Pregnancy

Pregnancy begins with the fertilization of the ovum and subsequent implantation into the uterine wall. The duration of pregnancy is counted in weeks of gestation from the first day of the last menstrual period and on average lasts 40 weeks. Presumptive signs of pregnancy include amenorrhea, nausea and vomiting, and breast enlargement and tenderness. Pregnancy can be confirmed definitively via positive serum or urine hCG tests and detection of the embryo on ultrasound. Ultrasound is also used to determine the gestational age and date of delivery. Women experience several benign, physiological changes during pregnancy (e.g., peripheral edema, dyspnea, increased urinary frequency). Regular check-ups should be performed to detect possible high-risk pregnancies as well as fetal and maternal complications.

See also maternal complications during pregnancy.

Trimesters of pregnancy

• First trimester (week 1–13)
• Second trimester (week 14–26)
• Third trimester (week 27–40)

Stages of pregnancy

Day/week	Stage	Possible disorders
Day 0	Capacitation: maturation of the sperm in the female genital tract Fertilization (conception): usually occurs in the upper end of the fallopian tubes (most commonly in the ampulla) within 1 day of ovulation Consists of 2 phases: the acrosome reaction (dissolution of the spermatic cell membrane and the zona pellucida of the ovum) and impregnation (penetration of the sperm into the ovum) Conjugation: fusion of the sperm and ovum to form the zygote (single cell)	Genopathies: injury to the gene locus Chromosomal aberrations (e.g., trisomy) Occur before conception
Day 1–5	The zygote travels down the fallopian tube towards the uterus Division of the zygote into the morula (16-cell mass) and then the blastocyst The blastocyst consists of 2 layers of cells: the outer trophoblasts and the inner embryoblasts.	Blastopathies Occurrence: up to 14 days after conception Congenital anomalies: complex congenital anomalies with double malformations or missing body parts High risk of spontaneous miscarriage Multiple pregnancy: conjoined twins especially
Day 6	Implantation (embryology) of the blastocyst (most commonly into the anterior or posterior wall of the uterus); The trophoblast penetrates the endometrium. This may result in brief implantation bleeding: bloody vaginal discharge occurring during implantation (may be mistaken for menstruation)
Days 6–14	Formation of the fetoplacental unit The trophoblast further divides into the syncytiotrophoblast, which is involved in the development of the placenta, and the cytotrophoblast, which forms the chorionic cavity, which surrounds the embryoblast. Syncytiotrophoblast begins secreting hCG (detectable in blood and urine one week and two weeks after conception, respectively) The maternal circulation becomes connected with the placental circulation The bilaminar embryonic disc develops (2 layers): epiblast and hypoblast
Week 3	Gastrulation: formation of the trilaminar embryonic disc (ectoderm, mesoderm, endoderm) The neural plate begins to form from the neuroectoderm.	Embryopathies: complex anomalies of individual organs during a time when the developing embryo is particularly susceptible to teratogens Etiology Infections Drug toxicity
Weeks 3–8	Embryogenesis Organogenesis: organ formation (chronological order) CNS: The neural tube closes by week 4. Heart: The heart begins to beat by week 4. Eyes and ears Upper and lower extremities Teeth and gums External genitalia (male/female characteristics) For more information, see the article on embryogenesis.
From week 9	Fetogenesis: the fetus matures and grows.	Fetopathies: structural abnormalities that occur during the maturation and growth of the fetus once organ formation is complete Etiology Infections: fetopathies caused by infectious agents or pathogens Antibodies: Rh incompatibility Metabolic: diabetes mellitus (e.g., macrosomia)

The earlier disruptions take place during fetal development, the more complicated the resulting congenital anomalies!

