The Care of the Pregnant Patient with GI Diseases Mary Pat Pauly, MD FACP AGAF Kaiser Permanente Clinical Professor of Internal Medicine and Gastroenterology at UC Davis

Outine Management of common GI diseases in pregnancy GERD PUD Constipation Special considerations for pregnancy patients requiring endoscopy Special considerations for patients with IBD Management of the pregnant patient with liver disease.

GERD Heartburn Heartburn occurs in 30 – 50% of pregnancies Usually mild symptoms Life style modifications Dietary modifications

35 yo female calls for advice 35 yo female calls for advice. She is about 3 months pregnant and having severe heart burn. She has tried life style changes without success. Her obstetrician advised her to take antacids. Her mother has her taking tums and her neighbor recommended sodium bicarbonate. Her mother in law takes pepcid. Her husband insists omeprazole is the drug of choice. What should she do?

Treatment of Reflux in pregnancy Antacids In general OK , short term – but AVOID Magnesium trisilicates (Gaviscon) Fetal nephrolithiasis, hyponatremia and respiratory distress Excessive calcium carbonate Milk alkali syndrome Hypercalcemia, renal impairment and metabolic alkalosis Avoid -Na HCO3 fetal metabolic alkalosis Fluid overload

FDA classification for the use of Medications in pregnancy FDA pregnancy category Interpretation A Controlled studies in animals and women show no risk in 1st trimester, and possible fetal harm is remote. B Either animal studies have not shown fetal risk but no controlled studies in pregnant women, or animal studies have shown an adverse effect that was not confirmed in women in 1st trimester. C No controlled studies in humans have been performed, and animal studies have shown AE, or studies in humans and animals are not available: give if potential benefit outweighs risk D Positive evidence of fetal risk is available, but the benefits may outweigh the risk if life threatening or serious disease. X Studies in animals or humans show fetal abnormalities: drug contraindicated

What about H2 Blockers and proton pump inhibitors? Category B Tagamet Ranitidine Many studies available supporting safety Pepcid Less data available…makes “choice of another agent prudent.”* PPI Category C Omeprazole Animal toxicity: embryonic toxicity and fetal mortality in preg rats and rabbits. Multiple cohort studies suggest low risk of human toxicity Slightly Increased risk of cardiac malformations Category B Esomeprazole, pantoprazole lansoprazole Limited data: low risk * AGA review of used of GI meds in pregnancy 2006

She is doing better on ranitidine twice daily and has changed to eating her main meal at noon and small dinner She reminds you that her father had history of GERD and Barrett’s esophagus and died of Esophageal cancer at age 40. She asks if she should have Endoscopy to check for Barrett’s?

Endoscopy in the Pregnant patient The need for procedure has to be driving force Must have good indication Elective procedures should be deferred Endoscopy is usually safe during pregnancy – during second and third trimesters Risks include Risk of sedation Risk of hypoxemia Risk of aspiration

35 year old G2 P1 female 32 weeks pregnant comes in with hematemesis and melena. BP 80/60 with pulse 120 and Hb 5.8 Conservative therapy is initially recommended. She is resussitated with fluids and given blood. BP 90/70 P 100. NGT shows BRB not clearing with lavage What do you recommend?

Endoscopy in pregnancy Be certain good indication for EGD For 2nd and third trimester Ob consultation Ob anesthesia consultation Fetal heart tone monitoring Either before and after the procedure or during the procedure if it may be prolonged. Position patient on left side laterally To avoid compression of vena cava by gravid uterus Sedation Minimize sedative drugs Topical anesthesia Recommendation is to “Gargle and spit”

Endoscopy in patient with active GI Bleed - preferred modes of intervention Endoclips Intervention of choice Bipolar cautery Minimizes chance of stray currents going through fetus Injection of epinephrine FDA pregnancy category C Can be associated with decreased uterine blood flow A note about Monopolar cautery Avoid having the uterus between the catheter and grounding pad Consider grounding pad in upper right arm if this mode is necessary

Hospital coures FHT were normal after the procedure She recovered from sedation Was kept on side with HOB elevated after procedure She was started on IV Pantoprazole …and the Clotest was positive for HP !! What would you recommend now?

