Work and pregnancy Authors Josephine R Fowler, MD, MSc Larry Culpepper, MD, MPH Section Editor Charles

J Lockwood, MD Deputy Editor Vanessa A Barss, MD Disclosures Last literature review version 19.3: September 2011 | This topic last updated: October 31, 2011 (More) INTRODUCTION Women accounted for 40.4 percent of the salaried global labor force in 2008 [1]. In the United States, three-fifths of women are in the salaried labor force and threefourths of these women are of reproductive age; many work multiple jobs [2,3]. Thus, issues about work and pregnancy commonly arise. Factors influencing a woman's ability to work during pregnancy include [4]: Pregnancy-related physiological changes (eg, back pain, sleep disruption, nausea) Comorbid maternal medical conditions Obstetrical complications Occupational issues: Environmental toxins and hazards (chemical, biological, radiation) Physical demands and ergonomic factors Exposure to excessive noise or vibration Shift work issues (length, scheduling)

PHYSICAL CHANGES IN PREGNANCY THAT MIGHT AFFECT WORK The first trimester of pregnancy can be a difficult time for pregnant women, especially for those experiencing their first pregnancy. Common discomforts of early pregnancy include nausea and vomiting, fatigue, urinary frequency, bloating, cramping, breast tenderness, emotional lability, and lightheadedness. Pregnant women, especially those with nausea and/or vomiting, may have difficulty tolerating any odors. The majority of these changes can be managed by taking a brief break, as needed, but sometimes a short-term absence from work is required. During the early second trimester, by comparison, women tend to have a burst of energy as nausea and vomiting resolve, the feeling of fatigue lessens, and they are less stimulated by the smell of foods and noxious odors. However, by the end of the second trimester and continuing through term, physical and physiologic changes bring on discomforts such as heartburn, urinary frequency, constipation, dyspnea, back pain, varicose veins, hemorrhoids, urinary incontinence, nasal and sinus congestion, itching, and physical discomfort from the enlarging uterus. (See "Respiratory tract changes during pregnancy" and "Musculoskeletal changes and pain during pregnancy" and "Maternal cardiovascular and hemodynamic adaptations to pregnancy" and "Maternal gastrointestinal tract adaptation to pregnancy" and "The skin, hair, nails, and mucous membranes during pregnancy".)

Both the woman and her employer should develop strategies to deal with the physical and emotional changes associated with pregnancy, as well as lost work time and interruptions in work flow. MATERNITY LEAVE The increasing number of pregnant women in the workforce has prompted change in workforce policies related to working mothers. Women of reproductive age should be familiar with pregnancy discrimination and parenting leave statutes, such as the Pregnancy Discrimination Act of 1978 and the Family and Medical Leave Act of 1993, discussed below. The Family Medical Leave Act (FMLA) mandates 12 weeks of unpaid leave for childbearing or family care in a 12-month period for eligible employees [5]. Eligibility criteria include working at least 12 months for the current employer, for at least 1250 hours over the previous 12 months, in a facility that has at least 50 employees. For women in smaller organizations, or who have worked less than 12 months, an arrangement between employer and employee should be made early in the pregnancy, allowing time for workload to be distributed appropriately and allowing opportunity for the employee to plan for leave and return to work. However, paid leave is not mandated and is at the discretion of the employer. According to one study, fewer than 40 percent of pregnant women received wages during maternity leave [6]. Women of reproductive age in the workforce should consider evaluating policies on maternity leave when searching for employment. They should also evaluate the company's policies on issues related to child care, such as flexible schedules, part time work, working from home, leaving early for child related needs, sick children/snow days, dependent care spending accounts, child care assistance, resource and referral programs, etc. Estimating the effects of maternal employment on children's development is difficult to study due to selection bias and missing data (eg, quality of child care, home environment, maternal sensitivity, paternal factors). The literature is conflicting, and generally shows any adverse effects of maternal employment on child development are small [7-9]. WORKPLACE DISCRIMINATION Federal law prohibits discrimination due to pregnancy under the Pregnancy Discrimination Act (PDA) [10]. The PDA is an amendment to the Title VII of the Civil Rights Act of 1964. The PDA protects the pregnant woman from firing discrimination, peer and employer misjudgments when suffering pregnancy related conditions, insurance payment unfairness, and fringe benefit discrimination. In 1991, the Supreme Court ruled that a rigid policy that banned women of reproductive age from certain jobs discriminated against women on the basis of their sex. Although several toxic substances found in the workplace also could harm men of reproductive age, men were not banned from jobs on that basis. Therefore, it is illegal for an employer to ban a woman from certain jobs because she might become pregnant while working there. During the fiscal year 2005, the Federal Equal Employment Opportunity Commission received more than 4000 complaints about pregnancy discrimination. More than half were related to unfair dismissal during pregnancy or immediately following maternity leave [11]. Pregnancyrelated complaints occurred more frequently than sexual harassment and sexual discrimination complaints. According to the Equal Opportunity Commission, the number of workforce discrimination charges has increased 67 percent in the last 15 years for all women and 76 percent for ethnic and racial minorities, although it is considered illegal [12]. Before considering pregnancy, women in the workplace should familiarize themselves with state laws about maternity leave, inquire about coverage under the Family Medical Leave Act

(FMLA), understand their rights in the workplace and benefits granted during maternity leave, and know standard duration in the workplace, along with expectations about return. Women who have concerns about unfair treatment during pregnancy should consider seeking legal services. DISABILITY The Pregnancy Discrimination Act also requires employers offering medical disability benefits to treat pregnancy-related disabilities just like all other disabilities. Pregnant workers must be provided the same insurance benefits, sick leave, seniority credits, and reinstatement privileges awarded workers disabled by other causes. DEMANDS OF WORKPLACE AND PERINATAL OUTCOME A woman with an uncomplicated pregnancy who is employed where there are no greater potential hazards than those encountered in routine daily life may continue to work without interruption until the onset of labor. However, the physical demands of the woman's job should be considered, especially in women at higher risk of preterm delivery. Studies on the effect of work on pregnancy outcome have shown wide variations in results. This is likely due, in part, to "healthy worker" effects whereby healthier workers are more likely to continue to work and work in more demanding jobs, thus biasing outcomes. A meta-analysis of 21 studies including 146,457 women identified a high cumulative work fatigue score as the strongest (OR 1.63) work-related risk factor for preterm birth [13]. The results of this analysis are summarized in the table (table 1). There is a general consensus that working during pregnancy should be limited or contraindicated in some women: Vaginal bleeding Short or dilated cervix before 36 weeks of gestation Uterine malformation Pregnancy-induced hypertension Fetal growth restriction Multiple gestation with complications Prior history of preterm birth Polyhydramnios Maternal medical disorders that are unstable or associated with impaired placental perfusion

The relationship between physical activity/work and preterm labor is discussed in more detail separately. (See "Risk factors for preterm labor and delivery", section on 'Physical activity and work'.) Frequent air travel is a component of some jobs, and is generally safe for pregnant women. (See "The initial prenatal assessment and routine prenatal care", section on 'Airline travel'.) WORKPLACE SAFETY DURING PREGNANCY Overview Whether or not a woman continues to work during her pregnancy depends on her health, the health of the baby, and the presence of workplace hazards that may affect the woman or her unborn child. Employers are mandated by law to provide information regarding work exposures that might affect reproductive outcomes.

There are several potential environmental exposures that a pregnant woman might encounter in the workplace that could have an adverse effect on the pregnancy (table 2A-B). Such exposures should be avoided, but all do not necessarily warrant leaving the job. Environmental exposures that may put pregnancy at risk include: Exposure to metals, chemicals, solvents Exposure to pharmaceutical agents Exposure to extreme heat Exposure to infections

Providers should inform women to minimize exposures and encourage them to ask employers for information regarding potential workplace risks. The Occupational Safety and Health Administration (OSHA) sets and enforces standards requiring employers to provide a workplace free from recognized hazards likely to cause serious physical harm. Every employer is mandated to have a Material Safety Data Sheet (MSDS) that contains information on the chemical properties and health effects of the substances used in the workplace. The sheet gives valuable information about the ingredients of a particular chemical, its appearance and odor, flammability, health hazards, reactivity data, precautions, spill and exposure procedures, pregnancy risk, preventive measures and first aid measures. Additional information can be obtained from the Organization of Teratology Information Specialists (www.otispregnancy.org or telephone 866626-6847). Selected environmental exposures will be discussed below. These issues are reviewed in more detail separately. (See "Occupational and environmental risks to reproduction in females" and "Overview of occupational and environmental health" and "Information and educational resources for occupational and environmental health issues in the United States".) Lead Maternal occupational exposure to lead has been linked to a variety of adverse outcomes (table 2A-B). Lead is the third most common occupational exposure in women. It enters the body via inhalation and ingestions and accumulates in the soft tissues, bones, blood, liver, and kidneys. Lead that is stored in the bones may mobilize during pregnancy and lactation due to bone demineralization [14,15]. Under federal and state law, employers should have written lead standards and air monitoring results. Symptoms of lead toxicity (fatigue, muscle and joint pain, abdominal cramps, headaches, and irritability) appear when lead levels are between 60 to 120 mcg/dL in the blood. The Occupational Safety and Health Administration (OSHA) recommends a level less than 30 mcg/dL to prevent reproductive problems. Neurologic, hematologic, and reproductive effects may occur at lower levels [16]. In pregnant women, blood lead elevations of 20 mcg/dL are of high concern because of the potential for adverse effects on the developing fetus, which is more susceptible to lead's toxic effects. Even lead levels less than 10 mcg/dL may be of concern in pregnancy in light of studies demonstrating intellectual impairment in children with blood lead concentrations below 10 mcg/dL. (See "Adult lead poisoning" and "Childhood lead poisoning: Clinical manifestations and diagnosis" and "Occupational and environmental risks to reproduction in females".) Women working in known areas of lead exposure should always wear protective clothing, change work clothing and shoes before going home, use respiratory equipment to avoid inhalation, and wash hands before handling food and drinks [17]. Women with symptoms of lead toxicity should have their lead levels checked and be removed from exposure. Chelating agents are not recommended during pregnancy. To reduce their risk if exposed to lead, pregnant women

