Hyperemesis+Gravidarum obstetrics and gynecology

Education

1. HYPEREMESIS GRAVIDARUM Dr.SABIRA AP-OBG PK DIMS

2. Contents 2 Introduction Epidemiology Pathogenesis Complication: Maternal Complications ; Fetal Complications Approach Clinical Presentation Laboratory Abnormalities Tools for assessing severity of NVP Management Principles Pregnancy Termination Prevention References

3. Introduction 3 Definition  Hyper – Emesis – Gravidarum = Excessive – Vomiting - Pregnancy No single accepted definition  Severe unrelenting N & V sufficiently enough to produce  Weight loss: > 5% of prepregnancy weight  Dehydration  Ketosis  acute starvation  Alkalosis  Loss of HCL  Hypokalemia

4. morning sickness 4 The term is misleading Only 2% during morning But 80% of symptomatic patients had nausea or vomiting throughout the day

5. Epidemiology 5  Nausea and vomiting occurs in > 50% of pregnancies Recurrence of nausea and vomiting of pregnancy with subsequent pregnancies ranges from 15–81%  HEG occurs in only about 0.5- 2% of pregnancies incidence is variable due to different diagnostic criteria and ethnic variation in study populations  HEG is the most common indication for of hospital admission during 1 st trimester and is 2 nd only to preterm labor as the most common reason for hospitalization during pregnancy

6. Pathogenesis 6 Risk factors Young age < 30yrs Primigravid Multiple gestation, Molar pregnancy Prior unsuccessful pregnancy Prior HG (Recurrence: 15 – 20 %) – Reported HG recurrence rates vary, from 15.2% in a Norwegian hospital registry study to 81% if using self- reported diagnosis (ACOG - 2018 Heartburn and acid reflux Non- use of multivitamins during peri- conceptional period

7. Female fetus: increases the risk by 1.5- fold unknown reasons— perhaps estrogen- related— a female fetus Family history of Hyperemesis Gravidarum (genetics) suggested by the concordance of MZ twins & family members are more likely to be affected unplanned pregnancies long- term users of marijuana Cannabinoid hyperemesis syndrome (CHS) Underweight and obesity 7

8. Protective factors – Maternal prepregnant smoking reduced the risk of hyperemesis 8 Cigarette smoking is associated with lower levels of hCG and estradiol, and numerous studies have shown that smokers are less likely to have hyperemesis gravidarum

9. While there are numerous theories regarding the cause of HEG, the cause remains controversial Theories  Hormonal  Psychogenic  Dietetic deficiency  Evolutionary Adaptation Theory  Allergic or immunological basis  Decreased gastric motility 9

10. 1) Hormonal 10 Hormone Source Proposed mechanism Beta hCG↑ Corpus luteum Placenta  Crossover with TSH, causing Gestational hyperthyroidism So HEG peaks at 8 – 12 weeks & and decline afterward Progesterone↑ Placenta  relaxation of cardiac sphincter (LES)  impaired gastric motility leading to retention of gastric fluids Estrogen ↑ Placenta  Trigger vomiting center

11. 2) Psychogenic 11 Is it a predisposing factor or a complication of HEG – Still controversial It probably aggravates vomiting center Conversion disorder, somatization, excess perception of sensations by the mother are the other theories

12. 3) Dietetic deficiency 12 Probably due to low carbohydrate reserve Deficiency of vitamin B6, Vit B1 and proteins may be the effects rather than the cause Unless it is not quickly rectified, features of dehydration and carbohydrate starvation supervene and a vicious cycle of vomiting appears  Vomiting  carbohydrate starvation  ketoacidosis  vomiting

13. 4) Evolutionary Adaptation Theory 13 suggest NVP is a healthy, protective response to pregnancy an evolutionary adaptation developed to protect the woman and her fetus from foods that might be potentially dangerous This may explain the temporary aversions to tastes and smells that pregnant women experience Clinical application It may lead to undertreatment

14. Natural Course 14 Mean onset of symptoms: 5- 6 weeks of gestation Peak: 9 th weeks majority of cases are resolved by week 16 - 18 of gestation About 15 – 20% continue until the third trimester About 5% continue until till delivery

15. Pathologic Changes 15 Pathological changes are due to the combined effect of dehydration & starvation consequent upon vomiting Circulatory Hemoconcentration  ↑ed Hb, RBC count, hematocrit Slight ↑ in the white cell count with ↑ in eosinophils There is concomitant reduction of extracellular fluid