References:^[2][3]

General principles

• All women with reproductive potential should be asked about their intention to become pregnant; by their healthcare provider; all those planning to become pregnant should be counseled.
• Prenatal counseling aims at:
  • Identifying and addressing any modifiable risk factors for the woman, future pregnancy, and the fetus
  • Educating a woman about the risk factors and options for their reduction or elimination

Medical conditions

• General chronic diseases: review history and identify chronic medical conditions which may affect the pregnancy (e.g., hypothyroidism, diabetes mellitus, chronic hypertension, etc.)
  • Hypothyroidism
    • Screen women with risk factors for thyroid disease (e.g., age > 30 years, obesity, history of head or neck radiation, pregnancy loss, preterm delivery, or infertility) ^[4]
    • Treat women with elevated TSH with L-thyroxine until TSH levels are normal.
  • Diabetes mellitus
    • Educate about the importance of maintaining normal glycemic levels before and during pregnancy.
    • Assess for complications of diabetes (retinopathy, nephropathy, etc.).
    • Aim for an HbA1c < 6.5% ^[5]
  • Hypertension
    • Assess for retinopathy, renal disease, and ventricular hypertrophy.
    • Avoid using ACE inhibitors and angiotensin receptor blockers, as they are teratogenic.
• Mental disorders
  • Review history of psychiatric disorders
  • Inform about the risks of untreated mental illness and risk of treatments for pregnancy.
  • Screen women with no history of mental conditions for anxiety and depression.
• Family history of heritable conditions: assess family history of genetic conditions and cancer (e.g., breast, uterine, colon cancer) and refer couples with a positive history for counseling.
• Communicable diseases
  • HIV-infection
    • Screen all women for HIV.
    • Initiate antiretroviral therapy in all women with HIV.
    • Counsel women with HIV regarding the risk of vertical transmission.
  • STIs, STDs, tuberculosis: screen women at high risk and manage as appropriate.
• Medications
  • Review current medications including herbal products and nutritional supplements.
  • Discontinue teratogenic drugs and switch to safer medications when possible.
  • Evaluate a patient's drug regimen and consider the lowest dose of medications necessary to control a patient's condition(s).
• Immunizations
  • Measles, mumps, rubella and varicella
    • Screen all women for immunity with antibody titer.
    • Vaccinate all nonimmune women (see measles, mumps, rubella vaccine and varicella vaccine).
    • Counsel to avoid conceiving 28 days after the last vaccine dose.
  • Tetanus, diphtheria, and pertussis: Vaccinate all women before pregnancy according to the guidelines for nonpregnant women (see Tdap vaccine).
  • Hepatitis B: Vaccinate women with high risk for hepatitis B (see hepatitis B vaccine).
  • Influenza: Administer annual influenza vaccination to all women.

Lifestyle modifications

• Recommend maintaining a normal body weight prior to conception.
• Encourage regular moderate-intensity exercise.
• Nutrition
  • Screen for sufficient intake of macronutrients and micronutrients such as calcium, iron, vitamin B12, vitamin B, vitamin D, etc.
  • Ensure vitamin A is not taken in excess.
  • Recommend intake of 0.4 mg of folic acid daily, ideally 4 weeks prior to pregnancy and continue for at least the first 2–3 months of pregnancy.
• Substance use
  • Screen all women for alcohol, tobacco, and drug use and educate about associated adverse effects for the maternal and fetal pregnancy outcomes.
  • Provide assistance and/or refer to the proper specialists for smoking cessation and alcohol and drug use discontinuation.

Management of exposures

• Exposures to harmful agents
  • Advise patients to assess workspace and household for potentially harmful agents (e.g., heavy metals, solvents, chemicals, etc.).
  • Educate the patient about the avoidance of harmful agents and refer them to occupational medicine programs as needed.
• Exposure to violence
  • Screen for family violence at each visit.
  • In case ongoing abuse is identified, providers should:
    • Provide community resources to the patient.
    • Report the case as appropriate.

