Hormones of Pregnancy

• hCG is secreted by placental trophoblast. Detected in the mother’s bld 8 d after conception. Maintains corpus luteum progesterone production. Structurally similar to LH, FSH, & TSH (same alpha-subunit). Doubles q48h early Preg. Max 8–10 w, ∼100000 mIU/mL → decline at 10–12 w → nadir at 20 w.

• hPL is produced by syncytiotrophoblasts. Detected at 2–3 w after fertilization. Levels rise steadily until 34–36 w to a peak 5–10 μg/mL. Effects include mat lipolysis → ↑ circulating free fatty acids to provide a source of energy for mother & fetus; anti-insulin action → increased mat insulin levels → increased prot synthesis; angiogenic action → fetal vasculature formation

• Progesterone is mainly produced by the ovary until 6–7 w gest when the placenta begins to produce. Maintains endometrial lining in early Preg & uterine quiescence. Production ∼250–600 mg/d (prepregnancy 0.1–40 mg/d).

• Relaxin is secreted by the corpus luteum → uterine relaxation, systemic vasodilation, & ↑ cardiac output. Serum concentrations peak at 1 ng/mL at 12–13 w → fall to 0.5 ng/mL for the remainder of the Preg (Am J Physiol Regul Integr Comp Physiol 2011:R267).

TYPE I DIABETES MELLITUS

Definition and Epidemiology (Diabetes Care 2012;35(suppl 1):S64)

• Gluc intolerance due to insulin insufficiency. Often caused by cell-mediated autoimmune Pancr β-cell destruction. Only about 5% of all diabetes.

• Incid increasing 2–5%. Prevalence 1 in 300 by age 18 (Endocrinol Metab Clin North Am 2010;3:481)

• A/w other autoimmune diseases (eg, Graves, Hashimoto, Addison dz) (Diabet Med 2011;28(8):896)

Etiology and Pathophysiology

• Genetic: 95% have either HLA-DR3 or HLA-DR4. Also positive for anti-GAD, anti-islet cell, & anti-insulin Abs.

• Environmental: Congen rubella infxn, enterovirus, coxsackievirus B, CMV, adenovirus, & mumps (Diabetes Care 2012(suppl 1):S64)

• Lymphocytic infiltration, β-cell ↓ → insulin deficiency (Diabetes Metab Res Rev 2011;8:778)

• Hyperglycemia at ∼80–90% β-cell loss

Clinical Manifestations

• Polyuria, polydipsia, polyphagia w/ weight loss, fatigue, weakness, muscle cramps, blurred vision, nausea, abdominal pain, changes in bowel mvmt

• Most present w/ acute sx of diabetes & markedly elevated bld gluc levels

Diagnostic Workup

• Screen high-risk individuals (h/o transient hyperglycemia or relative w/ type I DM)

• Islet auto Abs ↑ risk of developing type I DM. Criteria for DM same for type I or II (below).

Treatment and Medications (JAMA 2003;289(17):2254)

• Lifelong insulin therapy is started w/ either MDI therapy, or CSII. See insulin types, below.

• Gluc measurements can be done either preprandial only, or pre- & postprandial (shows greater improv in glycemic control) (Clin Med 2011;2:154)

• MDI nonphysiologic regimens – do not mimic nml insulin secretion

Once daily long-acting insulin (at bedtime)

Twice daily intermediate-acting insulin (breakfast & dinner time)

• MDI physiologic regimens – attempt to mimic nml insulin secretion

Twice daily intermediate-acting insulin w/ short-acting insulin (breakfast & dinner time)

Once daily long-acting insulin (at bedtime) w/ mealtime rapid-acting insulin

Twice daily intermediate-acting insulin (breakfast & bedtime) w/ rapid acting insulin w/ each meal

Premixed insulin (70% NPH/30% regular) given twice daily

• CSII – Rapid-acting insulin preparation administered through a catheter that is inserted into the SQ tissue. There is a basal insulin infusion rate (1 U/h) w/ patient-directed boluses given before meals.

• Nonpregnant goal: HgA1c <7%, fasting gluc 70–130 mg/dL, postprandial gluc <180 mg/dL

DIABETIC KETOACIDOSIS (DKA)

Definition

• An acute life-threatening complication due to insulin deficiency, w/ hyperglycemia, dehyd, & acidosis. Typically due to insulin noncompliance, acute illness/infxn, drugs, or new onset DM.

• Occurs in 5–10% of all pregnancies w/ DM. Can develop more rapidly & at less sev levels of hyperglycemia than in nonpregnant pts.

