Gastrointestinal complaints during pregnancy

Nausea, reflux and other functional gastrointestinal symptoms are common in pregnancy and can often be managed with dietary or lifestyle modification. Drug interventions, although safe for mother and child, are reserved for refractory symptoms. A careful history and diagnosis are necessary for pregnancy-associated liver disease. In the case of preeclampsia, HELLP syndrome or acute fatty liver of pregnancy, delivery is the only effective therapy. Gallbladder symptoms are common in pregnancy, and cholecystectomy should be performed laparoscopically in the second trimester. In choledocholithiasis, ERCP is a justifiable form of therapy.

The majority of all pregnant women suffer from nausea and vomiting mostly during the first trimester. The extreme form of nausea and vomiting, hyperemesis gravidarum, requires active treatment to ensure the health of both mother and child. In addition, functional gastrointestinal complaints such as heartburn, reflux and constipation are very common during pregnancy. Lifestyle modifications and a change in diet are often successful as initial measures. If symptoms persist, drug therapies are necessary to improve quality of life and prevent complications. Pregnancy-associated liver diseases are complex and potentially very severe medical conditions. The spectrum ranges from biliary colic and benign intrahepatic cholestasis to life-threatening preeclampsia and HELLP syndrome, which necessitate immediate delivery. Patients and physicians are often uncertain about low-risk medications or treatment options during pregnancy. This review presents the spectrum of pregnancy-associated gastrointestinal disorders and liver diseases and their therapy.

Nausea and vomiting

50-90% of all pregnant women suffer from nausea and vomiting mostly during the first trimester [1–3]. Risk factors for nausea and vomiting in pregnancy are recognized as young age, obesity, first pregnancy, and smoking. If symptoms persist into the third trimester, other causes should be investigated. For some women, dietary changes (smaller, high-carbohydrate meals) or alternative remedies such as acupuncture or ginger are sufficient for symptom management [4]. According to recent meta-analyses, however, the efficacy of alternative healing methods is questionable [5,6]. Vomiting should be differentiated from gastroesophageal reflux and regurgitation, which patients often refer to as “vomiting,” by taking a detailed history. For reflux or regurgitation, antacids, alginates, H2 receptor blockers, or, if necessary, proton pump inhibitors (PPIs) may be effective.

The extreme form of nausea and vomiting in pregnancy is hyperemesis gravidarum; rehydrating and antiemetic therapy is indicated for weight loss and exsiccosis. Thus, rare, severe complications such as Wernicke’s encephalopathy can be prevented by thiamine deficiency [7]. For severe nausea and vomiting, antiemetics that have a low risk to the fetus when used include metoclopramide (10 mg orally, rectally – soon to be available as a nasal spray), prochlorperazine (5 mg orally), trimethobenzamine (300 mg orally), and ondansetron (4-8 mg sublingually). However, after continuous use of metoclopramide, prochlorperazine, or trimethobenzamine during pregnancy, withdrawal symptoms and extrapyramidal side effects have been observed in neonates [3,8]. Doxylamine pyridoxine (10 g) and vitamin B6 (10 g) are recommended by several guidelines as safe and effective first-line therapies and have high fetal safety [9–11].

Gastroesophageal reflux

Reflux symptoms in pregnancy are no different from symptoms of typical gastroesopahegal reflux disease. Heartburn, belching, and regurgitation occur in 30-80% of pregnant women. Often, pre-existing reflux symptoms are exacerbated by pregnancy [2,12]. Extraesophageal manifestations of reflux disease are rare in pregnancy [13]. Pathophysiologically, there is a decrease in lower esophageal sphincter pressure during pregnancy due to increased estrogen levels. In addition, there are structural changes at the gastroesophageal junction, increased intra-abdominal pressure, and gastric compression due to the enlarged uterus.

Because of the relatively short duration of reflux during pregnancy, severe complications are rare. Thus, endoscopic diagnosis is necessary only in isolated cases and only in the presence of clear alarm symptoms such as dysphagia or evidence of gastrointestinal bleeding [2,14].

Lifestyle modifications and dietary changes have great therapeutic importance in gastroesophageal reflux in pregnancy. Figure 1 summarizes a possible treatment algorithm. For mild symptoms, elevating the head of the bed, avoiding late meals, and eating smaller meals more frequently are often sufficient.