References: ^[6][7]

• Amenorrhoea
• Nausea and vomiting
• Breast enlargement and tenderness
• Hyperpigmentation of the areola and formation of linea nigra
• Increased urinary frequency
• Fatigue
• Cravings for or aversions to certain foods
• Abdominal bloating and constipation

References:^[8][9]

Pregnancy test: measurement of human chorionic gonadotropin (beta-hCG)

• Urine beta-hCG test (e.g., home pregnancy test)
  • Qualitative test; less sensitive than serum pregnancy test
  • hCG may be detected in urine 14 days after fertilization
• Serum beta-hCG test (quantitative, high sensitivity)
  • Detectable 6–9 days (on average) after fertilization
  • Normal pregnancy: beta-hCG concentration doubles every 2.5 days in early pregnancy (for the first 4 weeks) ^[10]
    • Peaks at 10 weeks of gestation (peak value: ∼100,000 mlU/mL)
    • ↓ During 2^nd trimester
    • ↔︎ During 3^rd trimester
  • At beta-hCG level of 1,500–2,000 mlU/mL pregnancy is visible with transvaginal ultrasound (if beta-hCG < 1000 mlU/mL, repeat beta-hCG and transvaginal ultrasound in 2–3 days)
  • Low levels or slow rise in level may indicate
    • Ectopic pregnancy
    • Abortion
    • Edwards syndrome
    • Patau syndrome
  • High levels or fast rise in level may indicate
    • Beta-hCG secreting tumors (hydatidiform mole, choriocarcinoma)
    • Multiple pregnancy
    • Down syndrome
  • False-positive test results:
    • Recent mononucleosis infection or IgA deficiency due to heterophilic antibody formation, crossreacts with beta-hCG testing
    • Perform urine beta-hCG as antibodies do not cross glomerular membrane ^[11]

Ultrasound findings in normal pregnancy (abdominal or transvaginal)

• At 5–6 weeks of pregnancy: detection of the embryo
• At 10–12 weeks of pregnancy: detection of fetal heartbeat with Doppler ultrasound
• At 18–20 weeks of pregnancy: fetal movements

Transvaginal ultrasound findings in normal pregnancy	Weeks after last menstruation (gestational age)	β-hCG mlU/mL
Gestational sac	5	1500–2000
Yolk sac	5 [12]	2500
Fetal pole	7	5000
Fetal heartbeat	10 [13]	17000

Gestational age and estimated date of delivery

Gestational age and estimated date of delivery may be estimated using Naegele's rule or determined more accurately via ultrasound in the second and third trimester.

• Gestational age: the age (in weeks and days) of the fetus calculated from the first day of the last menstrual period
• Conceptional age: the age (in weeks and days) of the fetus calculated from the day of conception (fertilization)
• Naegele's rule: used to calculate the date of delivery (due date)
  • First day of the last menstrual period + 7 days + 1 year - 3 months
  • Inaccurate if:
    • The date of the last menstrual period is uncertain or unknown.
    • The patient has irregular menstruation cycles.
    • The patient conceived while taking contraceptive pills.
• Ultrasound: more accurate than Naegele's rule
  • Measurement of the crown-rump length (CRL) in the first trimester
  • Measurement of biparietal diameter, fetal femoral length, and abdominal circumference in the second and third trimesters (can be used for determining gestational age starting at 13 weeks) ^[14]
• Fundal height during pregnancy: correlates with the gestational age

References:^{[1][15][8][16][17]}

Numerous physiological changes occur during pregnancy in order to support fetal growth and prepare for delivery.