can be counseled to eat a well balanced diet that would increase iron, calcium, and zinc stores. As nutritional deficiencies in iron, calcium and zinc may increase lead absorption [18,19]. Mercury Mercury is found in numerous manufactured products. Inhaling metallic mercury over time can affect all systems in the body, but the brain and kidneys are the most likely to be affected at lower levels. In pregnancy, exposure to mercury can be associated with adverse effects (table 2A-B). (See "Epidemiology and toxicity of mercury" and "Occupational and environmental risks to reproduction in females".) Mercury can be found in elemental, organic and inorganic forms. Elemental mercury is inhaled through vapors and fumes and is the least absorbed form of mercury. Women working with dental amalgam are at risk of exposure to elemental mercury. Inorganic mercury is found in fungicides, antiseptics and disinfectants and may be absorbed in toxic levels through the skin. Organic mercury is consumed by eating fish with high levels of methyl mercury. The major source of mercury exposure occurs in the workplace. Persons working in light bulb manufacturing facilities, dental facilities, and gold mining industries in undeveloped countries where mercury fumes are high have the greatest risks of elemental exposures. Solvents Occupational exposure to solvents ranges from exposure to known toxic chemicals in the workplace to routine household solvents used for cleaning. Household solvents are usually not a major risk since exposure is episodic and air levels are low. However, women with industrial exposure appear to be at some risk [20-22], which depends on dose and duration of exposure. We advise women working with occupational solvents to request information regarding the solvent from their employers, work in well ventilated areas, and wear protective gear such as masks, gloves, and clothing while using these solvents [23]. Pharmaceutical agents Healthcare workers may be exposed to hazardous pharmaceutical agents. Exposure can occur through direct or indirect contact with these substances [24]. Although healthcare facilities recommend universal precautions, employees should ask for Material Safety Data Sheets (MSDS) when they work in areas exposed to hazardous materials. Hazardous materials should be prepared in well ventilated areas, handlers should wear protective clothing (double gloves, gowns, eye protective gear) and all spills should be cleaned immediately and cleaning material discarded properly. Employers should provide training sessions to employees about hazardous materials in the workplace. It is important to have guidelines and procedures on storage, use, preparation, cleaning spills, decontamination, and patient wastes. Occupational exposures to chemotherapeutic agents have been linked to adverse pregnancy outcomes. A systematic review that tested the hypothesis that oncology health care workers are at an increased risk of reproductive complications found no significant association between exposure to cytotoxic drugs and congenital malformations (OR 1.64; 95% CI, 0.91-2.94) or stillbirths (OR 1.16, 95% CI: 0.73-1.82), but did identify an association between exposure to chemotherapy and spontaneous abortions (OR 1.46, 95% CI 1.11-1.92) [25]. A subsequent systematic review found that nurses with occupational exposure to anesthetic gases were at increased risk of having a child with a congenital malformation (OR 1.33, 95% CI 1.06-1.68) and with spontaneous abortion (OR 1.27, 95% CI 0.99-1.63); this review did not find a statistically significant association between chemotherapy and spontaneous abortion (OR 1.21, 95% CI 0.80-1.83) [26]. Infection Healthcare workers are exposed to infections daily, and often repetitively. The likelihood of adverse sequelae if a pregnant woman becomes infected depends on several factors, including the type of infection and the trimester during which the exposure occurred (see

individual topic reviews on each infection) (table 3). Pregnant women working in health care facilities should always use universal precautions when coming in contact with children or adults who may have an infectious disease and should have appropriate immunizations before and during pregnancy (see "Immunizations during pregnancy"). Radiation A report by the United States Nuclear Regulatory Commission lists limits for prenatal radiation exposure [27]. Women should not be exposed to more than 5 mSv during the nine months of pregnancy and no more than 0.5 mSv during any gestational month. Women working in an environment with radiation exposure should wear a dosimeter badge, which is processed every two to four weeks. They should also be encouraged to wear proper shielding (eg, lead apron) if exposure is expected, minimize the time of exposure, and maximize their distance from the source of radiation. The risks of radiation exposure in pregnancy are discussed in detail separately. (See "Diagnostic imaging procedures during pregnancy".) Heat Heat is a workplace hazard for those working in agricultural industries, construction work, farming, and, in some areas, outside jobs. The human fetus' temperature is about 1 degree Celsius higher than the maternal temperature. Animal studies suggest that perinatal risks (eg, CNS, vascular disruption and neural defects [28]) increase with maternal heat exposure. Similar findings were found in human studies related to febrile illnesses, sauna use, and hot tub use [2931]. The National Institute of Occupational Safety and Health guidelines address protection of workers in hot environments [32]. Employers of facilities with risk for high temperature should institute measures to minimize environment and metabolic heat exposure (eg, good ventilation to draw steam and heat from work areas, cooling fans, heat shields, labor saving devices, rest periods in cooler areas, hydration) and provide training to employees on how to recognize heatrelated illnesses. In areas where heat is unavoidable, employees should take precautions to avoid heat stress and heat related complications. Pregnant women should be encouraged to increase fluid intake, request periodic breaks from the heated area, and to dress in light clothing to avoid over heating. Noise Persistent occupational noise stress does not appear to cause fetal structural anomalies [33]. The effect of noise on birth weight and length of gestation is unclear, as studies have reported discordant findings [34]. Environmental noise, if sufficiently loud, may damage fetal hearing, although data in humans are limited [35-38]. By the 20th week of gestation, the structures of the fetal auditory system are well-developed, enabling the fetus to detect sounds after the late second trimester of pregnancy [39]. Low-frequency sounds penetrate the maternal tissues and amniotic fluid more effectively than higher frequency sounds: external noise is minimally reduced for frequencies below 0.5 kHz, but reduced by 40 to 50 dB for frequencies above 0.5 kHz [40]. In one report, children with hearing loss at 4 to 10 years of age were more likely to have been born to women exposed to hours of occupational noise of 85 to 95 dB during their pregnancy than to women exposed to levels below 85 dB; low frequency noise increased the risk of hearing loss [36]. However, this study has been criticized for methodological shortcomings, such as absence of a matched control group, retrospective noise evaluation, and multiple confounders. Most countries have regulations about occupational noise exposure, but these standards typically do not specifically address pregnant women and fetal safety. The American Conference of Governmental Industrial Hygienists noted that eight hours total work exposure of 115 dB or a peak exposure of 155 dB to pregnant workers beyond the fifth month of pregnancy may cause hearing loss in the fetus [41]. The US Navy suggests that pregnant workers be vigilant about

wearing hearing protection whenever environmental noise exceeds 84 dB to minimize the effects of potentially unhealthy maternal physiological changes on the fetus, and recommends that extended exposures (more than 12 minutes) above 104 dB should be avoided after 20 weeks of gestation, even with the use of maternal hearing protection [42]. There is no method for shielding the fetus from environmental noise. Video display terminals Video display terminals emit very low frequency (VLF) and extremely low frequency (ELF) electromagnetic fields. They do not emit detectable levels of ionizing radiation. Literature reviews have generally concluded that there is no evidence of a significant association between a woman's use of a video display terminal (VDT) and fetal loss or other adverse reproductive outcomes [43,44]. However, ergonometric issues related to use of computers in the workplace (eg, carpal tunnel syndrome, low back pain) may be more problematic for pregnant women. Smoking Environmental tobacco smoke may have an adverse effect on the fetus, but there are few data. The effects of passive and active smoking on pregnancy are discussed in detail separately. (See "Secondhand smoke exposure: Effects in adults" and "Smoking and pregnancy".) Air travel Frequent business-related air travel is common and generally safe during pregnancy. Issues related to air travel are discussed separately. (See "The initial prenatal assessment and routine prenatal care", section on 'Airline travel'.) Shift work A systematic review that evaluated the influence of shift work among nurses found it moderately increased the risk of spontaneous abortion (OR 1.44, 95% CI 1.06-1.95) [26]. In another systematic review of epidemiologic studies on shift work and selected pregnancy outcomes, shift was associated with no or minimal increase in risk of preterm delivery, low birth weight, small for gestational infant, and preeclampsia (pooled RR 1.03-1.27 with wide confidence intervals) [45]. These results are consistent with previous analyses that observed only modest associations between shift-night work and preterm birth (OR 1.24, 95% CI 1.06-1.46) [13]. Cosmetologists Cosmetologists in hair salons are potentially exposed to hundreds of chemicals. There is no good evidence of teratogenic effects, but it is prudent for workers in hair salons to wear gloves when possible and attempt to work in well-ventilated areas since data are limited [46-52]. Pesticides Epidemiologic studies have reported adverse reproductive or developmental effects associated with mixed pesticide exposure in occupational settings, particularly when personal protective equipment was not used [53]. Every class of pesticide (organophosphates, carbamates, pyrethroids, herbicides, fungicides, fumigants, organochlorines) appears to have at least one agent capable of affecting a reproductive or developmental endpoint in animals or humans. Counseling patients who are concerned about reproductive and developmental effects of pesticides involves helping them assess their degree of exposure, weigh risks and benefits of this exposure, and adopt practices to reduce or eliminate exposure and absorption. One systematic review of childhood leukemia and parental occupational pesticide exposure determined that there was no overall association between childhood leukemia and any paternal occupational pesticide exposure (OR 1.09; 95% CI 0.881.34) [54]. However, childhood leukemia was associated with prenatal maternal occupational pesticide exposure (OR 2.09; 95% CI 1.512.88); this association was slightly stronger for studies with high exposuremeasurement-quality scores (OR 2.45; 95% CI 1.683.58) and farm-related exposures (OR 2.44;

95% CI 1.533.89). The risk was also elevated for prenatal maternal occupational exposure to insecticides (OR 2.72; 95% CI 1.475.04) and herbicides (OR 3.62; 95% CI 1.2810.3). SUMMARY AND RECOMMENDATIONS Every woman should be counseled about any risks associated with her job and the impact of the demands of her job on pregnancy. Employees should be advised to inquire about substances in the workplace that may pose risk to the unborn child. Employers, in turn, should be knowledgeable about these risks and exposures, offer ongoing education to all employees, and assist in minimizing these risks. Taking proper precautions, minimizing lifting and bending, using proper lifting techniques, taking regular breaks every few hours and a longer break after five hours, and drinking plenty of fluids are simple instructions that could reduce excessive fatigue and risk of pregnancy complications [13,55-57]. Discussing leaves and interim absences early in pregnancy can limit misunderstandings. Although women may not totally avoid discrimination in the workplace, identifying advocates in the workplace, knowing expectations of employers before becoming pregnant, and knowing rights and responsibilities can minimize stress related to workplace discrimination. Use of UpToDate is subject to the Subscription and License Agreement.