Pathophysiology (Clin Med 2011;2:154)

• Insulin deficiency → ↑ glucagon → ↑ hepatic gluconeogenesis & ↑ glycogenolysis → hyperglycemia → inability to use gluc → ↑ lipolysis → free fatty acids metabolized by liver (ketogenesis) as an alternative energy source → large quantities of ketones → acidosis

Clinical Manifestation (Hormones 2011;4:250)

• Nausea, vomiting, abdominal pain, confusion, Kussmaul respirations (deep labored breathing seen in metabolic acidosis).

Diagnostic Workup

• Bld gluc, bld gas (pH), Chemistry (bicarbonate, anion gap), serum ketones

Treatment

• Treat the underlying cause (eg, infxn). Inpatient admission.

• Fluids: 1 L NS 1st hour, then 250–500 mL/h. When gluc <250 mg/dL → change to 5% dextrose in ½ NS, and continue insulin till ketonemia resolved.

• Insulin: 0.1–0.4 U/kg IV bolus → 0.1 U/kg/h continuous infusion (or 2–10 U/h). Try for 50–70 mg/dL/h correction of serum gluc, or about 25% in 1st 2 h. When plasma gluc is ∼200 mg/dL → ↓ insulin to 0.05 U/kg/h (or about 1–2 U/h) until urine ketones cleared. Adjust till gluc ∼150–200 mg/dL. When pt can tolerate food, start her usual SQ insulin injection regimen.

• Potassium: K >5 mEq/L, no additional req. (Insulin drives K into cells w/ gluc → ↓ serum K.)

K 4–5 mEq/L → add 20 mEq/L to each liter of replacement fluid

K 3–4 mEq/L → add 40 mEq/L to each liter of replacement fluid

K <3 mEq/L → hold insulin, give 10–20 mEq/h until K >3.3, then 40 mEq/L in IVF

• Bicarbonate: pH <6.9 → give 100 mEq & 20 mEq of KCl in 400 mL of H₂O over 2 h

pH <7 or bicarbonate <5 mEq → give 50 mEq in 200 mL of water over 1 h until ph ↑ to >7

Do not give bicarbonate for pH >7

• Phosphate: If <1 mg/dL → give 20–30 mmol potassium phosphate over 24 h

• Calcium: Monit serum Ca level & replete prn

• Fetal HR monitoring for >24 w gest. Fetal loss 9–85% depending on severity of DKA.

TYPE II DIABETES MELLITUS

Definition and Epidemiology (Diabetes Care 2012;35(suppl 1):S64)

• Insulin resistance ± inadeq insulin production (ie, inadeq production for the sens of the target tissues). ∼26 million people w/ DM, ∼79 million prediabetes, & 1.9 million new cases of DM diagnosed in 2010 (National Diabetes Fact Sheet, www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf)

Pathophysiology

• Periph insulin resistance → ↑ insulin secretion → Pancr failure → defective insulin secretion in resp to ↑ gluc → increased liver gluconeogenesis → hyperglycemia

Clinical Manifestation

• Classical sx: Polyuria, polydypsia, polyphagia, fatigue, weakness, muscle cramps, blurred vision, nausea, abdominal pain, changes in bowel mvmt. Most are asx.

Diagnostic Workup

• Criteria for diagnosing T2DM outside of Preg: Hgb A1c ≥6.5%, fasting gluc ≥126 mg/dL, 2-h 75 g OGTT plasma gluc ≥200 mg/dL, or a random plasma gluc ≥200 mg/dL in a pt w/ classic sx or in hyperglycemic crisis

Treatment and Medications

• Goal of rx is to achieve & maintain HbA1c levels of <7%. See also for Preg, below.

• At dx: Lifestyle changes (weight loss, exercise) may ↓ HbA1c 1–2%

• Bariatric Surg consideration for adults w/ T2DM & BMI >35 kg/m²

• See appendix for oral hypoglycemic agent meds. See Ch. 1 for well-woman mgmt.

HYPEROSMOLAR HYPERGLYCEMIC STATE

Etiology and Pathophysiology (Emerg Med Clin North Am 2005;23:629)

• Extreme hyperglycemia + hyperosmolality, w/o ketoacidosis

• Infxn causing about 60% of cases → physiologic stress → ↓ effectiveness of circulating insulin → ↑ counter regulatory hormones (glucagon, catecholamines, cortisol, GH) → ↑ periph resistance → gluconeogenesis → hyperglycemia → glycosuria → hypertonic osmotic diuresis (dehyd) → unable to maintain adequate fluid intake (2/2 acute illness) → sev hyperosmolality & intracellular dehyd, renal failure

Diagnostic Workup

• Plasma gluc level of ≥600 mg/dL, serum osmolality of ≥320 mOsm/kg, ↑ serum urea nitrogen (BUN): Cr ratio, pH >7.3, small ketonuria, absent to low ketonemia, bicarbonate >15 mEq/L

Treatment

• Treat the underlying cause. Mgmt very similar to DKA (above).