16. Metabolic changes Inadequate food intake  low carbohydrate  glycogen depletion This time, fat reserve is broken down incomplete oxidation of fat  Ketosis acetone is ultimately excreted through the kidneys and in the breath ↑ endogenous tissue protein metabolism  ↑ urinary excretion of nitrogen Water and electrolyte metabolism are also seriously affected 16

17. Biochemical  Starvation  acidosis  Loss of HCL, water and salts in the vomitus Hypochloremic alkalosis, Hyponatremia, hypokalemia  Hepatic dysfunction ↑ blood urea, uric acid o hypoglycemia, hypoproteinemia and hypovitaminosis 17

18. Organ specific derangements 18 Liver  transient hepatic dysfunction  ↑ Liver enzymes  There is centrilobular fatty infiltration without necrosis Kidneys  Usually normal with occasional findings of fatty change in the cells of 1 st convoluted tubule, which may be related to acidosis  prerenal azotemia Heart  There may be subendocardial hemorrhage Brain  Small hemorrhages in the hypothalamic region giving the manifestation of WE

19. Maternal Complications 19 Serious and Life- Threatening Complications of Recalcitrant Hyperemesis Gravidarum  Acute kidney injury - may require dialysis  Dehydration  Stress ulcer in the stomach  Rhabdomyolysis Rare, but a potentially life- threatening syndrome Due to profound hypokalemia Which results in a diminished blood flow of muscle arterioles

20.  Esophageal rupture Mallory- Weiss tear nontransmural – a esophageal tear Much more common cause of upper GI bleeding during pregnancy due to mechanical trauma (continuous retching) at the GE junction from nausea and vomiting Boerhaave syndrome a transmural (full- thickness) perforation  upper gastrointestinal bleeding  UGIB, pneumothorax, pneumomediastinum, pneumopericardium 20

21.  Wernicke encephalopathy 21 Due to thiamine deficiency (Vit B1) - a coenzyme essential for intricate organic pathways and plays a central role in cerebral metabolism Triad ፡ – Encephalopathy (confusion), Oculomotor dysfunction (horizontal nystagmus), Gait ataxia abnormal EEG may be seen, and usually MR imaging shows findings long-term sequelae include blindness, convulsions, and coma Severe cases may progress to korsakoff psychosis associated with fetal death in 40% of cases

22.  Hypoprothrombinemia 22 vitamin K deficiency causing maternal coagulopathy fetal intracranial hemorrhage (vitamin K embryopathy) Mgt: vitamin K replacement  Thrombosis Risks: dehydration & bed rest Consider thromboprophylaxis for those with additional risk factors it constitutes a risk factor for thromboembolism. Consider thromboprophylaxis for those with additional risk factors

23. Fetal Complications 23 Studies have documented a lower rate of miscarriage among women with NVP and HEG when compared with controls This result is thought to be due to robust placental synthesis in a healthy pregnancy rather than a protective effect of vomiting No significant association of HEG with congenital anomalies has been demonstrated

24. a systematic review and metaanalysis of women with HEG showed a higher incidence of LBW and SGA infants and premature infants However, no association of HEG and perinatal or neonatal mortality has been demonstrated in large retrospective cohorts One study did show that women with HEG who gain < 7 kg during the entire pregnancy have a slightly higher risk of LBW & preterm birth But, no congenital anomalies or ↑ed risk of miscarriage or stillbirth noted 24

25. Clinical Presentation 25 Historical Findings  Excess vomiting & retching  Xerostomia (dryness of mouth)  sialorrhea or ptyalism (excess saliva)  Dysgeusia  Hyperolfaction  Oliguria  Seldom mental symptoms  Epigastric pain  Constipation  Spitting  Fatigue  Anorexia  History of PUD

26. Objective Findings 26  Vital signs: Tachycardia  Nutritional status ( Weight, BMI ? Weight loss  Signs of Dehydration Dry mucous membranes Dry coated tongue skin turgor sunken eyes, poor skin turgor Orthostatic hypotension or hypotension acetone smell in breath - Ketosis  jaundice is a late feature  Thyroid evaluation  Abdominal evaluation  Cardiac evaluation  Neurologic evaluation  Muscle wasting

27.  Urine Pregnancy test Quantity - ? Oliguria Ketonuria a systematic review & meta- analysis of biomarkers for the diagnosis of HEG found no association between ketonuria and severity of hyperemesis gravidarum (ACOG – 2018) Urine culture: for those with recurrent admission  Viral markers (HBsAg, anti HCV)  RBS  H. Pylori 27 Laboratory Abnormalities