Gall stone pancreatitis with Cholangitis Can be associated with sepsis, end-organ failure and death. Can lead to pre term labor and fetal loss Charcot’s triad – RUQ pain, jaundice and fever Reynold’s pentad – add hypotension and confusion Treatment of choice - ERCP But in general Best avoided until after first trimester when organogenesis is complete Wait until second or third trimester when possible

But the pain recurred 2 days ago and progressed 28 year old pregnant female at 34 weeks gestation presents to ER at 11pm with severe RUQ pain,N,V,T and shaking chills. These sx are similar to sx that resolved spontaneously when she was 8 weeks pregnant with gall stones pancreatitis and recovered with conservative medical therapy. Plan was to have cholecystectomy after delivery. But the pain recurred 2 days ago and progressed she noticed dark colored urine the day of presentation. Temp 102

Which antibiotics are safe to be used in pregnancy? Initial vs: T 101, BP 100/70 P 120 O2 sat 1--% on 2 L with resp 16 RUQ tenderness Labs: ALP 456 AST/ALT 468/502 Bilirubin 3.1 Amylase and lipase nl Creatinine 1.3, Initial management included IV fluids, O2,NPO, admission to ICU and antibiotics Which antibiotics are safe to be used in pregnancy?

Antibiotics inidcated and contraindicated in pregnancy Safe in pregnancy Cephalosporins Penicillins Clindamycin Gentamycin Contraindicated in pregnancy Quinolones Tetracyclines streptomycin Avoid during the first trimester metronidazole (flagyl) Avoid during second and third trimester sulfonamides nitrofurantoin

The patient was placed on Zosyn The next day the patient was still in pain requiring IV pain medications. VS 110/40 100 resp 20 and O2 sat 100% on 2L O2 Labs: ALT and AST still >450 Bilirubin 5.9 US – 8 mm stone in 11 mm distal CBD – What is the best management at this point?

ERCP in pregnancy Keep procedure and fluoro time to minimum Pre op Antibiotics Ampicillin (B) and gentamycin (B) Positioning of pt Prone is difficult On back increases compression of aorta and/or vena cava Preferably left lateral position Head up a little to avoid aspiration Radiation Shield the baby Lead between patient and table radiation comes from below Keep procedure and fluoro time to minimum

What about sedation? Use as little sedation as possible Propofol and demerol are drugs of choice. Small amounts of IV versed are OK if needed Fentanyl crosses BBB more quickly Many recommend FHT monitored during procedure or at least prior to and after procedure OB consult and preferably OB Anesthesia to assist Esp if case may be long Cetacaine or hurricane spray is OK but most recommend “gargle and spit.” If breast feeding, pump and dump.

What about cautery Sphincterotomy requires Monopolar cautery Put grounding pad on right arm Never allow uterus to be between the cautery and the grounding pad. Amniotic fluid is good conducting medium

She was evaluated by OB FHT checked just prior to sedation Our most experienced and expert endoscopist did ERCP Cannulated and aspirated bile Made a sphincterotomy and extracted stone OB returned to check FHT 30 minutes later. Uneventful recovery Cholecystectomy scheduled for later …after delivery.

What is my chance of transmission to my baby? 24 yo Hmong female 25 weeks pregnant with Hepatitis B asks for advice. She has had HBV since she was born and transmission at birth as her mother had HBV and now has cirrhosis. She in HBeAg positive, HBeAb negative persistently normal ALT 17 – 19. High viral load 6 x 10 (9) What is my chance of transmission to my baby? Is there anything that can be done to decrease the chance of transmission

Anti- viral therapy decreases rate of transmission of HBV Active and passive immunization has decreased transmission rates of HBV 90% effective HBIG and vaccination within 12 hours of birth Followed by additional 2 doses of vaccination If HBV viral load >10 (8) chances of transmission is higher Up to 38% in some studies Lamivudine100 mg daily in third trimester decreases rate of transmission

28 year old female with Hepatitis C asks for advice. She has hepatitis C genotype 2 viral load 392,000 IU/ml normal ALT no signs of chronic liver disease INR, bilirubin, and platelet count are normal No medical problems Contemplating pregnancy Effect of pregnancy on disease? Effect of disease on pregnancy? Chance of passing disease on to baby?