Organ system	Changes
Cardiovascular	↑ Progesterone → ↓ vascular tone → ↓ peripheral vascular resistance (↓ afterload) ↑ Cardiac output by up to 40% (↑ preload) ↑ Stroke volume (by ∼ 10–30%) ↑ Heart rate (by ∼ 12–18 bpm) → ↑ uterine perfusion ↓ Mean arterial pressure Innocent systolic murmur The apex beat is displaced upward. Varicosity and edema of lower limbs
Respiratory	↑ Oxygen consumption (by ∼ 20%) The diaphragm is displaced upwards → ↓ total lung capacity, residual volume, functional residual capacity, and expiratory reserve volume ↑ Intra-abdominal pressure through uterine growth → dyspnea Progesterone stimulates the respiratory centers in the brain → hyperventilation (aimed to eliminate fetal CO2 more efficiently) → physiological, chronic compensated respiratory alkalosis ↑ Tidal volume (by ∼ 40%) → ↑ minute ventilation ↓ PCO2 (∼ 30 mm Hg)
Renal	↑ GFR → ↓ BUN and creatinine ↑ Aldosterone → ↑ plasma volume + hypernatremia ↑ Glucose levels in urine (increased glomerular filtration results in overload of the glucose carrier responsible for its resorption) ↑ Urinary frequency
Endocrine	Human placental lactogen increases insulin levels and insulin resistance (both increase in the second trimester to satisfy high fetal demand) ↑ Triglycerides and cholesterol (due to increased lipolysis and fat utilization) Hyperplasia of lactotroph cells in the anterior pituitary → physiological enlargement of the pituitary gland (up to 40% increase from pregestational volume)
Hematologic	↑ Plasma volume → ↓ hematocrit particularly towards the end of pregnancy (30–34th week of gestation); dilutional anemia ; (minimal hemoglobin value is 11 g/dL) ↑ RBC count (increases from 8–10th week of gestation until the end of pregnancy by approx. 15–30%) ↓ Platelet count ↑ WBC count ↓ Albumin ↑ Fibrinogen and factor VII, VIII, ↓ protein S → reduced prothrombin and partial thromboplastin times → hypercoagulability (to reduce the risk of intrapartum blood loss) ↑ Alkaline phosphatase (placental isoenzyme)
Gastrointestinal	↑ Salivation ↓ Motility → constipation Hemorrhoids
Musculoskeletal	Increased lumbar lordosis and relaxation of the ligaments supporting the joints of the pelvic girdle can cause lower back pain
Skin	Spider angioma Palmar erythema Striae gravidarum Hyperpigmentation: chloasma, linea nigra, hyperpigmentation of the nipples
Mammary glands	↑ Size
Uterus	↑ Size
Vulva and vagina	Vaginal discharge Formation of varicose veins

A physiological systolic murmur may be heard due to increased cardiac output and increased plasma volume!

Physiological hypercoagulability during pregnancy leads to an increased risk of thrombosis! Patients suffering from thrombophilia should receive adequate thrombosis prophylaxis!

References:^[18][19]

Basic principles

• Nutritional intake: needs to be adapted to meet both the demands of the mother and the fetus.
• Dietary recommendations
  • Limit caffeine intake: daily recommended dose < 200 mg
  • Avoid alcohol and tobacco use throughout pregnancy
  • Avoid unwashed or uncooked foods
    • Raw fish (contamination with parasites and bacteria) and seafood of unknown origin (methylmercury contamination)
    • Raw milk products: high risk of congenital listeriosis
    • Raw meat: high risk of congenital toxoplasmosis
• Supplementation of vitamins and minerals: recommended (see table below)

Recommended vitamin and mineral supplementation in pregnancy
	Supplementation	Reason for increased demand	Consequences of deficiency
Folic acid [20]	Folic acid 0.4–0.8 mg/day: Ideally, women should begin intake 4 weeks prior to pregnancy and continue with this dose for at least the first 2–3 months of pregnancy.	Fetal neural tube development Maternal and fetal erythropoiesis	Neural tube defects in the infant (e.g., anencephaly, meningomyelocele)
Vitamin B12	Recommended for pregnant women who adhere to a vegan diet 2.6 mcg per day	Increased erythropoiesis	Maternal and fetal anemia
Iron [21]	30–60 mg/day	Increased erythropoiesis	Maternal and fetal anemia (most common type of anemia in pregnancy) Increased risk of placental insufficiency
Calcium [22]	1000–1300 mg/day (50% increase)	Increased fetal demand Lactation	Maternal: muscle aches and cramps, brittle nails Premature birth Low birth weight
Iodine [23]	250 μg/day	Increased metabolism and excretion	Hypothyroidism of the mother and child

Recommended weight gain during pregnancy

• The recommendations are determined by the BMI prior to the pregnancy:
  • BMI < 18.5 (underweight): 28–40 lb (12–18 kg)
  • BMI 18.5–24.9 (normal weight): 25–35 lb (11–16 kg)
  • BMI 25–29.9 (overweight): 15–25 lb (7–11 kg)
  • BMI ≥ 30 (obese): 11–20 lb (5–9 kg)
• Average recommended daily calorie intake:
  • First trimester: 2200 kcal
  • Second and third trimester: 2500 kcal
• Regular physical activity is recommended (see the Physical activity during pregnancy section below).

