Organ Systems Involved
Endocrine
Many of the physiologic changes associated with pregnancy can be attributed to changes in hormones produced by the placenta. One such hormone is human chorionic gonadotropin (hCG), specifically, the beta subunit (beta-hCG). Beta-hCG is produced by the syncytiotrophoblastic cells of the placenta and is responsible for stimulating the corpus luteum to produce progesterone, which is essential in maintaining pregnancy.[1] Beta-hCG stimulates and maintains the corpus luteum, preventing further ovulation. In addition, beta-hCG is responsible for stimulating the ovaries to produce elevated levels of estrogen and progesterone until the end of the first trimester (approximately weeks 10-12), at which time the placenta is mature enough to take over the production of estrogen and progesterone.[2]
In a nonpregnant individual, the hypothalamus produces and releases thyrotropin-releasing hormone (TRH), which stimulates the release of thyroid-stimulating hormone (TSH) and prolactin (PRL) from the anterior pituitary. In a pregnant individual, the placenta releases additional TRH, which leads to the further release of TSH and PRL. Thyroid hormone production increases by about 50% during pregnancy but free T3 and free T4 remain unchanged due to the simultaneous increase in thyroid-binding globulin (TBG).[3] These additional thyroid hormones are necessary for appropriate brain development and thyroid function of the growing fetus.[4] During pregnancy, the pituitary gland enlarges by approximately 135% due to lactotroph hyperplasia, further increasing circulating prolactin levels.[5] Prolactin levels increase 10-fold throughout pregnancy, allowing breast tissue development and milk production.[6]
Relaxin is a peptide hormone released by the corpus luteum in both pregnant and nonpregnant individuals and by the placenta and decidua in pregnant individuals. This hormone allows for connective tissue remodeling and subsequent softening of the birth canal, mammary gland growth and differentiation, and inhibition of uterine contractile activity.[7] Relaxin also mediates nitric oxide (NO) release, allowing systemic vasodilation and decreasing blood pressure during pregnancy.[8]
Free cortisol levels are about 2.5 times higher in the pregnant versus nonpregnant state.[9] This increase in cortisol levels is essential for the normal development of the fetal brain. However, excess maternal levels of glucocorticoids can be neurotoxic to the fetus, resulting in impaired neural development.[10] Endorphins and enkephalin concentrations also increase in pregnancy, leading to an elevated pain threshold to counteract the pain due to labor.[11]
Cardiovascular
The cardiovascular system of a pregnant individual will undergo significant physiologic changes, including an increased heart rate, stroke volume, cardiac output, and a decrease in vascular resistance.[12] Increased ventricular wall mass, myocardial contractility, and cardiac compliance are also seen.
Within the first trimester, vasodilatory effects of NO, prostaglandins, and progesterone occur, leading to peripheral vasodilation, which, by eight weeks of gestation, leads to a 20% increase in cardiac output (CO). Additionally, peripheral vasodilation leads to a fall in systemic vascular resistance (SVR), compensated for by an increase in CO of approximately 40% throughout pregnancy. Peripheral vasodilation also leads to a decrease in blood pressure early in pregnancy, with blood pressure reaching its lowest point at about 20-24 weeks gestation leading to physiologic hypotension.
Cardiac output is the product of heart rate and stroke volume. The increase in cardiac output is mainly due to increased stroke volume and, to a lesser extent, an increase in heart rate.[13] This increase in cardiac output directs blood toward the uterus, placenta, kidneys, skin, and extremities. Cutaneous and extremity blood flow raises maternal skin temperature and is a mechanism of maternal thermoregulation. Cardiac output increases by 75% following delivery due to relief of inferior vena cava (IVC) compression.[14]
While early in pregnancy, the stroke volume is responsible for maintaining the elevated CO, during the third trimester, it is an increase in heart rate that becomes responsible for maintaining an increase in CO. Increased CO is needed later in pregnancy, as uterine blood flow increases 10-fold and renal blood flow increases 50%. There are minimal alterations in blood flow to the liver and brain. During active labor, uterine contractions cause "auto-transfusion" of approximately 500 mL of blood back into the maternal circulation.
Over 90% of pregnant patients will develop a systolic murmur in pregnancy that will disappear following delivery, and 18% of pregnant patients will develop a diastolic murmur. A third heart sound is common in pregnancy, occurring in over 80% of pregnant individuals, with a fourth heart sound occurring in approximately 16% of pregnant individuals.[15]
Normal ECG findings in pregnancy may include small Q waves and inverted T waves in lead III, ST-segment depression and T-wave inversion in the lateral and inferior leads, and left-axis shift of the QRS complex.[13]
Respiratory
Functional residual capacity (FRC) is the sum of expiratory reserve volume (ERV) and residual volume (RV). Throughout pregnancy, due to the enlarging uterus, the resting position of the diaphragm shifts up approximately 5 cm, leading to bibasilar alveolar collapse and basilar atelectasis, thus decreasing the ERV and FRC. Vital capacity (VC) remains unchanged, as reduced ERV is accompanied by an increased IRV.
Increased progesterone concentrations, beginning in the first trimester, cause an increase in tidal volume by approximately 30-50%. The product of tidal volume and respiratory rate is minute ventilation, which will increase by 30-50%. The respiratory rate remains unchanged from the nonpregnant state.
Progesterone stimulates respiration and can lead to hyperventilation (exhaling more than inhaling). Due to this, the arterial partial pressure of oxygen (PaO2) increases to 105 mmHg, while the arterial partial pressure of carbon dioxide (PaCO2) decreases to approximately 30 mmHg.[16] This blood gas change results in slight respiratory alkalosis metabolically compensated by increased bicarbonate excretion by the kidneys to approximately 20 mEq/L.[17] The oxyhemoglobin dissociation curve is shifted to the right, favoring oxygen dissociation and facilitating oxygen transfer across the placenta.