REFERENCES
1. Global trends for women. Global Employment Trends for Women, March 2009. 2. Chao, EL, Utgoff, KP. Women in the Labor Force: A Databook, US Department of Labor, Bureau of Labor Statistics, Report 1973, February 2004. 3. Women's Safety and Health Issues at Work. From the National Institute for Occupational Safety and Health. DHHS (NIOSH) Publication Number 2001-123. 4. Health-related Maternity leave in the Uncomplicated Pregnancy and Birth. Alberta Perinatal Health Program. February 2008. www.aphp.ca (accessed July 2008). 5. www.dol.gov/esa/whd/fmla/ (Accessed March 22, 2006). 6. O'Connell, M. Maternity leave arrangements: 1961-85. In: Work and family patterns of American women, Government Printing Office, Washington DC 1991.
7. Brooks-Gunn J, Han WJ, Waldfogel J. Maternal employment and child cognitive

outcomes in the first three years of life: the NICHD Study of Early Child Care. National Institute of Child Health and Human Development. Child Dev 2002; 73:1052.
8. Hill JL, Waldfogel J, Brooks-Gunn J, Han WJ. Maternal employment and child

development: a fresh look using newer methods. Dev Psychol 2005; 41:833.
9. Zoritch B, Roberts I, Oakley A. Day care for pre-school children. Cochrane Database

Syst Rev 2000; :CD000564. 10. www.eeoc.gov/abouteeoc/35th/thelaw/pregnancy_discrimination-1978.html (Accessed March 22, 2006). 11. The U.S. Equal Employment Opportunity Commission. Pregnancy Discrimination Charges_EEOC & FEPAs Combined: FY 1992 - FY 2005, January 2006. 12. The Us Equal Employment Opportunity Commission. Pregnancy and Discrimination Charges, 1997-2007. http://www.eeoc.gov/stats/enforcement.html.

13. Mozurkewich EL, Luke B, Avni M, Wolf FM. Working conditions and adverse

pregnancy outcome: a meta-analysis. Obstet Gynecol 2000; 95:623.

14. Thompson GN, Robertson EF, Fitzgerald S. Lead mobilization during pregnancy. Med J

Aust 1985; 143:131.

15. Gomaa A, Hu H, Bellinger D, et al. Maternal bone lead as an independent risk factor for

fetal neurotoxicity: a prospective study. Pediatrics 2002; 110:110. 16. Substance Data Sheet for Occupational Exposure to Lead -1926. 62 App A. US Department of Labor. Occupational Safety and Health Administration, 57 FR 26627, May 4, 1993, as amended at 58 FR 34218, June 24, 1993. 17. Lead OSHA standards. US Department of Labor, Occupational Safety and Health Administration. Toxic and Hazardous Substances. Employee standard Summary 1910. 18. Hertz-Picciotto, I, Schramm, M, Watt-Morse, M, Chantala, K, et al. Patterns and determinants of blood lead during pregnancy. American Journal of Epidemiology 152:829.
19. Aimo L, Oteiza PI. Zinc deficiency increases the susceptibility of human neuroblastoma

cells to lead-induced activator protein-1 activation. Toxicol Sci 2006; 91:184.

20. Laslo-Baker D, Barrera M, Knittel-Keren D, et al. Child neurodevelopmental outcome

and maternal occupational exposure to solvents. Arch Pediatr Adolesc Med 2004; 158:956. 21. Rouvet, JF, Westall, C, Koren, G, Till, C. Maternal Occupational Exposure to Organic Solvents during Pregnancy and Infant Visual Processing. University of Toranto. Workplace Safety and Insurance Board of Ontario, November 2006.
22. Taskinen H, Kyyrnen P, Hemminki K, et al. Laboratory work and pregnancy outcome. J

Occup Med 1994; 36:311. 23. Mercury OSHA standards. US Department of Labor, Occupational Safety and Health Administration. Toxic and Hazardous Substances. Employee standard Summary 1910. 24. Preventing Occupational Exposure to Antineoplastic and other Hazardous Drugs in Healthcare Settings. National Institute for Occupational Safety and Health. DHHS (NIOSH) Publication Number 2004-165.
25. Dranitsaris G, Johnston M, Poirier S, et al. Are health care providers who work with

cancer drugs at an increased risk for toxic events? A systematic review and meta-analysis of the literature. J Oncol Pharm Pract 2005; 11:69.
26. Quansah R, Jaakkola JJ. Occupational exposures and adverse pregnancy outcomes among

nurses: a systematic review and meta-analysis. J Womens Health (Larchmt) 2010; 19:1851. 27. Instruction Concerning Prenatal Radiation Exposure. US Nuclear Regulatory Commission, Regulatory guide 8.13, DG-6014, June 1999.
28. Cadwell-Smith, J, Upfold, J, Edwards, M, et al. Neural Tube and other Developmental

Anomalies in the Guinea Pig following Maternal Hyperthermia during Early Neural Tube Development. Teratogenesis Carcino. Mutagen 1992; 12:1.

29. Graham JM Jr, Edwards MJ, Edwards MJ. Teratogen update: gestational effects of

maternal hyperthermia due to febrile illnesses and resultant patterns of defects in humans. Teratology 1998; 58:209. 30. Graham, JM, Edwards, MJ, Lipson, AH, et al. Gestational Hyperthermia as a Cause for Moebius Syndrome. Teratology 37:461.
31. Edwards MJ. Review: Hyperthermia and fever during pregnancy. Birth Defects Res A

Clin Mol Teratol 2006; 76:507. 32. www.cdc.gov/niosh/86-113.html (accessed April 5, 2007).
33. Kurppa K, Rantala K, Nurminen T, et al. Noise exposure during pregnancy and selected

structural malformations in infants. Scand J Work Environ Health 1989; 15:111.

34. Noise: a hazard for the fetus and newborn. American Academy of Pediatrics. Committee

on Environmental Health. Pediatrics 1997; 100:724. 35. www.Reprotox.org (Accessed September 22, 2009).
36. Lalande NM, Htu R, Lambert J. Is occupational noise exposure during pregnancy a risk

factor of damage to the auditory system of the fetus? Am J Ind Med 1986; 10:427.
37. Daniel T, Laciak J. [Clinical observations and experiments concerning the condition of

the cochleovestibular apparatus of subjects exposed to noise in fetal life]. Rev Laryngol Otol Rhinol (Bord) 1982; 103:313.
38. Nurminen T, Kurppa K. Occupational noise exposure and course of pregnancy. Scand J

Work Environ Health 1989; 15:117.

39. Gerhardt KJ, Pierson LL, Huang X, et al. Effects of intense noise exposure on fetal sheep

auditory brain stem response and inner ear histology. Ear Hear 1999; 20:21.
40. Gerhardt KJ, Abrams RM. Fetal exposures to sound and vibroacoustic stimulation. J

Perinatol 2000; 20:S21. 41. ACGIH: 2003 TLVs and BEIs. Publication No. 103. 42. Navy and Marine Corps Public Health Center Technical Manual NMCPHC-TM-OEM 6260.01C. Reproductive and developmental hazards: A guide for occupational health professionals. http://www.nmcphc.med.navy.mil/downloads/occmed/Repro2010d2.pdf (Accessed on April 12, 2011).
43. Shaw GM. Adverse human reproductive outcomes and electromagnetic fields: a brief

summary of the epidemiologic literature. Bioelectromagnetics 2001; Suppl 5:S5.

44. Robert E. Intrauterine effects of electromagnetic fields--(low frequency, mid-frequency

RF, and microwave): review of epidemiologic studies. Teratology 1999; 59:292.

45. Bonzini M, Palmer K, Coggon D, et al. Shift work and pregnancy outcomes: a systematic

review with meta-analysis of currently available epidemiological studies. BJOG 2011; 118:1429.
46. Blackmore-Prince C, Harlow SD, Gargiullo P, et al. Chemical hair treatments and

adverse pregnancy outcome among Black women in central North Carolina. Am J Epidemiol 1999; 149:712.
47. Burnett C, Goldenthal EI, Harris SB, et al. Teratology and percutaneous toxicity studies

on hair dyes. J Toxicol Environ Health 1976; 1:1027.

48. Holly EA, Bracci PM, Hong MK, et al. West Coast study of childhood brain tumours and

maternal use of hair-colouring products. Paediatr Perinat Epidemiol 2002; 16:226.

49. Gallicchio L, Miller S, Greene T, et al. Cosmetologists and reproductive outcomes.

Obstet Gynecol 2009; 113:1018.

50. Kersemaekers WM, Roeleveld N, Zielhuis GA. Reproductive disorders due to chemical

exposure among hairdressers. Scand J Work Environ Health 1995; 21:325.

51. Efird JT, Holly EA, Cordier S, et al. Beauty product-related exposures and childhood

brain tumors in seven countries: results from the SEARCH International Brain Tumor Study. J Neurooncol 2005; 72:133.
52. McCall EE, Olshan AF, Daniels JL. Maternal hair dye use and risk of neuroblastoma in

offspring. Cancer Causes Control 2005; 16:743.