References:^{[24][25][26][27][28]}

• Regular physical activity (i.e., aerobic and strength-training exercise) is considered beneficial and is recommended before, during, and after pregnancy.
• Careful evaluation of medical and obstetric disorders is necessary before recommending any exercise program.
• Modifying normal exercise routines may be necessary; activities considered unsafe should be avoided.

Safe and unsafe activities during pregnancy
Safe activities*	Walking Running or jogging*** Swimming Stationary cycling Pilates Yoga** Racquet sports*** Strength training***
Unsafe activities	Contact sports (e.g., soccer, basketball) Activities associated with a high risk of falling (e.g., snow skiing, water skiing, gymnastics, surfing) Hot yoga Hot Pilates Skydiving Scuba diving
* In pregnancies without complications as determined by an obstetrician ** Avoid positions associated with ↓ venous return *** May be considered safe in women who took part in these exercises before the pregnancy and as determined by an obstetrician

Physical activity should be discontinued if the patient presents with any of the following: antepartum or postpartum hemorrhage, uterine contractions, amniotic fluid leakage, chest pain, dyspnea before exertion, dizziness, headaches, calf pain/swelling, and/or muscle weakness with impaired balance!

References:^[29]

Oligohydramnios

• Definition: amount of amniotic fluid < 500 mL in the third trimester
• Etiology
  • Fetal anomalies
    • Urethral obstruction (e.g., posterior urethral valves)
    • Bilateral renal agenesis
    • Autosomal recessive polycystic kidney disease (ARPKD)
    • Chromosomal aberrations (e.g., trisomy 18)
    • Intrauterine infections (e.g., congenital TORCH infections)
    • In multiple pregnancies: twin-to-twin transfusion syndrome
  • Maternal conditions
    • Late or post-term pregnancies (> 42 weeks of gestation)
    • Placental insufficiency
    • Preeclampsia
    • Premature rupture of membranes
  • Idiopathic
• Complications
  • Intrauterine growth restriction (diminished mobility of the fetus)
  • Intrauterine compression and decreased amniotic fluid ingestion → Potter sequence: pulmonary hypoplasia (cause of death due to severe neonatal respiratory insufficiency), craniofacial abnormalities, limb anomalies
  • Birth complications (e.g., umbilical cord compression)
• Diagnosis
  • Abdominal girth and uterine size small for gestational age
  • Ultrasound
    • Amniotic fluid index (AFI): semiquantitative tool to assess amniotic fluid volume (normal: > 5–24 cm)
      • Oligohydramnios: ≤ 5 cm
    • Assess for fetal anomalies
• Treatment
  • Amnioinfusion: infusion of fluid into the amniotic cavity through amniocentesis
  • Treat underlying cause (see preeclampsia, premature rupture of membranes, placental insufficiency for details)
  • Delivery is advised if the fetus is close to term.

Polyhydramnios

• Definition: excessive amniotic fluid volume (> 2000 mL in the third trimester) that results in uterine distention and is associated with an increased risk of fetal complications
• Etiology
  • Fetal anomalies
    • Gastrointestinal anomalies (e.g., esophageal atresia, duodenal atresia and stenosis)
    • CNS anomalies (e.g., anencephaly , meningomyelocele )
    • Chromosomal aberrations
    • Intrauterine infections (e.g., congenital TORCH infections)
    • Multiple pregnancy: twin-to-twin transfusion syndrome
  • Maternal conditions
    • Diabetes mellitus
    • Rhesus incompatibility: hemolytic disease of the newborn
• Complications
  • Fetal malposition
  • Umbilical cord prolapse
  • Premature rupture of membranes
  • Premature uterine contractions
  • Premature birth
• Diagnosis
  • Abdominal girth and uterine size large for gestational age
  • Ultrasound
    • AFI ≥ 24 cm
    • Assess for fetal anomalies
• Treatment
  • Amnioreduction: drainage of excess amniotic fluid
  • Treat the underlying cause
    • Glycemic control in diabetic mothers
    • Intrauterine exchange transfusion for newborns with hemolytic disease

References:^{[31][32][33][34]}