HCV - Modes of Transmission Blood Blood transfusions – before 1992 Intra venous Drug abuse Dialysis Tattoos, piercing, razors, toothbrush Other Intranasal cocaine Sexual Mother to baby (< 5 %) Associated with higher viral load HIV co-infection

Pregnancy in patients with Inflammatory Bowel Disease The highest age adjusted incidence of IBD overlap the peak productive years Newer medications allow patients to be healthier and disease free For longer periods of time And this …leads to Increased opportunity of successful conception

AGE AND SEX DISTRIBUTION OF IBD Crohn’s disease and ulcerative colitis can have their onset at any age, but the peak incidence is in late adolescence and early adulthood. In some studies there is a second peak of Crohn’s colitis in women during their 6th and 7th decades of life. In general, the frequency of ulcerative colitis and Crohn’s disease is similar in males and females with a very slight female predominance in some studies. Multiple studies demonstrate a correlation of proximal Crohn’s disease (gastric, duodenal and small bowel location) with early onset disease and of colonic inflammation with late onset Crohn’s disease. • Rogers BH, Clark LM, Kirsner JB. The epidemiologic and demographic characteristics of inflammatory bowel disease: an analysis of a computerized file of 1400 patients. Journal of Chronic Disease 1971;24:743.

32 year old woman newly diagnosed with Crohn’s disease Moderate to severe ileo-colonic CD She has questions about the most effective therapies After complete review with physician she is placed on budesonide 9 mg daily She has concerns about the impact on pregnancy Disease medications

Treatment of Crohn’s Disease Surgery Bowel rest Cyclosporine Anti TNF agents Infliximab Adalimumab certolizumab 6MP, AZA, MTX Corticosteroids Antibiotics mesalamine

Before pregnancy Be sure disease under good control Preferably in remission Active disease associated with Decreased ability to conceive Increased risk of spontaneous abortion Ideally healthcare maintenance up to date Check iron, B12, folate, vitamin D leve Vitamin D deficiency is associated with infertility Identify high risk obstetrician Counseling regarding medications during Pregnancy Breast feeding

Common questions Inheritance? Fertility ? Effect of pregnancy on disease activity? Effect of disease on pregnancy outcomes? Safety of medications? Management of flares?

Inheritance Multifactorial One parent with CD 5% chance for offspring One parent with UC 1.6% If both parents have IBD a child’ risk of IBD is higher Pregnancy should not be discouraged for this reason

Fertility With either UC of CD, the risk of infertility prior to surgery is probably similar to the general population In UC patients there seems to be decreased fertility after IPAA (J pouch) As much as 40-80% One study from Scotland * fertility was only 1/5th of those with UC prior to IPAA. *Olsen KO et al. Gastro 2002;122:15-19

Effect of Pregnancy on Disease Activity in IBD Chances of flare Same as non pregnant patient 33%per year Postpartum flares Usually associated with medication discontinuation

Pregnancy outcome in IBD In general Healthy pregnancies Healthy babies Even with disease in remission Higher rates of adverse outcomes preterm birth Spontaneous abortion Low birth weight Complications of labor and delivery

Medications in IBD use during pregnancy Stopping medications during pregnancy can be harmful Increased risk of flare Harmful to pregnancy Impair ability of mother to care for child after delivery Most medications are low risk and compatible with pregnancy and lactation Except METHOTREXATE (X) Teratogenic Discontinue 3-6 months prior to pregnancy

Medications in IBD use during pregnancy Mesalamine (B) Safe for use in preg Sulfasalazine Folate 2 gm daily ASACOL (C) Recently reclassified to class “C” Due to presence of dibutyl phthalate in the coating Azothioprine and 6-mercaptopurine (D) controversial Consider risks and benefits Teratogenic in animals Increased rate of VSD and ASD* Increased rated of Premature birth Low birth weight Probably disease related * Swedish Medical Birth Register Cleary Birth Defects Research 2009;85: 647-54

Corticosteroids ( C) Prednisone Considered low risk during pregnancy Can be used for flare up Risk in mother Gestational Diabetes Risk to baby Overall risk of malformations is low Increased risk of cleft palate Use in first trimester

Anti –TNF agents Inlfiximab and adalimumab Certolizumab Low risk Low risk, can be used in pregnancy IgG1 antibodies Cross placenta Can be detected in infant for up to 6 m after delivery Last dose at 30 -32 w Avoid live vaccines for 6 m Certolizumab Low risk Can be used in pg Fab fragment Minimal placental transfer by passive diffusion Continue through pg No change in vaccination schedule

The same 32 year old woman recently diagnosed with Crohn’s disease and currently being treated with Budesonide returns 16 weeks pregnant with problems. Remember Moderate to severe ileo-colonic CD Presentation pain, distention, n,v, and obstipation. T 102, palpable mass in LQ. ESR 64, CRP 6.8, WBBC 17,800 Admitted and placed on Antibiotics and underwent imaging study to rule out abscess.