53. Frazier LM. Reproductive disorders associated with pesticide exposure. J Agromedicine

2007; 12:27.
54. Wigle DT, Turner MC, Krewski D. A systematic review and meta-analysis of childhood

leukemia and parental occupational pesticide exposure. Environ Health Perspect 2009; 117:1505.
55. Saurel-Cubizolles MJ, Zeitlin J, Lelong N, et al. Employment, working conditions, and

preterm birth: results from the Europop case-control survey. J Epidemiol Community Health 2004; 58:395.
56. Fortier I, Marcoux S, Brisson J. Maternal work during pregnancy and the risks of

delivering a small-for-gestational-age or preterm infant. Scand J Work Environ Health 1995; 21:412.
57. El-Metwalli AG, Badawy AM, El-Baghdadi LA, El-Wehady A. Occupational physical

activity and pregnancy outcome. Eur J Obstet Gynecol Reprod Biol 2001; 100:41. Diagnostic imaging procedures during pregnancy Author Jonathan B Kruskal, MD, PhD Section Editors Louise Wilkins-Haug, MD, PhD Deborah Levine, MD Deputy Editor Vanessa A Barss, MD Disclosures Last literature review version 19.3: September 2011 | This topic last updated: March 21, 2011 (More) INTRODUCTION Preconceptional ovarian exposure to diagnostic levels of ionizing radiation has no measurable effect on future pregnancies. Therefore, the ideal time to schedule radiologic procedures in women of reproductive age is during the first 10 days of the menstrual cycle, if possible. At the time of the radiologic examination, all women of childbearing potential should be asked if they could be pregnant [1]. If any doubt exists, the results of a pregnancy test should be obtained before proceeding. Sometimes diagnostic imaging is necessary during pregnancy, and utilization rates appear to be increasing [2]. Sonographic examination of the uterus and its contents is a common occurrence

in pregnant women, but other types of radiological evaluation may also be required. Although the safety of radiation exposure during pregnancy is a common concern, a missed or delayed diagnosis can pose a greater risk to the woman and her pregnancy than any hazard associated with ionizing radiation [3]. In many cases, the perception of fetal risk is higher than the actual risk [4,5]. For the woman herself, the effects of ionizing radiation are the same whether or not she is pregnant, and will not be dealt with in this topic. RADIATION BASICS Any discussion of the effects of radiation requires a background knowledge of radiation nomenclature and dosimetry. The absorbed dose of radiation is the amount of energy deposited per kilogram of tissue and is measured in "rads." One rad is the energy transfer of 100 ergs per gram of any absorbing material. The following relationships apply to diagnostic X-rays in soft tissue: 1 rad = 0.01 gray (Gy) = 0.01 sievert (Sv) = 1 rem (roentgen-equivalent man) and 0.001 rad = 1 mrad = 0.01 mGy

In the United States, the average person is exposed to an effective radiation dose equivalent of approximately 3.6 mGy (360 mrad) whole-body exposure per year from all sources (natural and man-made) [6]. The US Nuclear Regulatory Commission recommends that occupational radiation exposure of pregnant women not exceed 5 mGy (500 mrad) to the embryo/fetus during the entire pregnancy [7]. (See "Biology and clinical features of radiation injury in adults", section on 'Examples of possible radiation exposures'.) EFFECTS OF IONIZING RADIATION ON THE FETUS Overview There are no studies in humans from which to derive data on risks of ionizing radiation; most of our information is based upon case reports and extrapolation of data from investigations of survivors of the atomic bomb in Japan and the Chernobyl accident [8-14]. Based on these data, the potential deleterious consequences of ionizing radiation can be divided into four categories [15,16]: Pregnancy loss (miscarriage, stillbirth) Malformation Disturbances of growth or development Mutagenic and carcinogenic effects

The occurrence of each effect depends upon the gestational age at the time of radiation exposure, the dose of radiation absorbed by the fetus, and fetal cellular repair mechanisms. Cellular damage caused by low levels of radiation exposure is usually repaired by a number of physiologic processes. In contrast, high level exposure can interrupt important events in cell development and maturation, which may cause permanent injury or death. The effects of radiation can be considered as either deterministic (exposure affects severity of outcome) or stochastic (exposure affects probability of outcome). The deterministic effects are dose-related and occur when many cells are affected by radiation; a large number of affected cells results in more significant clinical problems. If injury to these cells occurs during a critical stage of organogenesis (primarily but not exclusively days 15 to 50 after conception), impairment, agenesis, or deformity of the developing organ can occur (figure 1). As an example, microcephaly develops if a large number of differentiating central nervous system cells are injured.

Stochastic effects are monoclonal, resulting in changes to the cell genome and altered differentiation and function of the affected cells. The probability, but not the severity, of the effect increases with the radiation dose. As an example, the increased risk of thyroid cancer as a result of in utero exposure to radiation after the Chernobyl accident is a stochastic effect [8]. Exposure less than 0.05 Gy (5 rads) Diagnostic imaging procedures typically expose the fetus to this level of radiation (table 1). There is NO evidence of an increased risk of fetal anomalies, intellectual disability, growth restriction, or pregnancy loss from ionizing radiation at doses less than 0.05 Gy [17-19]. The margin of safety is augmented by the fact that most human exposures from diagnostic imaging will be fractionated over a period of time; this type of exposure is less harmful than acute exposure [17]. Carcinogenesis Animal data suggest that carcinogenic effects are most pronounced during late fetal development [18]. Low levels (eg, 0.01 to 0.02 Gy [1 to 2 rad]) of in utero radiation exposure may increase the risk of childhood cancer, particularly leukemia, by a factor of 1.5 to 2 over the baseline incidence [17,20]. However, the carcinogenic potential of low level radiation is controversial since nonirradiated siblings of these children also have a higher incidence of leukemia. Furthermore, children exposed in utero at the bombing of Hiroshima and Nagasaki have not developed a significantly increased rate of cancer [21]. An estimate of the risk of childhood leukemia in various populations is shown in the table (table 2). Although an increased risk of radiation-induced carcinogenesis in children exposed in utero cannot be excluded, the general consensus is that this risk is not likely to exceed 1 in 1000 children per rad of exposure [19]. Solid cancer incidence rates have been examined among survivors of the atomic bombings of Hiroshima and Nagasaki who were in utero (n = 2452) or younger than 6 years (n = 15388) at the time of the bombings [22]. Both the in utero and early childhood groups exhibited statistically significant dose-related increases in incidence rates of solid cancers, but the lifetime risks following in utero exposure were much lower than for early childhood exposure. At age 50, the estimated excess absolute rate per 10,000 person-years per Gy was 6.8 (95% CI <0 to 49) for those exposed in utero and 56 (95% CI 36 to 79) for those exposed as young children. There was NO increase in oncogenic risk for exposures less than 0.2 Gy. Exposure 0.05 to 0.50 Gy (5 to 50 rads) The threshold at which an increased risk of congenital malformations is observed in radiation exposed embryos/fetuses has not been definitively determined. The evidence suggests the risk of malformations is increased at doses above 0.10 Gy, whereas the risk between 0.05 and 0.10 Gy is less clear [23]. It is important to note that even those diagnostic imaging procedures associated with high fetal radiation exposure (eg, abdominal or pelvic CT, barium enema, cystourethrogram) almost never expose the fetus to this level of radiation (table 1). First 14 days after conception The developing human is most sensitive to the lethal effects of ionizing radiation during the first 14 days after conception. During this period, the radiationexposed "embryo" either survives undamaged or is resorbed (termed the "all or none" phenomenon) [24]. Radiation-induced teratogenesis, growth restriction, or carcinogenesis are NOT observed during this stage of development [17], presumably because of the pluripotent nature of each cell of the very early embryo. For human exposure, a conservative estimate of the threshold for death at this stage is more than 0.1 Gy rads (10 rads) [18]. A fetal dose of 1 Gy (100 rads) will likely kill 50 percent of embryos; the dose necessary to kill 100 percent of human embryos or fetuses before 18 weeks of gestation is about 5 Gy (500 rads).

After the first 14 days During the period of organogenesis (approximately 2 to 8 weeks after fertilization or 4 to 10 weeks after the last menstrual period), the embryo may be damaged as a result of radiation-induced cell death, disturbances in cell migration and proliferation, or mitotic delay [25]. Lethality is rare. The major sequelae of radiation damage at this stage are fetal growth restriction and congenital malformations, particularly of the central nervous system (eg, microcephaly, intellectual disability, gross eye abnormalities). Microcephaly is the most frequently cited manifestation of radiation injury in utero [26]. In the absence of any of these findings, the presence of other types of malformations in humans should not be attributed to radiation exposure [17]. After approximately 20 to 25 weeks of gestation, the fetus is relatively resistant to teratogenic effects of ionizing radiation [27].

Malformations For the developing fetus under 16 weeks of gestation, the threshold for possible prenatal radiation effects is approximately 0.10 to 0.20 Gy (10 to 20 rads) [18]. After 16 weeks of gestation, the consensus of most researchers is that this threshold is much higher, at least 0.50 to 0.70 Gy (50 to 70 rads). Mental retardation Studies in survivors of the Hiroshima atomic bomb demonstrated that the risk of mental retardation and microcephaly was highest for radiation exposures at 8 to 15 weeks after conception [9]. The abnormalities were attributed to alterations in neuronal development. No cases of severe intellectual disability were identified in the children of atomic bomb survivors who were exposed prior to 8 weeks or after 25 weeks following conception. The risk appeared to be a linear function of dose, with a threshold of 0.12 Gy (12 rads) at 8 to 15 weeks, and 0.21 Gy (21 rads) at 16 to 25 weeks [10-13]. In addition, at 8 to 15 weeks, the average IQ loss was approximately 25 to 31 points per Gy (per 100 rads) above 0.1 Gy (10 rads), and the risk for severe intellectual disability was approximately 40 percent per Gy (per 100 rads) above 0.1 Gy (10 rads). By comparison, at 16 to 25 weeks, the average IQ loss was approximately 13 to 21 points per Gy at doses above 0.7 Gy, and the risk of severe intellectual disability was approximately 9 percent per Gy above 0.7 Gy.