• 1st-line therapy is aggressive IV hydration, fluid deficit may be 8–12 L. Replace 1/2 of the fluid deficit in the 1st 12 h, & the remainder in the next 12–24 h w/ NS.

• Insulin infusion when potassium is ≥3.3 mEq/L. Regular insulin started at 0.1 U/kg/h w/ or w/o a 0.15 U/kg bolus.

• Once the serum gluc ≤300 mg/dL, D5 should be added & the insulin infusion ↓ to 0.05 U/kg/h

• If serum potassium level is <3.3 mEq/L → replete w/ KCl at a rate of up to 40 mEq/L/h until levels are above 3.3 mEq/L. 20 mEq/L KCl can then be added to each 1 L of IV fluid. Goal is to maintain nml serum K levels. Check K every 1–2 h.

DIABETES IN PREGNANCY

Epidemiology

• Pregestational diabetes in ∼1% of all pregnancies, mostly type II.

• 90% of diabetes in Preg is GDM (see GDM, below)

Clinical Manifestation

• Type I usually known prior to Preg. Type II may have been unrecognized, but if gluc intolerance before 20 w, consider pregestational. Goal preconception HgA1c <6.5%. Consider hospital admission for very poor control during organogenesis.

• Fetal malformation rate in a nml Preg is 2–3% vs. 6–12% in pregnancies c/b diabetes (Obstet Gynecol 2003;102:857). Rate of fetal malformations w/ Hgb A1c 7–8.9 = 5–10%; Hbg A1c 9–10.9 = 10–20%, HbgA1c >11 = >20%

• “Usual” defects include cardiac, renal, neural tube. Esp double outlet RV, truncus arteriosus, & caudal regression syn/sacral agenesis (considered pathognomonic).

• Risks of DM in Preg: ↑ malformations, ↑ SAB, ↑ IUGR, ↑ progression of nephropathy, retinopathy, cardiovascular dz, ↑ polyhydramnios, ↑ preeclampsia, ↑ labor dystocia & C/S deliv, ↑ fetal macrosomia, ↑ lacerations, ↑ shoulder dystocia, ↑ neonat RDS/hypoglycemia.

Screening for DM in Pregnancy

• Univ GDM screening std. Screen early if risk factors. Consider no screening by criteria.

• On 50 g oral gluc challenge test, serum gluc ≥140 mg/dL identifies 80% GDM; ≥130 mg/dL identifies 90% GDM. Serum gluc ≥200 mg/dL → GDM w/o other testing. Positive screening test → 3 h fasting gluc challenge (100 g test; diagnostic table, below).

• 3-h OGTT: Consume ≥150 g of carbohydrate per day for 3 d, then fasting. 100 g oral gluc challenge → fasting + 1-, 2-, 3-h post challenge bld gluc. 1 abn value = gluc intolerance (a/w fetal macrosomia). Dx of GDM made ≥2 abn values.

• New Endo one step Guideline differs from ACOG (J Clin Endo Metab 2013;98:4227)
Universal DM testing before 13w gest, repeat if abnormal on different day to confirm. 8–14hr Fasting gluc ≥126 mg/dL, untimed ≥200mg/dL, or HbA1C ≥6.5% = overt DM; Fasting 92-125 mg/dL = GDM
24-28w screen if not prev dx, w/ 75g OGTT (after 8hr fast)

Fasting gluc >126mg/dL or 2hr >200 mg/dL = overt DM;

Fasting 92–125 mg/dL or 1hr >180 mg/dL or 2hr 153–199 mg/dL = GDM

Management of DM in Pregnancy

• GDM

Nutrition advice, diet/exercise, & 4×/d bld gluc testing (fasting + 1- or 2-h postprandial)

If inadeq control → oral hypoglycemic agents (glyburide), if inadeq w/ max dose → insulin

GDM-A1 no monitoring, no early deliv (routine induction at 41–42 or for OB indications)

GDM-A2 antenatal testing (NST/BPP from 32–34 w) & deliver by 40 w

• Pregestational diabetes

Diet: 1800–2400 kcal daily, w/ 20% prot, 60% carbs, & 20% fat. The American Diabetes Association recommends insulin for pregnant women w/ type I or II DM. NPH & rapid-acting insulin combination used (see Table with insulin types, above). Type I DM usually ↑ insulin 50–100%. Type II DM often ↑ >200% in Preg. Consider baseline HELLP labs, thyroid testing (40% type I DM – thyroid d/o) & 24-h urine prot early Preg.