28.  CBC 28 elevated level of RBC & hematocrit indicating dehydration  Serum electrolytes Hypokalemia, hypochloremia, Hyponatremia, hypocalcemia  Liver Function Test ↑ enzymes (usually < 300 units/L), ↑ serum bilirubin (< 4 mg/dL), and ↑ serum amylase or lipase concentrations (up to 5 X)  Ultrasonography: ? Molar, Multiple pregnancy, gynecological, surgical or medical causes of vomiting

29.  Chemical hyperthyroidism 29 Due to thyroid- stimulating activity of hCG – Low TSH; ↑ fT4/TT4 (4- 6 X); ↑ fT3/TT3 Features indicating gestational Hyperthyroidism  TT3/TT4 ratio < 20, but in Graves hyperthyroidism (ratio > 20)  Discrepancy between biochemical hyperthyroidism & signs and symptoms Usually: mild or absent No: tachycardia > 100 bpm; hyper defecation; muscle weakness, tremor; ophthalmopathy This thyroid hyperfunction - does not require treatment it is mild and subsides as hCG production falls (as does the vomiting) If it persists beyond 1 st trimester, it is probably not hCG- mediated

30.  Ophthalmoscopy 30 Its is required if patients is seriously ill Visual loss and optic neuropathy associated with WE Retinal hemorrhage and detachment of the retina are the most unfavorable signs  ECG when there is abnormal serum potassium level

31. The Motherisk- PUQE scoring index developed by clinicians and researchers in Canada Three questions - focused on symptoms experienced during the previous 12 hours Modified PUQE Score : include symptom profile over the previous 24 hours more recently, over a longer period of time (over the course of the entire 1 st trimester) 31 Validated Tools for assessing severity of NVP

32. PUQE & Modified PUQE score 1 point 2 points 3 points 4 points 5 points Duration of nausea in the past X hours ≤ 1 hour 2 to 3 hours 4 to 6 hours >6 hours Number of vomiting episodes in the past X hours 1 to 2 3 to 4 5 to 6 ≥7 Number of episodes of dry heaves in the past X hours 1 to 2 3 to 4 5 to 6 ≥7 Total score Vs Severity of NVP ≤ 6: mild 7- 12: moderate ≥13: severe X hours  12 for PUQE and 24 for Modified 32 PUQE: Pregnancy- Unique Quantification of Emesis

33. 2) Rhodes Index 33 originally validated to measure N & V in patients taking chemotherapy revised to measure nausea, vomiting, and retching includes 8 items quantifies physical symptoms, the resulting stress and psychological symptoms (Gold standard) more cumbersome: a tool for research The Modified PUQE score yields similar results to the gold standard

34. Severity Grading 0: None 1- 8: Mild 9- 16: Moderate 17- 24: Severe 24- 32: Great 34

35. Classify severity (SPHMMC Mgt Protocol) 35 Category Symptoms Impact on daily activities and/or employment Mild Nausea <1 hour during the day Little to none Moderate Nausea and vomiting up to twice in a day Moderate Severe Persistent symptoms for 6 or more hours with 5 or more episodes of vomiting and retching per day. Significant: requires hospitalization for IV hydration

36. Management Principles 36 Settle the Diagnosis Goals of Treatment Decide where to manage based on severity Outpatient Management Inpatient Management Keys Components of HEG Management Follow- up During Treatment When to Discharge Refractory HEG

37. Settle the Diagnosis 37 Differential Diagnoses Gastrointestinal conditions Gastroenteritis Gastroparesis Achalasia Biliary tract disease Hepatitis Intestinal obstruction Peptic ulcer disease Pancreatitis Appendicitis Conditions of the genitourinary tract Pyelonephritis Uremia Ovarian torsion Kidney stones Degenerating uterine leiomyoma Metabolic conditions Diabetic ketoacidosis Porphyria Addison’s disease Hyperthyroidism Hyperparathyroidism Neurologic disorders Pseudotumor cerebri Vestibular lesions Migraine headaches Tumors of the central nervous system Lymphocytic hypophysitis Miscellaneous conditions Drug toxicity or intolerance Psychologic conditions Pregnancy- related conditions Acute fatty liver of pregnancy Preeclampsia