Growth restriction Atomic bomb survivor data showed a permanent restriction of physical growth with increasing radiation dose, particularly above 1 Gy [18]. This was most pronounced when the exposure occurred in the first trimester. A 3 to 4 percent reduction in height at age 18 occurred when the dose was greater than 1 Gy.

Genetic effects Radiation may increase the frequency of naturally occurring mutations; it does not induce mutations unique to this source. Small increases in the rate of genomic mutation are difficult to detect because the background rate of spontaneous mutation is already high (about 10 percent), recessive mutations take several generations to become apparent, and autosomal dominant mutations are rare [11]. There is currently no way to distinguish radiation-induced genetic mutations from similar conditions arising from other environmental exposures. Studies attempting to estimate the incidence of radiation mutagenesis have been based largely upon animal and plant experiments. Very few human data are available, apart from observations in the offspring of Japanese atomic bomb survivors. An increased risk of genetic disorders induced by ionizing radiation has not been demonstrated in any human population at any radiation dose [11,28]. FETAL EXPOSURE FROM COMMON PROCEDURES There are no known significant fetal effects from exposure to diagnostic ultrasound or magnetic resonance imaging involving a

magnetic field at 1.5 Tesla or lower. (See 'Ultrasound' below and 'Magnetic resonance imaging' below.) The estimated fetal exposures for some common imaging procedures involving ionizing radiation are listed in the table (table 1) [25,29,30]. Although several such tables are available, dosimetry calculations vary widely. When counseling a pregnant woman about the radiation risks associated with a diagnostic procedure, the estimated dose for the specific patient should be calculated by a radiologist familiar with dosimetry. Factors to be considered include the number and type of projections, exposure time, distance, x-ray output, and use of digital acquisition systems designed to limit dosage. ISSUES BY TYPE OF DIAGNOSTIC IMAGING PROCEDURE Diagnostic imaging during pregnancy can involve ionizing radiation (eg, plain x-rays, fluoroscopy and angiography, computed tomography [CT], nuclear medicine) or nonionizing techniques (eg, ultrasound, magnetic resonance [MR] imaging). In addition, various contrast agents may be administered to enhance diagnostic sensitivity. Procedures using ionizing radiation Diagnostic x-rays of the head, neck, chest, and limbs produce almost no scatter to the embryo; any radiation received would not result in a measurably increased risk. Nevertheless, the patient should wear a lead apron to minimize fetal exposure from radiation scatter whenever non-abdominopelvic sites are being imaged. A fast film/screen combination or digital radiography can also be used to reduce total radiation exposure. Plain films Several techniques can be used to minimize fetal radiation exposure during abdominopelvic x-ray procedures: A posterior-anterior (PA) exposure lowers the radiation dose by 0.02 to 0.04 mGy (2 to 4 mrad) compared with the traditional anterior-posterior (AP) exposure because the uterus is located in an anterior pelvic position, Shutters can be employed to collimate the radiation beam and reduce scatter. Avoiding both magnification near the uterus and use of grids results in a decreased dose of radiation.

Fluoroscopy and angiography During fluoroscopic and angiographic procedures, modifying the exposure time, number of films obtained, beam size, and imaging area can reduce the amount of radiation exposure. Intravenous pyelography Renal and pelvic ultrasound are recommended as the initial diagnostic imaging study when an obstructing calculus is suspected. Ultrasound is useful for detecting secondary signs of obstruction, such as hydronephrosis or hydroureter, while avoiding exposure to ionizing radiation. Endovaginal ultrasound is more sensitive than transabdominal ultrasound for detecting distal ureteral calculi [31]. (See "Renal and urinary tract physiology in normal pregnancy", section on 'Ureters'.) If after ultrasound examination it is still considered necessary to obtain an intravenous pyelogram (IVP), the radiation dose can be minimized by obtaining a single abdominal radiograph approximately five minutes after intravenous administration of contrast material [32]. This will provide information about the relative excretory function of each kidney, and will demonstrate the site and extent of obstruction of a ureter. The single-shot IVP delivers about 0.5 mGy (50 mrad) to the fetus, a value that is equal to federal guideline for the maximum radiation exposure recommended for pregnant women over a one-month interval.

Computed tomography The fetal radiation dose from a CT scan is affected by several variables, including the number, location, and thickness of slices. When CT imaging is performed in pregnancy, using a narrow collimation and wide pitch (ie, the patient moves through the scanner at a faster rate) results in a slightly reduced image quality, but provides a large reduction in radiation exposure. Scanning protocols should also be modified. As an example, if performing a CT scan with contrast, the number of acquisitions can be reduced by eliminating the precontrast series. (See "Principles of computed tomography of the chest".) Fetal radiation exposure during nonabdominal CT scans is minimal. As an example, the radiation exposure from maternal head CT is approximately 2 mGy (200 mrad) for the mother and less than 0.10 mGY (10 mrad) for the fetus if the abdomen is shielded. Dental x rays The radiation dose to the fetus from maternal dental radiography is minute, 0.0001 mGy (0.01 mrads) for an average study, and is not considered harmful. Although one population based case-control study found an association between antepartum dental radiography of >0.4 mGy (40 mrads) to the maternal thyroid and low birthweight (less than 2500 g) [33], this association is not consistent with findings from multiple other studies and is not biologically plausible [16]. Further investigation is needed before any change is made to the recommendations for dental imaging in pregnant women. (See 'Summary and recommendations' below.) Mammography Mammography during pregnancy is discussed separately. (See "Breast imaging: Mammography and ultrasonography", section on 'Pregnancy and lactation'.) Contrast materials Iodinated contrast materials cross the placenta and can produce transient effects on the developing fetal thyroid gland, although clinical sequelae from brief exposures have not been reported. Iodinated contrast materials may be used in pregnancy, when indicated. The use of contrast agents in breastfeeding women is discussed separately. (See "Principles of medication use during lactation", section on 'Intravenous contrast agents'.) Gadolinium Gadolinium, the contrast agent most commonly used for MR imaging because of its magnetic properties, crosses the placenta and is excreted by the fetus into the amniotic fluid. It is then swallowed so it can be reabsorbed into the fetal circulation. Given the potentially long half-life in the fetus and few data from human pregnancy, it is not recommended for use in the pregnant patient unless the potential benefit justifies the potential risk to the fetus [19,34]. When use of gadolinium is essential, available data are reassuring. Although limited to descriptions of individual cases and small case series, adverse fetal or pregnancy effects from gadolinium exposure have not been reported in human pregnancies [35-38]. Animal studies have not shown adverse effects from clinically-based doses and a murine study found that fetal levels were undetectable 48 hours after maternal administration [39]. Doses 2.5 to 12.5 times usual human doses (usual dose: 0.1 mmol/kg to 0.2 mmol/kg) given daily for 10 to 13 days have resulted in slight retardation of development in rats and rabbits. In one study of rabbits that received doses of 0.3, 0.9 or 2.0 mmol/kg/day, morphological examination of fetuses exposed to 2.0 mmol/kg/day revealed small eye/microphthalmia and/or retinal irregularities and vertebral abnormalities in some fetuses [40]. Nuclear medicine Nuclear medicine studies (eg, pulmonary ventilation-perfusion, thyroid, bone, and renal scans) use a radioisotope bound to a chemical agent. The effect of these substances on the fetus depends upon placental permeability, fetal distribution, tissue affinity, and the half-life, dose, and type of radiation emitted. Substances that can localize in specific fetal organs and tissues, and thus may be of concern, include iodine-131 or iodine-123 in the thyroid,

iron-59 in the liver, gallium-67 in the spleen, and strontium-90 and yttrium-90 in the skeleton. Fetal exposure also results from proximity to radionuclides excreted into the maternal bladder; maternal hydration and frequent voiding can reduce this type of exposure. Some radionuclides will appear in breast milk. After administration of radionuclides, breast feeding should be suspended for the period of time that radioactivity is present; this will depend upon the half-life of the specific agent. Breast milk can be pumped and discarded until nursing is resumed. (See "Principles of medication use during lactation", section on 'Radiopharmaceuticals'.) Pregnant women may have contact with individuals who have received radioactive materials as part of a diagnostic study; the minimal residual radioactivity does not result in a measurably increased risk to the embryo. Radiation exposure from close contact is higher after some types of therapeutic radiation (eg, radioiodine therapy of thyroid cancer, brachytherapy implants for prostate cancer) [41,42]. A period of restricted contact may be prudent, depending upon the type of therapy and degree of exposure. Ventilation-perfusion and helical CT A ventilation-perfusion (V-P) scan for suspected pulmonary embolus is among the most common nuclear medicine studies obtained in pregnant women. The procedure involves perfusion with Tc 99m macroaggregates of albumin and ventilation with radiolabeled xenon gas or 99m Tc DTPA aerosol. Helical CT is another commonly used test for diagnosis of suspected pulmonary embolus and is also associated with a low radiation dose to the fetus. One study estimated that in the third trimester, fetal radiation exposure from chest radiography, helical CT, V-P scanning, and pulmonary arteriography (with a brachial approach) was 0.01, 0.13, 0.37, and 0.50 mGy, respectively [43]. The mean radiation dose was lower earlier in gestation. (See "Deep vein thrombosis and pulmonary embolism in pregnancy: Epidemiology, pathogenesis, and diagnosis".) Thyroid scan By the 10th to 12th week of gestation, radioiodine isotopes are readily absorbed by the fetal thyroid. Although there are no reports of adverse fetal effects from diagnostic doses of radioactive iodine, it should NOT be administered to pregnant women because induction of thyroid cancer in the offspring is a concern [25]. If a diagnostic scan of the thyroid is required, the preferred agents are Technetium Tc 99m or I-123 (but not I-131) [19,44]. Positron emission tomography There is minimal information regarding positron emission tomography (PET) in pregnancy. This technique involves injection of a radioisotope, fludeoxyglucose F 18. Animal reproduction studies have not been conducted with fludeoxyglucose F 18 Injection and it is not known whether fludeoxyglucose F 18 Injection can cause fetal harm when administered to a pregnant woman, or can affect reproduction capacity. The radiation dose to the uterus is 3.70 to 7.40 mGy, for the usual dose range of isotope injected [45]. As discussed above, this is a low fetal dose and not associated with adverse effects on development or growth. Because of the lack of safety data in human pregnancy, MR imaging or CT are generally preferred to PET as they usually provide similar information, but the decision needs to be made on a patient specific basis. Ultrasound No biologic effects have been documented from diagnostic ultrasound in the pregnant patient, despite intensive use over several decades. The potential for deleterious consequences from heat and cavitation exists since ultrasound uses sound waves that interact with biological tissues. B-mode and M-mode imaging operate at acoustic outputs that do not produce harmful temperature rises. However, Doppler ultrasound does have this potential;

therefore, guidelines for Doppler use in pregnancy have been formulated. The use of ultrasound in pregnancy is discussed in detail separately:

(See "Ultrasound examination in obstetrics and gynecology".) (See "Basic principles and safety of diagnostic ultrasound in obstetrics and gynecology".) (See "Doppler ultrasound of the umbilical artery for fetal surveillance".) (See "Venous Doppler for fetal assessment".)