Eye exam in 1st trimester, & baseline ECG (age >30 y or hypertensive).

Pregestational DM obtain early sonogram, confirm viability, offer mat serum AFP for NT defects, US for anatomy & fetal echocardiography.

1–2×/w fetal NST/AFI from 32–34 w or earlier. Serial fetal growth scans every 4–6 w to eval for IUGR or macrosomia. Deliv not later than 39–40 w, depending on gluc control in Preg.

Labor and Delivery for Diabetics

• Consider cesarean deliv for EFW >4500 g for pts w/ diabetes (>5000 g for nondiabetic)

• Insulin mgmt during labor: Usual intermediate insulin at bedtime. Morning dose insulin withheld. W/ active labor or gluc <70 mg/dL start D5NS IVF. Check bld gluc hourly in labor. Usually pregestational DM → IV insulin drip & titrate. Tight gluc control to avoid neonat hypoglycemia.

• Fetal lung maturity may be delayed in DM, even with reassuring FLM result.

Postpartum Management

• Usually insulin-dependent pregestational DM → resume prepregnancy regimen, or ½ of end Preg dose. GDM can stop rx, unless suspected DM 2. GDM resolves w/ deliv.

• Postpartum 75 g gluc tol test to identify nongestational DM for all GDM pts.

GESTATIONAL DIABETES (GDM)

Definitions, Epidemiology, and Pathophysiology

• GDM is carbohydrate intolerance w/ onset or 1st recognition during Preg

• Classification: A1GDM is diet controlled; A2GDM requires pharmacologic intervention

• GDM in ∼5–10% of pregnancies. 20–50% will → nongestational DM in 10 y; 30–50% → recurrent GDM.

• ↑ human placental lactogen/cortisol/progesterone/estrogen → ↓ periph insulin sens → impaired gluc resp → hyperglycemia. Screening per above, under Diabetes in Pregnancy.

Treatment and Medications

• See mgmt in Diabetes in Pregnancy, above.

• Oral hypoglycemics considered if dietary mgmt fails. Glyburide equiv to insulin for gluc control (starting dose: 1.25–2.5 mg twice daily → ↑ 2.5 mg as needed; max 10 mg BID). Insulin needs ↑ markedly btw 28 & 32 w gest (Obstet Gynecol 2003;102(4):857). See starting insulin schematic, above. Consider lower dose for insulin naive pt.

HYPOTHYROIDISM

Definition and Epidemiology

• Inadeq thyroid hormone to meet the requirements of periph tissues.

• Primary hypothyroidism: Hashimoto’s thyroiditis, surgical removal, radioactive ablation, invasive fibrous thyroiditis, iodine deficiency. Secondary hypothyroidism: Pituitary/hypothalamic neoplasm, trauma, ischemic necrosis (Sheehan’s syn), infxn.

• Subclinical hypothyroidism: Chronic autoimmune thyroiditis, partial thyroidectomy, radioactive iodine therapy for rx of hyperthyroidism, infiltrative disorders, drugs impairing thyroid fxn, inadeq replacement therapy for overt hypothyroidism, iodine deficiency

• 3.7% of the US pop. Females > males.

Etiology

• In women, most common cause (95%) is autoimmune (Hashimoto’s thyroiditis).

• Hashimoto’s thyroiditis: Lymphocytic thyroid infiltration → gland atrophy & fibrosis

• Subclinical hypothyroidism: Elevated TSH w/o overt hypothyroidism or low T₃/T₄. Early, mild thyroid failure. ∼60–80% have ⊕ antithyroid peroxidase or antithyroglobulin Abs. Progression to overt hypothyroidism in women is about 4%/y. No need to treat TSH <10 mU/L & asx.

Clinical Manifestations and Diagnosis

• Weakness, dry skin, cold intolerance, hair loss, constip, weight gain, poor appetite, dyspnea, hoarse voice, menorrhagia, paresthesias, impaired hearing

• ↑ TSH, ↓ free T₄, ⊕ anti-TPO & other thyroid Abs. May also see HoNa, hypercholesterolemia, anemia, & elevated serum Cr kinase.