Medication should be considered for persistent, severe symptoms. Antacids may improve symptoms in the short term and have no teratogenic effects. However, sodium bicarbonate (risk of metabolic alkalosis and fluid overload) and long-term therapy with magnesium-containing preparations (risk of decreased uterine contractility) should be avoided [8]. Alginate preparations (e.g., ^Gaviscon® 5-10 ml after meals and before going to bed) form a viscous layer on the stomach contents, reducing acid and non-acid reflux for up to two hours. This mechanism reduced the number of reflux episodes in studies compared to conventional antacids (^Alucol®) [15]. The safety and efficacy of the use of ^Gaviscon® during pregnancy has already been demonstrated in clinical studies [16,17]. Sucralfate is also not absorbed and, along with alginates, appears to be another first-line drug option in pregnancy, although limited data on its use are available [18–20].

If there is no response to the above measures, H2 receptor blockers may be used. Although one study reported an increased preterm birth rate with regular medication with H2 blockers, large meta-analyses were able to refute this conjecture [8,21].

Proton pump inhibitors (PPIs) should be used only in cases of refractory symptoms, as increased embryonic mortality had been shown in animal studies at therapeutic doses of omeprazole. No relevant toxicity to the fetus has been demonstrated for esomeprazole and lansoprazole in animal studies. Prospective studies of human use are not available [3,22,23], but according to larger retrospective studies and meta-analyses, the use of omeprazole, esomeprazole, lansoprazole, and pantoprazole appears to be safe in humans during pregnancy even in the first trimester [23–29]. If PPIs are used in pregnancy, they show a good effect on reflux symptoms in many patients. Table 1 summarizes the risk stratification of the individual PPIs that can also be used in pregnancy at standard doses [3].

Flatulence, constipation and other abdominal complaints

Bloating and constipation are also common during pregnancy, occurring in 25-40% of pregnant women. These symptoms are mainly hormonal (slowing effect on gastrointestinal motility and altered water absorption). Additionally, decreased physical activity contributes to constipation [2,30,31]. Constipation in pregnancy rarely has a serious cause, yet a careful history and clinical examination are mandatory. Endoscopic workup should be considered only when alarm symptoms are present.

In this patient group, hemorrhoids are the first thing to think of when fresh blood is discharged ab ano. Anemia is very common in pregnancy and is physiological up to a hemoglobin level of approximately 105 g/l. However, a lower hemoglobin value should be clarified. Mostly it is caused by iron deficiency with ferritin <20 µ/l. In these cases, iron should be substituted [32]. In addition, folate and vitamin B12 deficiency may occur. These vitamins should also be substituted to avoid complications such as low birth weight and prematurity [33].

Pregnant women should be advised to maintain adequate fluid intake and physical activity [34]. A diet rich in fiber is equally important. Fiber-rich stool regulants are effective in pregnant women but may also increase bloating [35,36].

Only in cases of severe constipation symptoms is drug therapy indicated during pregnancy. Many drugs with prokinetic agents, such as antraquinone and castor oil, are contraindicated because of their teratogenic or labor-inducing effects. In contrast, bulking agents such as psyllium (e.g., ^Metamucil®) or Sterculia (e.g., ^Normacol®) and also osmotic laxatives such as polyethylene glycol (PEG) can be used safely in pregnancy; these appear to be effective [37].

Hemorrhoids

One third of all pregnant women suffer from symptomatic hemorrhoids. Again, stool-regulating measures and local therapies should be recommended. Scheriproct® can be used as a topical measure after the first trimester [38]. For persistent bleeding from internal hemorrhoids, rubber band ligation, infrared coagulation, or sclerotherapy during pregnancy are safe and effective [39,40].

Inflammatory bowel disease and pregnancy

Inflammatory bowel disease (IBD) includes Crohn’s disease  and ulcerative colitis. With currently available therapeutic options, a good outcome of pregnancy and IBD can be expected in more than 80% of patients, especially with remission at the time of conception [41]. While the clinical course of Crohn’s disease is not affected by pregnancy, disease activity of ulcerative colitis appears to be somewhat increased during and immediately after pregnancy [41,42]. The reasons for this are unclear, but could be related to hormonal effects or smoking cessation.

Significant activity of IBD during pregnancy increases the risk of preterm birth, low birth weight, and genital blood leakage, among others [43–46].

For investigations and therapies during pregnancy, the risk of intestinal inflammation to the pregnancy must be weighed against potential risks of the therapies [41]. Endoscopy is also justifiable in pregnancy after careful consideration of the benefits and risks, whereas imaging procedures should be limited to ultrasound or MRI. 5-Aminosalicylic acid is considered a safe drug, and azathioprine should also be passed during pregnancy. Methotrexate is absolutely contraindicated due to its highly teratogenic effect. For infliximab and adalimumab, a pause in therapy during the third trimester should be considered to minimize transfer to the unborn child via the placenta. Short-term glucocorticoid administration is considered acceptable when well indicated, at least after the first trimester. In case of doubt and complicated courses, always consult with a center [41].