A limitation of ultrasound is that it does not show soft tissue detail as well as magnetic resonance imaging or computed tomography. Magnetic resonance imaging Magnetic resonance (MR) imaging uses electromagnetic radio waves, rather than ionizing radiation, to generate detailed computer images. At the cellular level, possible direct biologic effects of MR imaging consist of (1) induction of local electric fields and currents from the static and time varying magnetic fields, and (2) radiofrequency radiation resulting in heating of tissue. Other potential dangers include trauma from projection of metal objects into the magnetic field (eg, small metal fragments can be projected into the eyes), interference with the operation of electronic devices (eg, cardiac pacemakers) or position of metallic implants, burns from heating of conductive materials in implants, and acoustic damage from high intensity noise. Despite these concerns, there are NO reported harmful effects from MR imaging of the pregnant woman or fetus [46-48]. However, safety studies have been performed predominantly at or below 1.5 Tesla magnetic field strengths. There may be an increased risk of tissue heating at higher field strengths. In some cases, MR imaging is the preferred diagnostic modality because it provides better images than ultrasonography, while avoiding the ionizing radiation of computed tomography. Although the National Radiological Protection Board advises that MR imaging be avoided in the first trimester since there is limited experience assessing safety during organogenesis, MR imaging should be considered in the first trimester when the benefit exceeds the theoretic risk. As an example, first trimester MR imaging is a reasonable option in a pregnant women with suspected appendicitis in whom the appendix cannot be visualized by ultrasound examination. (See "Overview of use of magnetic resonance imaging in obstetrics and gynecology".) SUMMARY AND RECOMMENDATIONS

Ideally, semi-elective radiologic procedures are scheduled during the first 10 days (follicular phase) of the menstrual cycle. All women of childbearing potential should be asked of they could be pregnant at the time of a radiologic examination. If any doubt exists, a pregnancy test should be obtained prior to the diagnostic procedure. The perceived risk of radiation exposure is much greater than the actual risk, but a full explanation of these risks to the woman and her family is best given prior to, rather than after, the exposure. (See 'Introduction' above.) During pregnancy, ultrasound examination and magnetic resonance imaging are generally preferred to imaging modalities that involve ionizing radiation. (See 'Ultrasound' above and 'Magnetic resonance imaging' above.) However, concern about the possible effects of ionizing radiation should not prevent medically indicated diagnostic procedures using the best available modality for the clinical situation. When procedures requiring ionizing radiation are necessary, various

techniques can be employed to minimize the radiation dose. (See 'Effects of ionizing radiation on the fetus' above and 'Issues by type of diagnostic imaging procedure' above.)

Radiation risks should be discussed with the pregnant patient, including an explanation of the background population risk for miscarriage, congenital anomalies, genetic disease, and growth restriction (approximately 20, 4, 10, and 10 percent, respectively), as well as the risk of developmental disorders. Consultation with a radiologist should be obtained to plan the optimum study using the least amount of radiation or to reconstruct the amount of radiation exposure from examinations performed prior to knowledge of the pregnancy. (See 'Effects of ionizing radiation on the fetus' above and 'Fetal exposure from common procedures' above.) At doses less than 0.05 Gy, there is no evidence of an increased risk of fetal anomalies, intellectual disability, growth restriction, or pregnancy loss from ionizing radiation. There may be a small increased risk of childhood cancer, 1 in 2000 versus the 1 in 3000 background rate. (See 'Exposure less than 0.05 Gy (5 rads)' above.) During the first 14 days after fertilization, intact survival or death are the most likely outcomes of radiation exposure above 0.05 Gy (5 rads). A conservative estimate of the threshold for intrauterine death is more than 0.1 Gy (10 rads). (See 'First 14 days after conception' above.) After the first 14 days, radiation exposure over 0.5 Gy may be associated with an increased risk of congenital malformations, growth restriction, and intellectual disability. (See 'After the first 14 days' above.) Gadolinium is currently NOT recommended for use in the pregnant patient. (See 'Contrast materials' above.) Although there are no reports of adverse fetal effects from diagnostic doses of radioactive iodine, it should NOT be administered to pregnant women because induction of thyroid cancer in the offspring is a concern. If a diagnostic scan of the thyroid is required, the preferred agents are Technetium Tc 99m or I-123 (but not I-131). (See 'Thyroid scan' above.) The National Radiological Protection Board advises that magnetic resonance imaging be avoided in the first trimester since there is limited experience assessing safety during organogenesis. (See 'Magnetic resonance imaging' above.)

Use of UpToDate is subject to the Subscription and License Agreement.

REFERENCES
1. Applegate K. Pregnancy screening of adolescents and women before radiologic testing:

does radiology need a national guideline? J Am Coll Radiol 2007; 4:533.

2. Lazarus E, Debenedectis C, North D, et al. Utilization of imaging in pregnant patients:

10-year review of 5270 examinations in 3285 patients--1997-2006. Radiology 2009; 251:517.

3. McCollough CH, Schueler BA, Atwell TD, et al. Radiation exposure and pregnancy:

when should we be concerned? Radiographics 2007; 27:909.

4. Ratnapalan S, Bona N, Chandra K, Koren G. Physicians' perceptions of teratogenic risk

associated with radiography and CT during early pregnancy. AJR Am J Roentgenol 2004; 182:1107.
5. Bentur Y, Horlatsch N, Koren G. Exposure to ionizing radiation during pregnancy:

perception of teratogenic risk and outcome. Teratology 1991; 43:109. 6. www.doh.wa.gov/ehp/rp/factsheets/factsheets-htm/fs10bkvsman.htm (Accessed October 31, 2007). 7. www.nrc.gov/reading-rm/doc-collections/cfr/part020/full-text.html (accessed October, 31, 2007).
8. Castronovo FP Jr. Teratogen update: radiation and Chernobyl. Teratology 1999; 60:100.

9. United Nations Scientific Committee on the Effects of Atomic Radiation, Sources and Effects of Ionizing Radiation, UN Publication E.94.IX.2, UN Publications, United Nations, New York, 1993.
10. Hall EJ. Scientific view of low-level radiation risks. Radiographics 1991; 11:509.

11. Committee on Biological Effects of Ionizing Radiation, Board on Radiation Effects Research Commission on Life Sciences, National research Council. Health effects of exposure to low levels of ionizing radiation: BEIR V. Washington, DC, 1990. p. 352. 12. Schull, WJ, Otake, M. Neurological deficit among the survivors exposed to the atomic bombing of Hiroshima and Nagasaki: A reassessment and new directions. In: Radiation risks to the developing nervous system, Schmahl, W, Gerber, GB, Stive, FE (Eds), Gustave Fischer Verlag, New York 1986.
13. Otake M, Schull WJ, Yoshimaru H. A review of forty-five years study of Hiroshima and

Nagasaki atomic bomb survivors. Brain damage among the prenatally exposed. J Radiat Res (Tokyo) 1991; 32 Suppl:249.
14. Wertelecki W. Malformations in a chornobyl-impacted region. Pediatrics 2010;

125:e836.
15. Yamazaki JN, Schull WJ. Perinatal loss and neurological abnormalities among children

of the atomic bomb. Nagasaki and Hiroshima revisited, 1949 to 1989. JAMA 1990; 264:605.
16. Brent RL. Saving lives and changing family histories: appropriate counseling of pregnant

women and men and women of reproductive age, concerning the risk of diagnostic radiation exposures during and before pregnancy. Am J Obstet Gynecol 2009; 200:4.
17. Brent RL. The effect of embryonic and fetal exposure to x-ray, microwaves, and

ultrasound: counseling the pregnant and nonpregnant patient about these risks. Semin Oncol 1989; 16:347. 18. www.bt.cdc.gov/radiation/prenatalphysician.asp (accessed October 31, 2007).
19. ACOG Committee on Obstetric Practice. ACOG Committee Opinion. Number 299,

September 2004 (replaces No. 158, September 1995). Guidelines for diagnostic imaging during pregnancy. Obstet Gynecol 2004; 104:647.
20. Stewart A, Kneale GW. Radiation dose effects in relation to obstetric x-rays and

childhood cancers. Lancet 1970; 1:1185.

21. Kato H. Mortality in children exposed to the A-bombs while in utero, 1945-1969. Am J

Epidemiol 1971; 93:435.

22. Preston DL, Cullings H, Suyama A, et al. Solid cancer incidence in atomic bomb

survivors exposed in utero or as young children. J Natl Cancer Inst 2008; 100:428. 23. www.icrp-84.org.
24. De Santis M, Cesari E, Nobili E, et al. Radiation effects on development. Birth Defects

Res C Embryo Today 2007; 81:177. 25. Bentur, Y. Ionizing and nonionizing radiation in pregnancy. In: Maternal-fetal toxicology, 2nd ed, Koren, G (Ed), Marcel Dekker, New York 1994. 26. Mettler, FA, Upton, AC. Medical Effects of Ionizing Radiation, 2nd ed, WB Saunders, Philadelphia, 1995.
27. De Santis M, Di Gianantonio E, Straface G, et al. Ionizing radiations in pregnancy and

teratogenesis: a review of literature. Reprod Toxicol 2005; 20:323.