During labor, minute ventilation increases by as much as 140-200% depending on the stage of labor, leading to an even more pronounced decrease in PaCO2.[18] Metabolic oxygen consumption rises during childbirth due to uterine contractions, sympathetic activity, and maternal Valsalva maneuvers to deliver the fetus. As oxygen demand outpaces oxygen delivery during active labor, anaerobic metabolism ensues, and lactic acid production occurs.[19]
Hematologic
In a pregnant individual, plasma renin levels rise, and atrial natriuretic peptide (ANP) levels tend to fall, leading to systemic vasodilation and increased vascular capacitance. This physiologic process, without compensation, would lead to an underfilled vascular system. To compensate for this and blood loss during delivery, the maternal blood volume is increased by approximately 1.5 liters. In addition, maternal erythropoietin production is increased, leading to an increase in red blood cell (RBC) mass by approximately 30%. This increase in plasma volume greater than RBC mass results in dilutional anemia, or physiologic anemia of pregnancy.[20]
An increase in RBC mass, coupled with increased blood flow to the uterus, leads to optimized oxygen transport to the fetus. However, an increase in RBC mass also means an increase in the physiologic demand for iron throughout pregnancy. Approximately 1,000 mg (1 gram) of iron is needed during pregnancy, two-thirds for needs of the gravida and one-third for placental-fetal tissue growth and needs. Less iron is required in the first trimester (0.8 mg/day), with more daily iron necessary for the third trimester (3.0-7.5 mg/day).[21]
Pregnancy is a hypercoagulable (prothrombotic) state, with increased levels of coagulation factors caused by elevated estrogen levels mediating an increase in protein synthesis. As the pregnancy progresses, clotting factors VII, VIII, X, XII, vWF, and fibrinogen levels markedly increase. Due to the increase in factor VIII, activated partial thromboplastin time (aPTT) is typically shortened, while prothrombin time (PT) and thrombin time (TT) remain unchanged.[20] Due to this hypercoagulable state, pregnant individuals are up to five times more likely to develop a deep vein thrombosis (DVT) than their nonpregnant counterparts.[22]
Renal
Increased cardiac output, as previously mentioned, leads to increased blood flow to the kidneys, increased glomerular filtration rate (GFR) by about 50%, and increased renal plasma flow (RPF) by as much as 80%. This increased GFR leads to a subsequent decrease in the serum concentration of creatinine, urea, and uric acid. Due to fluid retention, the kidneys enlarge, and physiologic hydronephrosis occurs. Due to the actions of progesterone and relaxin on smooth muscles, dilation of the urinary collecting system occurs, which can lead to urinary stasis and a 40% increase in the predisposition for urinary tract infections and pyelonephritis with asymptomatic bacteriuria in pregnancy.[23]
Upregulation of the renin-angiotensin-aldosterone system (RAAS) typically occurs in a normal pregnancy. Estrogen produced by the placenta increases the synthesis of angiotensinogen by the liver, which leads to an increase in angiotensin II. Renin is released from the ovaries and decidua of the uterus. At approximately eight weeks of gestation, aldosterone levels rise and continue to increase 3-6x the upper limit of normal in the third trimester. The result is a net gain of approximately 1.5 liters of water (as previously mentioned).[23]
Gastrointestinal
Gastroesophageal reflux disease (GERD) is common in pregnant patients due to multiple factors. Increased progesterone in pregnancy leads to reduced resting muscle tone of the lower esophageal sphincter (LES), delayed gastric emptying, and increased small bowel transit time. These findings, in addition to compression from a gravid uterus, predispose to GERD.[24]
Integumentary
During pregnancy, elevated hormone levels such as estrogen or progesterone can stimulate excess melanin production, leading to hyperpigmentation of the face, known as melasma. Linea nigra, a hyperpigmented line running down the center of the abdomen, may also occur due to pregnancy-related hyperpigmentation and is typically associated with increased pigmentation of the areolae, axillae, and genitals.[25]
Clinical Significance
Medication use is common in pregnancy, with multiple studies showing that 75-97% of pregnant individuals take at least one over-the-counter (OTC) medication during their pregnancy.[26][27] This statistic is important for physicians and pharmacists to remember, as many maternal changes in pregnancy can affect the pharmacodynamic and pharmacokinetic (absorption, distribution, metabolism, and elimination) properties of certain medications. Failure to consider the maternal physiologic adaptations during pregnancy can lead to maternal morbidity due to over or under-treating the pregnant individual.
The increase in renal clearance during pregnancy can increase the elimination of renally cleared medications. For example, lithium, a medication used to treat bipolar disorder, is renally cleared. Lithium clearance is doubled during the third trimester of pregnancy, leading to sub-therapeutic levels.[28] Additional renally cleared medications to remember are ampicillin, cefazolin, cefuroxime, piperacillin, digoxin, and atenolol, among others.[29]
As soon as pregnancy is confirmed, hypothyroid patients requiring levothyroxine should increase their dose by 30%, and serum thyrotropin levels should be closely monitored.[30] Additionally, physiologic hypotension of pregnancy is essential to understand when dealing with pregnant patients who are already hypertensive and taking hypertension medication.
Whether family medicine, cardiology, or obstetric anesthesia, clinicians in every medical specialty should understand the physiologic changes pregnant individuals undergo and adapt accordingly within their practice and care of that patient.