Antibiotics indicated and contraindicated in pregnancy Safe in pregnancy Cephalosporins Penicillins Clindamycin Gentamycin Contraindicated in pregnancy Quinolones Tetracyclines streptomycin Avoid during the first trimester metronidazole flagyl Avoid during second and third trimester sulfonamides nitrofurantoin

Imaging studies in CD CT should be avoided in pregnancy US MRI No contraindications MRI OK if imaging study is needed but Avoid gadolinium – especially in first trimester Teratogen

She was treated with Zosyn and underwent MRI There was inflammatory mass in RLQ Ileum She improved clinically Afebrile, no distention, good BMs, Steroids were added and she was started on a taper She was switched to anti TNF agent certiluzimab

One more consideration… Modes of delivery Usually at discretion of high risk Obstetrician C-section preperred Active perianal diseae Ileal-pouch anal anastomosis Preserves sphincter continence

Pregnancy in patients with cirrhosis Pregnancy is usually NOT encouraged in patients with cirrhosis Pregnancy is rare in patients with cirrhosis Advanced liver disease does not typically occur until later in life Until after most patients have completed their reproductive years. Higher incidence of anovulation and amenorrhea Due to metabolic and hormonal derangements Maternal mortality is higher in cirrhosis

Pregnancy in cirrhosis – effects on the fetus Data is sparse Increased spontaneious abortin rate Increased risk of prematurity Increased perinatal death rate

Effects of cirrhosis and portal hypertension Esophageal variceal bleeding – varices get worse during pregnancy Reported in 18 – 32% with cirrhosis Up to 50% of those with known portal hypertension Up to 78% in those with pre-existing varices. Most commonly in 2nd and 3rd trimester Blood volume highest Fetus compreses IVC Mortality rates are high Reports up to 18 – 50% mortality in cirrhosi with PHTN – and only about 2-6% in pateints with non cirrhotic portalhypertension

Treatment of variceal bleeding Endoscopic variceal band ligation Superior to sclerotherapy – no chemicals instilled into blood stream. -Expert opinion Octreotide (B) Safety in pg not determined Could cause arterolar vasospasm Decreased placental perfusion and increased risk of placental abruption as well as HTN, MI, peripheral ischemia Endoscopy Safe when done with caution

Prophylactic treatment of varices in cirrhosis Screening EGD Before pregnancy Or at beginning of second trimester* Blood volume increased Gravid uterus compressing IVC Prophylaxis – options non selective beta blockers Or variceal band ligation * AASLD recommendations

Pregnancy and cirrhosis Review of data from 1984 – 2009 Kings College Hospital 62 pregnancies in 29 women Median MELD was 7 (range 6 – 17) Median CPS was 5 ( range 5-8) Live birth rate was 58% Median gestational age 36 w Westbrook RH et al ClinGastroHep 2011;9: 694-9

Pregnancy and cirrhosis Maternal complications occurred in 10% Ascites Encephaolpathy Variceal hemorrhage Associated with MELD > 10 MELD predicted which patients were to have liver related complications AUC 0.8 83% sensitivity and 83% specificity No one with MELD <6 had any liver related complications Westbrook RH et al ClinGastroHep 2011;9: 694-9

Constipation in pregnancy Fiber is first line therapy Lactulose (B) Magnesium containing products (B) Senna (C)* Lubiprostone (C)* PEG (C)* Do not use Castor oil (X) – associated with uterine rupture *Low risk if used short term

In summary Many young women who are pregnant have GI problems and will seek care from gastroenterologists It is very important for the mother to be as healthy as possible Treat the disease in mother so she will be able to have a healthy baby When treating patients you must consider the effects of the medications on the baby as well as the mother No drugs that we routinely use are class A Use class B or C drugs when the benefit outweighs the risk

Remember special concerns when performing endoscopy And special considerations for sedation Propofol when available and position pt appropriately Patients with IBD and cirrhosis have higher rates of complications when pregnant Patients with IBD need extra special care and follow up Get disease under control with as safe a medication as possible Patients with cirrhosis have high risk of variceal bleeding and other complications Pregnancy is strongly discouraged Screen for varices and treat prophylactically when possible.