28. Ritenour ER. Health effects of low level radiation: carcinogenesis, teratogenesis, and

mutagenesis. Semin Nucl Med 1986; 16:106. 29. Kereiakes, JG, Rosenstein, M. Handbook of Radiation Doses in Nuclear Medicine and Diagnostic X-ray, CRC Press, Boca Raton 1980. 30. United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR). Sources and Effects of ionizing radiation. Report to the General Assembly, 1977. p. 319.
31. Laing FC, Benson CB, DiSalvo DN, et al. Distal ureteral calculi: detection with vaginal

US. Radiology 1994; 192:545.

32. Butler EL, Cox SM, Eberts EG, Cunningham FG. Symptomatic nephrolithiasis

complicating pregnancy. Obstet Gynecol 2000; 96:753.

33. Hujoel PP, Bollen AM, Noonan CJ, del Aguila MA. Antepartum dental radiography and

infant low birth weight. JAMA 2004; 291:1987.

34. Kanal E, Barkovich AJ, Bell C, et al. ACR guidance document for safe MR practices:

2007. AJR Am J Roentgenol 2007; 188:1447.

35. De Santis M, Straface G, Cavaliere AF, et al. Gadolinium periconceptional exposure:

pregnancy and neonatal outcome. Acta Obstet Gynecol Scand 2007; 86:99.
36. Barkhof F, Heijboer RJ, Algra PR. Inadvertent i.v. administration of gadopentetate

dimeglumine during early pregnancy. AJR Am J Roentgenol 1992; 158:1171.

37. Shoenut JP, Semelka RC, Silverman R, et al. MRI in the diagnosis of Crohn's disease in

two pregnant women. J Clin Gastroenterol 1993; 17:244.

38. Marcos HB, Semelka RC, Worawattanakul S. Normal placenta: gadolinium-enhanced

dynamic MR imaging. Radiology 1997; 205:493.

39. Mhler MR, Clment O, Salomon LJ, et al. Maternofetal pharmacokinetics of a

gadolinium chelate contrast agent in mice. Radiology 2011; 258:455.

40. Okuda Y, Sagami F, Tirone P, et al. [Reproductive and developmental toxicity study of

gadobenate dimeglumine formulation (E7155) (3)--Study of embryo-fetal toxicity in rabbits by intravenous administration]. J Toxicol Sci 1999; 24 Suppl 1:79.

41. Grigsby PW, Siegel BA, Baker S, Eichling JO. Radiation exposure from outpatient

radioactive iodine (131I) therapy for thyroid carcinoma. JAMA 2000; 283:2272.
42. Cattani F, Vavassori A, Polo A, et al. Radiation exposure after permanent prostate

brachytherapy. Radiother Oncol 2006; 79:65.

43. Winer-Muram HT, Boone JM, Brown HL, et al. Pulmonary embolism in pregnant

patients: fetal radiation dose with helical CT. Radiology 2002; 224:487.
44. Ginsberg JS, Hirsh J, Rainbow AJ, Coates G. Risks to the fetus of radiologic procedures

used in the diagnosis of maternal venous thromboembolic disease. Thromb Haemost 1989; 61:189. 45. www.easternisotopes.com/products/package_insert.html. (Accessed November 10, 2005).
46. Duncan KR. The development of magnetic resonance imaging in obstetrics. Br J Hosp

Med 1996; 55:178.

47. Kirkinen P, Partanen K, Vainio P, Ryynnen M. MRI in obstetrics: a supplementary

method for ultrasonography. Ann Med 1996; 28:131.

48. Nicklas AH, Baker ME. Imaging strategies in the pregnant cancer patient. Semin Oncol

2000; 27:623.

19.3 News from UpToDate | Contact us | About UpToDate | Help

New Search

Patient Info

What's New

Calculators

 Feedback Log In

Top of Form
pregnancy

Bottom of Form

Back to Search Results for "pregnancy" Calcium physiology in pregnancy Find Print Email

Calcium physiology in pregnancy Author Elizabeth H Holt, MD, PhD Section Editors Charles J Lockwood, MD Marc K Drezner, MD Deputy Editor Vanessa A Barss, MD Disclosures Last literature review version 19.3: September 2011 | This topic last updated: October 20, 2011 (More) INTRODUCTION The pregnant woman's body provides 25 to 30 g of calcium to support the developing fetal skeleton. Much of the fetal calcium demand occurs in the third trimester of pregnancy, when the fetal skeleton undergoes mineralization. Pregnancy related changes in maternal calcium regulation, as well as contributions from the fetoplacental unit and its mediators, are essential to meeting fetal calcium requirements without depleting the maternal skeleton. Characteristics of calcium physiology during pregnancy can be summarized as follows: Total calcium concentration falls because of physiologic hypoalbuminemia Free ionized calcium concentration does not change The placental produces 1,25-dihydroxyvitamin D, which results in increased intestinal absorption of calcium Calcium is actively transported across the placenta, facilitated by parathyroid hormonerelated peptide

Calcium homeostasis is a function of dietary intake, intestinal absorption, skeletal accretion and resorption, and urinary excretion. The key organs involved in the changes in calcium metabolism during pregnancy include the maternal parathyroid gland, the maternal intestine, and the fetoplacental unit. An increase in 1,25-dihydroxyvitamin D, derived primarily from the placenta, stimulates intestinal absorption of calcium and phosphate, and appears to be the key regulatory

factor during pregnancy. Maintenance of fetal calcium homeostasis largely depends upon parathyroid hormone-related peptide (PTHrP), which regulates active placental calcium transfer. The oscillations in these and other regulators throughout pregnancy accommodate the calcium requirements at each stage of fetal development. MATERNAL CALCIUM PHYSIOLOGY Calcium concentration About 40 percent of calcium ions are circulated in the plasma bound to albumin and other proteins, 10 percent are complexed with other ions, while 50 percent circulates in the free form. It is this "free" Ca2+ ion that is metabolically active. The active, ionized calcium level does not change significantly during pregnancy, although total serum calcium declines across gestation [1-3]. The decrease in total serum calcium concentration is likely an effect of plasma volume expansion, leading to decreased concentrations of binding proteins [2], and reflects a decrease in the concentration of protein-bound calcium. The upper limit of normal for total serum calcium is 9.5 mg/dL in pregnancy. Calcium absorption and excretion Maternal calcium absorption from the gut increases significantly in the second and third trimesters, and then declines to prepregnancy levels with lactation and weaning [4]. Increased intestinal calcium absorption satisfies the fetal demand to mineralize the skeleton, while sparing to some extent the calcium contained in the maternal skeleton. Maternal urinary calcium excretion is increased throughout pregnancy [1,3,4]. This combination of increased calcium absorption and excretion has resulted in the term "absorptive hypercalciuria" to describe the changes in calcium metabolism during pregnancy [1]. Role of 1,25-dihydroxyvitamin D and PTH 1,25-dihydroxyvitamin D is the main stimulus for increased intestinal calcium absorption. The level of 1,25-dihydroxyvitamin D rises dramatically during pregnancy [1-3]. Levels of free 1,25-dihydroxyvitamin D and total serum 25hydroxyvitamin D (the storage or precursor form of active 1,25-dihydroxyvitamin D) are also elevated [5]. In the nonpregnant individual, conversion of 25-hydroxyvitamin D to its active form 1,25dihydroxyvitamin D via the enzyme 1-alpha-hydroxylase is generally thought to occur primarily in the kidneys, stimulated primarily by parathyroid hormone (PTH). Levels of phosphorus, estrogen, calcitonin, calcium, calcitriol (by feedback inhibition) and other factors also play regulatory roles. In contrast to the importance of PTH in 1,25-dihydroxyvitamin D regulation in non-pregnant individuals, the increase in 1,25-dihydroxyvitamin D during gestation does not follow an increase in PTH [2,3,6]. Intact PTH levels decline in the first half of pregnancy, reaching a nadir in the second trimester, and then rising thereafter (figure 1) [2-4,6]. This suggests that the rise in 1,25-dihydroxyvitamin D during pregnancy derives from another source, unrelated to the kidney. There is substantial evidence that this source is the placenta, which possesses 1-alpha-hydroxylase activity and is able to produce 1,25-dihydroxyvitamin D from its precursor 25-hydroxyvitamin D [7,8]. (See "Chapter 6F: Hormonal regulation of calcium and phosphate balance" and "Parathyroid hormone secretion and action".) The paradoxical decrease in PTH during gestation is likely due to direct inhibition of PTH production either by already high levels of 1,25-dihydroxyvitamin D or by increased intestinal absorption of calcium. Bone metabolism Maternal bone loss during pregnancy is minimal despite the high calcium requirements of the fetus. Studies of bone density during pregnancy have been limited by reluctance to image central sites, such as the lumbar spine or hip, due to concerns over fetal radiation exposure. However, some data are available: a two-year prospective study of bone mineral density in 59 pregnant and lactating women evaluated ultra-distal radius bone mineral