38. Goals of Treatment 38 ↓ symptoms through changes in diet/environment and by medication Correct complications – Fluid depletion, hypokalemia, nutritional deficiencies and metabolic alkalosis … Minimize fetal effects of maternal nausea and vomiting and their treatment

39. Outpatient Management 39 Criteria Mild to Moderate symptoms Ketonuria +2 or less Diagnosis confirmed Manage dehydration Infuse first liter over 1 – 2 hours then 1000mls over 4hours  Reassess – Dehydration, urine ketone – Diclegis If improved- Antiemetics will be given and discharged (Pyridoxine + Doxylamine) or Meclizine + Pyridoxine or Pyridoxine + Metoclopramide or Promethazine Advice on dietary and environmental modification If no improvement  inpatient management

40. Inpatient Management 40 Indications for admission  Severe hyperemesis  Significantly abnormal urea and electrolyte  Loss of 10% or more body weight  Symptoms suggestive of another cause for vomiting  Persistent vomiting after OPD hydration  Persistent large ketosis after OPD rehydration  Persistent dehydration after OPD hydration  Presence of co morbidity  Unsettled diagnosis

41. Keys Components of HEG Management 41  Avoid Noxious Stimuli  Control Vomiting  Correct Fluid & Electrolyte Imbalance  Calorie Replacement  Prevent Wernicke Encephalopathy

42. Avoid Noxious Stimuli 42 Avoid environmental triggers Stuffy rooms, odors (perfume, chemicals, food, smoke) heat, noise and visual or physical motion (lights, driving) Avoid stress Avoid drugs that may cause N & V e.g. iron supplement should be temporarily discontinued Get enough rest, particularly after eating Have frequent naps and shorten working hours Keep oral hygiene Taking prenatal vitamins before bed with a snack, may also be helpful

43. Control Vomiting 43 Non Pharmacologic Dietary Modification Ginger Other interventions Pharmacotherapy Pyridoxine (vitamin B6) Anti- emetics Anti- acids

44. Dietary Modification 44 Dietary Manipulations Avoid coffee, spicy, odorous, high fat, acidic, and very sweet foods Substitute snacks/meals that are protein dominant , salty, low fat, and/or dry (peanuts, cereal, pea) Avoid Empty stomach : eat before or as soon as they feel hungry Full stomach : Small frequent meals every 1 to 2 hrs Consume fluids - at least 30 minutes before or after solid food  Cold solid foods are tolerated better than hot (less odor & require less preparation & exposure time.

45. Ginger 45 Systematic reviews of randomized controlled and nonrandomized controlled trials have found that ginger was associated with improvement in nausea ; but, none of the trials showed benefit in reducing vomiting

46. Other interventions 46 There is little evidence Acupressure, acupuncture, or electrical nerve stimulation (acustimulation) at the P6 or Neiguan point Hypnosis Psychotherapy

47. Pyridoxine (Vitamin B6) 47 Navidoxine 25 mg po TID 1 st line Treatment of nausea and vomiting vitamin B 6 (pyridoxine) alone or vitamin B6 (pyridoxine) plus doxylamine ( Diclegis ) FDA has approved, but the manufacturer ceased worldwide production due to liability costs a recent systematic review of RCTs and non- RCTs found Pyridoxine- improves mild nausea and vomiting symptoms no measurable teratogenic effects

48. Anti- emetics 48 ACOG Early treatment of NVP - prevents progression to HEG In a RCT of women with a history of severe NVP in their previous gestation antiemetic therapy (Diclegis) before onset of N & V was associated with a reduction in the severity than initiating after the onset of symptoms

49. Recommended antiemetics (RCOG - 2016) First line Second line Third line 49 Antihistamines (H1 antagonists) Cyclizine 50 mg PO, IM or IV 8 hourly Dopamine antagonists Phenothiazines Prochlorperazine 5–10 mg 6–8 hourly PO; 12.5 mg 8 hourly IM/IV; 25 mg PR daily Promethazine 12.5–25 mg 4–8 hourly PO, IM, IV or PR Chlorpromazine 10–25 mg 4–6 hourly PO, IV or IM; or 50–100 mg 6–8 hourly PR Dopamine antagonists Benzamides: Metoclopramide 5–10 mg 8 hourly PO, IV or IM (maximum 5 days’ duration) Domperidone 10 mg 8 hourly PO; 30–60 mg 8 hourly PR Serotonin antagonists Ondansetron 4–8 mg 6–8 hourly PO; 8 mg over 15 minutes 12 hourly IV Corticosteroids hydrocortisone 100 mg twice daily IV and once clinical improvement occurs, convert to prednisolone 40–50 mg daily PO, with the dose gradually tapered until the lowest maintenance dose that controls the symptoms is reached Shift from first to second line if emesis continues without improvement after 24 hrs of therapy