Treatment

• Daily levothyroxine 2 μg/kg body weight (typically 100–150 μg; start at 50–100 μg depending on severity). Adjust q4w 12.5–25 μg by TSH levels. Annual TSH levels recommended for nonpregnant.

Hypothyroidism in Pregnancy (Lancet 2012;379(9821):1142)

• Similar causes as nonpregnant. Also postpartum thyroiditis (autoimmune inflammation) → thyrotoxicosis → hypothyroidism. W/i 1-y postpartum.

• Mat hypothyroidism can ↑ SAB, placental abruption, preterm deliv, preeclampsia, mat HTN, postpartum hemorrhage, low birth weight, stillbirth, & ↓ intellectual & psychomotor dev of the fetus.

• Difficult to assess in early Preg: Total T₃/T₄ ↑ due to hCG cross reaction and stimulation of the TSH receptor & also ↑ TBG. In 1st trimester total T₄ ↑ & TSH ↓, w/ no real hypo or hyperthyroidism.

• ACOG does not recommend routine screening of asx pregnant pts. Test if on therapy, goiter, nodularity, h/o thyroid d/o/neck irradiation, prior infant w/ thyroid dysfxn, type I DM, FHx.

• Rx similar to nonpregnant pts. Preg may ↑ thyroid hormone requirements; monit TSH & adjust.

• Treat subclinical hypothyroid → improved obstetrical outcome, but did not modify long-term neurologic dev in the fetus. Maintain TSH <2.5 mU/L in 1st trimester & <3 mU/L thereafter.

HYPERTHYROIDISM

Definition, Epidemiology, and Etiology (Endocr Pract 2011;17(3):456)

• Hyperthyroidism is caused by excess synthesis & secretion of thyroid hormone

• The prevalence of hyperthyroidism is 1.2% (0.5% overt & 0.7% subclinical)

• The most common causes are:

Graves dz (80%): Autoimmune TRAbs → bind TSH-R → ↑ TSH. Accounts for 95% of hyperthyroidism in Preg. 5–10× more than .

Thyroiditis (10%): Painless inflammation of thyroid due to viral infxn or postpartum inflammation → release of preformed thyroid hormone. May resolve and → hypothyroid.

Toxic adenomas: Single or multinodular, autonomously functioning, secrete thyroid hormone. More common in setting of iodine deficiency.

Other: Amiodarone, struma ovarii (ovarian dermoid), TSH secreting pituitary adenoma, gestational trophoblastic dz, follicular cell carcinoma, iodine-induced, thyrotoxicosis factitia.

Clinical Manifestation and Physical Exam (Lancet 2003;362(9382):459)

• Nervousness, anxiety, heat intolerance, tremor, palps, weight loss, oligomenorrhea, tachy, exophthalmos, thyromegaly. Thyrotoxicosis in 1 of 500 pregnancies → ↑ preeclampsia, thyroid storm, CHF, IUGR, preterm deliv, stillbirth.

• Tachy (&/or arrhythmias), HTN, warm/moist/smooth skin, lid lag, goiter, tremors

• Thyroid storm: Medical emergency, extreme hypermetabolism → seizures, arrhythmia, stupor, shock, coma. Do not delay therapy while FT₄, FT₃, TSH pending.

Diagnostic Workup (Endocr Pract 2011;17(3):456)

• Graves dz: ↓ TSH, ↑ FT₄, ↑ FT₃, ±antithyroid peroxidase Ab (TPO), ⊕TSI, ⊕TRAb, other antithyroid Abs poss.

When clinical presentation is not diagnostic, RAIU is performed (J Fam Pract 2011; 60(7):388): Diffuse, homogeneous = Graves dz; diffuse, heterogeneous = toxic multinodular goiter; focal = adenoma; no uptake = thyroiditis. IgG crosses placenta → fetal Graves

• Subclinical hyperthyroidism: ↓ TSH; nml FT₄ & FT₃. Asx.

Treatment (Endocr Pract 2011;17(3):456)

• Symptom mgmt: b-blocker to control tachy (propranolol also blocks T₄ conversion to T₃)

• ATDs: PTU is 1st-line drug during the 1st trimester; blocks both iodide organification & periph T₄ → T₃ conversion; monit liver fxn. Methimazole okay in 2nd trimester. Titrate meds to fT₄ q2–4w.

• RAI: Started for pts w/ contraindications to ATD use. Pretreat w/ methimazole prior to RAI to prevent worsening of hyperthyroidism. Contraindicated in Preg.

• Surg: For symptomatic compression, large goiter, low uptake, documented or suspected malig