. Blood tests are then ordered, primarily measuring serum bile acid levels, which are typically elevated in ICP. Liver function tests may also show elevated enzymes like ALT and AST. If bile acids are above the diagnostic threshold, usually 10 micromoles per litre, along with consistent symptoms, a diagnosis of cholestasis is made, while other causes of liver dysfunction are ruled out.²

Summary 

This article compares PUPPP (pruritic urticarial papules and plaques of pregnancy) and ICP (intrahepatic cholestasis of pregnancy), two pregnancy-related conditions that both cause itching but have very different causes and implications. PUPPP is a benign, itchy rash that usually appears in the third trimester, starting in stretch marks and sparing the belly button. It poses no risk to the baby and resolves after delivery. In contrast, due to elevated bile acids, ICP is a liver disorder marked by intense itching without a rash, especially on the palms and soles. It can lead to serious fetal complications, including stillbirth, and requires prompt treatment and monitoring.

PUPPP is diagnosed based on appearance and symptoms, while ICP is confirmed through blood tests showing elevated bile acids and liver enzymes. PUPPP is treated symptomatically with creams and antihistamines, while ICP is managed with medications like ursodeoxycholic acid to lower bile acid levels. The article also clarifies that, unlike common pregnancy itching, ICP involves liver dysfunction, making early diagnosis and intervention crucial.