50. Ondansetron 50 ideally, a combination of two oral agents should be tried and found to be unsuccessful before initiating ondansetron off- label use for NVP 4 mg can be taken (Po/IV) – TID, as needed The dose is increased if necessary, but limited to ≤ 8 mg/dose cause QT prolongation , particularly in patients with underlying arrhythmia risk factors Risky patients: family or personal history of prolonged QT interval, heart failure, hypokalemia, hypomagnesemia ECK and electrolyte monitoring is recommended use in the 1 st trimester  cleft palate ( insufficient data )

51. Metoclopramide 51 5 to 10 mg Po, IV, or IM (ideally 30 minutes prior to meal and at bedtime) every 6 – 8 hours In randomized trials evaluating this drug in women with hyperemesis, metoclopramide 10 mg was as effective as promethazine 25 mg and ondansetron 4 mg

52. Anti- acids 52 Manage those with heartburn/acid reflux Antacids suspension Antacids containing aluminum or calcium are safe and preferable than those containing bismuth or bicarbonate, which may have adverse fetal/neonatal effects The H2 receptor antagonists: safe during px Ranitidine, Cimetidine ( Male fetus- antiandrogenic properties ) PPIs (Category c): Pantoprazole, Esomeprazole

53. Correct Fluid & Electrolyte Imbalance 53 Fluid replacement 1) Replace fluid deficit – Fluid deficit can be estimated from history and physical examination findings Early Phase: patient - thirsty, slight increase in PR ~ 2 % loss of body weight with the estimated deficit is 25 ml/kg Moderate Phase: serious sense of thirst, weakness of skeletal muscle and dry mucous membranes usually occurs after 3 days of water deprivation ~ 6% loss of body weight & deficit is estimated to be around 35ml/kg Severe Phase / Shock 7 – 15% body weight lost & deficit ~ 100ml/kg

54. Replacement of fluid deficit 54 Use isotonic saline (0.9% NS) and RL Repletion rate 1 to 2 liters as rapidly as possible, then 1- 2 L over the next 2- 3 hours until the clinical signs of hypovolemia improve low BP, low urine output, and/or impaired mental status Avoid dextrose containing fluid - until thiamine is supplemented with the initial rehydration fluid

55. 2) Give maintenance fluid 55 calculated based on weight (100 ml/kg/24- hours = 4 ml/kg/hr) for the 1st 10 kg (50 ml/kg/24- hours = 2 ml/kg/hr) for the 2 nd 10 kg (20 ml/kg/24- hours = 1 ml/kg/hr) for the rest 5% dextrose in normal saline 3) Replacement of ongoing loss The lost vomitus and urine in 24 hours is to be replaced with 5% dextrose

56. Electrolyte supplementation 56 Potassium supplementation – KCL is preferred for potassium repletion Mild to moderate hypokalemia (2.5 - 3.5meq) 20- 80 meq/day of KCL is recommended 1vial of KCL can be added in each bag of maintenance fluid Severe hypokalemia (< 2.5meq/l) or symptomatic hypokalemia 20meq/2- 3hrs with careful monitoring every 2- 4 hrs 2- 3 vials of KCL(40- 60meq)can be added in each bag of maintenance fluid Other electrolytes – Interdisciplinary management and ICU care for patients with severe or combined electrolyte abnormalities

57. Calorie Replacement 57 Daily calorie requirement of a pregnant woman ~ 2500 kcal/day The minimum amount of calorie to prevent ketosis Non pregnant adult: 400 Kcal daily = 100 gram of glucose Pregnancy: ↑ed glucose requirement (150 - 200 grams /day) So, how can we achieve 150 mg per a day Three liters of 5% DNS (maintenance fluid) or Add 6 – 7 vial of 40% dextrose in each bag of NS