Gall bladder disease during pregnancy

Pregnancy, gallbladder disease prior to becoming pregnant, and obesity are risk factors for developing gallstone disease. The incidence is 0.3-0.5%, and the symptoms of biliary colic or cholecystitis are the same as in non-pregnant patients [47–49]. In the first trimester, symptomatic cholecystolithiasis should be treated conservatively with analgesics and antibiotics. Laparoscopic cholecystectomy as the surgical method of choice should be performed only in the second trimester. Several studies show that continuation of conservative therapy until delivery increases the risk of recurrence of biliary colic with complications including pancreatitis [2,50]. In cases of choledocholithiasis, endoscopic retrograde cholangiopancreatography (ERCP) is acceptable, even in pregnant women, provided that the use of ionizing radiation is minimized [50,51].

Liver diseases of pregnancy

Pregnancy-associated liver disease is described in up to 3% of all pregnancies. The individual diseases occur at different stages of pregnancy, which can facilitate diagnosis (Tab. 2) . During pregnancy, liver function and blood flow change due to hormonal influences. Gamma-glutamyltransferase (GGT)  is decreased, as is albumin. Alkaline phosphatase (AP) is elevated due to the production of an isoenzyme in the placenta. In contrast, alanine transaminase (ALT) and aspartate transaminase (AST) are within the normal range during pregnancy. Any transaminase elevation should be clarified [2,52].

In the first trimester, hyperemesis gravidarum may explain elevated transaminases. In 70% of patients with this clinical picture, there is an increase in transaminases, which disappears after adequate rehydration. Risk factors include late-onset hyperemesis and severe ketonuria. Intrahepatic pregnancy cholestasis occurs from the 30th week of pregnancy and disappears after delivery [53]. The etiology is multifactorial and includes genetic risks and alterations in progesterone metabolism. The increase in bile acids can cause severe pruritus and jaundice. Transaminases and GGT are often normal. Gestational cholestasis is associated with prematurity and increased fetal mortality [54]. Ursodeoxycholic acid (UDCA) reduces pruritus and jaundice as does cholestyramine. Because bile acid sequestrants decrease the absorption of fat-soluble vitamins (A, D, E, K), vitamin supplementation should be considered during cholestyramine therapy [55].

Preeclampsia and HELLP syndrome

Preeclampsia accounts for more than half of all cases of elevated liver enzymes in pregnancy and occurs in 2-8% of all pregnancies, usually after 20 weeks of gestation. Hypertension, proteinuria, and edema are leading symptoms. First-time mothers, women with multiple pregnancies, and patients with pre-existing arterial hypertension or diabetes mellitus are particularly at risk [53]. A 1.5- to 5-fold increase in transaminases and mild AP elevation with normal liver function are observed in the setting of preeclampsia. Although pregnant women with preeclampsia require close monitoring and possibly antihypertensive therapy (magnesium sulfates), therapy for elevated liver enzymes is not necessary [54].

In 5-10% of patients, severe preeclampsia develops into HELLP syndrome characterized by hemolytic anemia, transaminase elevation, and thrombocytopenia. HELLP syndrome typically occurs in the second and third trimesters. However, especially in the setting of preexisting preeclampsia, HELLP syndrome may also manifest at most two days postpartum. Clinically, HELLP syndrome presents with nausea, vomiting, headache, and visual disturbances. Coagulation disorders and renal failure are often complicating factors [54]. The only effective therapy is delivery. Maternal mortality is 1-3.5%, and infant mortality is determined by gestational age at delivery [56].

Acute fatty liver of pregnancy

Acute fatty liver of pregnancy is a serious condition that occurs in the last trimester of pregnancy. A defect in the metabolism of long-chain fatty acids leads to an accumulation of the fatty acids first in the liver of the unborn child and subsequently in the liver of the mother with consecutive liver damage. Nausea, vomiting, upper gastrointestinal bleeding due to liver failure, encephalopathy, renal and multi-organ failure are part of the clinical picture of acute fatty liver of pregnancy. Delivery is also the treatment of choice in this case. In severe cases, liver transplantation is necessary in the mother. Neonatal mortality in mothers with acute fatty liver of pregnancy ranges from 20% to 60% [54].

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