58. Prevent Wernicke Encephalopathy 58 Thiamine is a cofactor for several key enzymes important in energy metabolism, including transketolase, alpha- ketoglutarate dehydrogenase, and pyruvate dehydrogenase Administering dextrose to an individual in a thiamine- deficient state exacerbates the process of cell death by providing more substrate for biochemical pathways that lack sufficient amounts of coenzymes Thiamine (vitamin B1) Give 100 mg (10 ampoules) - with the initial rehydration fluids before administration of dextrose containing fluids One ampoule (2ml) of Vit B complex contains: B1=10mg, B2=4mg, B6=4mg Then, 100 mg daily for the next 2 – 3 days  3 Ampules/liter

59. Follow- up During Treatment 59 Hyperemesis gravidarum follow up chart Maternal Vital signs: BP, PR, RR, TT Input & Output Weight Urine ketones Serum K Vomiting episodes Medications Improvement Subjective wellbeing Gain in appetite ↓ in frequency of N & V Weight gain Disappearance of ketonuria

60. When to Discharge 60 No ketones in the urine Tolerating oral fluids and possibly food for at least 24hrs after ketone is free and with PO antiemetics Appropriate Anti- emetic to take home Navidoxine 25 mg po BID – QID Plus meclizine 25mg PO TID or promethazine 12.5- 25mg every 6 hours or metoclopramide 10mg every 6- 8 hours Should be taken for at least one week

61. Advices on discharge 61  Advise them to eat as soon as they feel hungry  To eat small meals and snacks  To eat foods high in protein or carbohydrates, but not fat. These include biscuits, fries, bread, and nuts.  Avoid foods that are spicy, greasy, or acidic (such as oranges).  Drink cold, clear beverages.  Avoid coffee. Also, try to drink between meals, rather than with a meal.

62.  Brush their teeth right after eating.  Avoid lying down right after meal.  Avoid things in the environment that upset their stomach, such as stuffy rooms, strong smells, hot places, or loud noises.  Have someone to make their meals.  Inform the woman and her partner that there is a chance of recurrence on discharge 62

63. Refractory HEG Definition When there is no response to the most effective antiemetic with maximum dose ACOG suggests consideration of testing for H. pylori infection in patients who are unresponsive to standard therapy Rx Methylprednisolone ( use at < 10wks  cleft palate ) 16mg IV/PO every 8 hrs for 2 – 3 days  if there is Response  taper over 2 weeks the tapered dose may be stopped and the patient continued on the effective dose for up to 6 weeks (Maximum period – to limit serious maternal adverse effects) No response within 3 days  less likely to respond, so stop treatment 63

64. Enteral tube feeding (nasogastric or nasoduodenal) first- line treatment to provide nutritional support to the woman with HEG who is not responsive to medical therapy and cannot maintain her weight Several case reports and small series suggest that enteral tube feeding is well tolerated in pregnancy Total parenteral nutrition is a potentially life- threatening intervention due to associated sepsis and thromboembolic events should be considered a last resort Centrally placed venous catheters have higher morbidity rates (50%) compared with peripherally inserted lines (9%) serial scans to monitor fetal growth 64

65. Pregnancy Termination 65 exact incidence is unknown ~ 2% of affected pregnancies leads to elective pregnancy termination Indication: for those who doesn’t show improvement and deteriorating despite taking all available therapeutic measures Wernicke's Encephalopathy Severe hypokalemia Jaundiced Renal complications: ATN If women felt they are too sick to care for their family or themselves

66. Prevention 66  Multivitamin at the time of fertilization Two studies found that women who were taking a multivitamin at the time of fertilization were less likely to need medical attention for vomiting Proposed mechanism (ACOG - 2018) generalized optimization of nutritional status increasing levels of vitamin B6 (pyridoxine) So taking prenatal vitamins for 1 month before pregnancy may reduce incidence and severity of NVP  Dietary adjustments as stated above  Early treatment of nausea and vomiting of pregnancy  Manage heartburn & acid reflux prior to pregnancy

67. References 67  ACOG Practice Bulletin No. 189: Nausea And Vomiting Of Pregnancy. Obstetrics & Gynecology. 2018;131(1).  SPHMMC OaGDo. SPHMMC OBGYN Management Protocol. 2020.  Williams Obstetrics, 25th Edition. 2019.  UpToDate 2018.  Gabbe's Obstetrics, 7th Edition. 2018.  Gynaecologists R- RCoOa. The Management of Nausea andVomiting of Pregnancy and Hyperemesis Gravidarum. Green- top Guideline No 69. June 2016.  R.K. Creasy RR, J.D. Iams, C.J. Lockwood, T.R. Moore, M. Greene. Creasy and Resnik's Maternal- Fetal Medicine, 7th Edition. 2014.