density during pregnancy and reported a minimal 2 percent decrease [9], indicating that the maternal skeleton may be the source of a small amount of the calcium transported to the fetus. Examination of biochemical markers reveals that the bone remodeling rate, also referred to as bone turnover, changes throughout pregnancy. During early pregnancy, levels of osteocalcin (a marker of new bone formation) decline, reaching a nadir at mid-gestation, and then rise to prepregnancy levels by term (figure 2) [2,4,6]. Urine deoxypyridinoline (a marker of bone resorption) is increased during the third trimester [4]. This pattern is similar to the changes in PTH levels during pregnancy (initial decline followed by a rise), and indicates a progressive decrease and then increase in bone turnover during pregnancy [2,6]. Calcium and vitamin D requirements Calcium The Institute of Medicine of the National Academy of Sciences (IOM) conducted an extensive review of the available literature and, in 2010, recommended an average daily intake of 1300 mg of calcium for girls ages 9 to 18 and 1000 mg per day for women ages 19 to 50. Safe upper limits for calcium were defined as 3000 mg daily for girls ages 9 to 18 and 2500 mg daily for women ages 19 to 50, but 2000 mg for women over age 50 and for men. Their recommendations are the same during pregnancy and lactation [10]. According to data from the Continuing Survey of Food Intakes of Individuals, only 13 percent of girls ages 12 to 19 and 22 percent of women ages 20 and above are meeting those recommendations. (See "Nutrition in pregnancy".) Vitamin D Vitamin D deficiency is common throughout the world, with prevalence related to sun exposure, dietary vitamin D intake (fish or fortified milk), skin pigmentation, and obesity [11,12]. Areas with a high prevalence of vitamin D deficiency include southern Europe, the Middle East, India, China and Japan [11]. (See "Overview of vitamin D" and "Causes of vitamin D deficiency and resistance".) Vitamin D sufficiency is assessed by measurement of serum 25-hydroxyvitamin D. The optimal level of serum 25-hydroxyvitamin D is controversial, but increasing data support a level of 30 ng/mL (75 nmol/mL) as a lower limit of optimal [13]. A large body of data also supports 20 ng/mL as the lower limit of optimal; this is the target serum 25-hydroxyvitamin D level for all healthy individuals defined by the IOM. The third National Health and Nutrition Examination Survey (NHANES III) revealed hypovitaminosis D (defined as a serum 25-hydroxyvitamin D level 37.5 nmol/L) in 42 percent of African American and 4 percent of white American reproductive age women [14]. Using 75 nmol/mL threshold as the lower limit of normal, 69 percent of pregnant women and 78 percent of nonpregnant women aged 13-44 years were deficient [15]. Much of the difference between the two groups was explained by differences in vitamin D intake (primarily from fortified cereal and milk) and sun exposure [14]. Of note, obese women and their neonates were twice as likely to be vitamin D deficient as their leaner counterparts [12]. The 2010 IOM report suggested the recommended daily allowance of vitamin D is 600 international units daily for all reproductive-age women, including during pregnancy and lactation [13]. However, it may behoove physicians to treat with vitamin D doses of 800 to 1000 international units/day, as suggested in many articles, to achieve a level of 30 ng/mL [16].These recommended doses are unlikely to lead to vitamin D excess (defined by the IOM as a serum 25hydroxyvitamin D level >50 ng/mL) and appear to raise 25-hydroxyvitamin D levels between the first and third trimester [15]. The intake at which the dose of vitamin D becomes toxic is not clear, but a tolerable upper limit of dosing was set by the IOM at 4000 international units per day [13].

Adverse pregnancy outcomes associated with deficiency Calcium After a review of the published literature, the United States Food and Drug Administration (FDA) concluded the available evidence did not support a correlation between maternal calcium intake and preeclampsia [17]. A subsequent Cochrane Review of the available data concluded that calcium supplementation reduced the risk of preeclampsia by half, and was relatively safe [18]. However, this meta-analysis included many studies from nutritionally deprived women living in developing countries. This analysis and others have suggested that the reduction in preeclampsia occurs primarily in women at high risk of preeclampsia and who are calcium deficient. Women with preeclampsia have reduced urinary calcium excretion, which may reflect lower intestinal calcium absorption due to low 1,25-dihydroxyvitamin D [19]. (See "Prevention of preeclampsia", section on 'Calcium supplementation'.) Vitamin D Two of three studies reported a connection between vitamin D deficiency and preeclampsia [20-22], but a causal relationship has not been proven. There is also conflicting data regarding the relationship between vitamin D Deficiency and fetal growth. Two studies observed low maternal vitamin D levels were associated with an increased risk of delivery of a small for gestational age infant [23,24], while a third study did not find an association [25]. Further investigation is needed to better clarify these possible relationships. There is emerging evidence to support a connection between maternal vitamin D deficiency and an increased risk for gestational diabetes mellitus. This increased risk exists even after controlling for body mass index, age, and family history of diabetes [26]. Additional research is needed to understand this connection, including interventional studies where vitamin D deficiency is prevented through adequate supplementation. Vitamin D deficiency in early pregnancy has also been linked to an increased risk of preeclampsia [21]. Research on the effect of vitamin D supplementation in pregnant women reveals that there is a strong relationship between maternal and neonatal vitamin D sufficiency at delivery. Vitamin D status, in turn, influences neonatal serum calcium and PTH levels. Neonates of vitamin D deficient mothers may have abnormally low serum calcium levels, and PTH levels above normal, a pattern consistent with secondary hyperparathyroidism [27]. Infants born to African-American women have significantly lower 25-hydroxyvitamin D levels than do their Caucasian counterparts, corresponding to the higher incidence of vitamin D deficiency in the AfricanAmerican mothers [28,29]. In a longitudinal study, women with reduced concentrations of maternal 25-hydroxyvitamin D during late pregnancy and reduced levels of umbilical-venous calcium had offspring with a reduction in bone mass at nine years of age; however, a causal association was not proven [30]. Multivitamin use during pregnancy may not be sufficient to correct preexisting maternal vitamin D deficiency or to prevent neonatal vitamin D deficiency [29]. Studies of supplementation of deficient women have shown that dosages as high as 1600 IU per day over the course of a pregnancy are inadequate to correct vitamin D deficiency [31]. More research is needed before specific guidelines can be made regarding repletion of vitamin D in deficient pregnant women. (See "Treatment of vitamin D deficiency in adults".) Causes of hypercalcemia The upper limit of normal for total serum calcium is 9.5 mg/dL in pregnancy. Causes of hypercalcemia in pregnant and postpartum women are listed below, a more detailed discussed on the diagnosis and management of these disorders can be found in separate topic reviews. Common:

 Rare:

Primary hyperparathyroidism Immobilization (eg, bedrest) Familial hypocalciuric hypercalcemia Postpartum hypercalcemia in hypoparathyroidism PTHrP-induced hypercalcemia Malignancy Thyrotoxicosis Adrenal insufficiency Vitamin A or D overdose Drugs (eg, thiazide diuretics, lithium) Milk alkali syndrome Acute and chronic renal failure Total parenteral nutrition Granulomatous disease (eg, sarcoidosis, tuberculosis, histoplasmosis, coccidioidomycosis)

Causes of hypocalcemia The lower limit of normal calcium levels in pregnancy is 8.1 mg/dL. Causes of hypocalcemia in pregnant and postpartum women are listed below, a more detailed discussed on the diagnosis and management of these disorders can be found separately. (See "Etiology of hypocalcemia in adults".)

Hypoalbuminemia Hypoparathyroidism Pseudohypoparathyroidism Magnesium sulfate therapy (see "Management of preeclampsia", section on 'Anticonvulsant therapy') Disorders of magnesium metabolism Vitamin D deficiency Sepsis Surgery Chemotherapy Fluoride poisoning Pseudohypocalcemia related to gadolinium Blood transfusion

FETAL CALCIUM PHYSIOLOGY Fetal calcium balance is characterized by active placental transport of calcium ions from mother to fetus, so that the fetus is relatively hypercalcemic. Hypercalcemia inhibits fetal PTH activity and stimulates fetal calcitonin release. This environment (high calcium, low PTH, high calcitonin) is ideal for skeletal mineralization.

Calcium level Little is known about fetal serum calcium levels across gestation due to the obvious difficulties in obtaining data. At term, the fetal ionized calcium concentration is significantly higher than the maternal (2.8 versus 2.2 mEq/liter) [32]. Calcium is transported from the maternal circulation to the fetal despite the higher concentration of ionized calcium in the fetal circulation; this suggests active transport of calcium across the placenta must occur. Ionized calcium levels decline in the first 24 to 48 hours after birth. (See "Etiology of hypocalcemia in infants and children", section on 'Transient neonatal hypocalcemia'.) Placental transport Skeletal mineralization occurs in the latter weeks of pregnancy, so most of the 25 to 30 g of calcium present in the term fetus is crosses the placenta over a period of a few weeks, peaking at the 35th week. In fact, between the 20th and 35th week of gestation, placental calcium transport increases from 50 to 330 mg per day [33]. The proposed mechanism of active transport of calcium across the placenta is largely based upon animal models. Movement of calcium from the maternal and into the fetal circulation against its concentration gradient is likely provided by an energy-dependent calcium-ATPase on the fetal side of the trophoblastic cell [34,35]. PTHrP appears to be the main hormonal regulator of placental calcium transport [36,37], and may act by directly activating the calcium ATPase [38], thus stimulating calcium transport. PTHrP is produced by the fetus and/or the amnion overlying the placenta [36,37] and is homologous to PTH. They both act through the PTH/PTHrP receptor, but their effects are different. PTHrP is ubiquitously expressed in epithelial, smooth muscle, and nervous tissues. Its paracrine activity is essential for embryologic development of multiple tissues [39]. During pregnancy, maternal serum levels of PTHrP rise as the gestation progresses (figure 3) [6,40]. This PTHrP is likely derived from the fetus since levels are highest in umbilical arterial blood, slightly lower in umbilical venous blood, and lowest in maternal blood at delivery [36]. PTHrP is also found in amniotic fluid, amnion, chorion, placenta, and uterus [37,41] and is thought to act in an autocrine or paracrine fashion to regulate calcium transport from the maternal to the fetal bloodstream. PTHrP released from the fetal parathyroid gland may also play a role [42]. Support for a role of PTHrP in placental calcium transport comes from in vitro studies of freshly prepared human trophoblast cells demonstrating that these cells increase PTHrP release as extracellular calcium decreases [43]. The ability of trophoblast cells to perceive extracellular calcium appears to be mediated via the same calcium-sensing receptor present on the surface of the parathyroid cell [44]. Once it has been transported by the calcium ATPase into the placental epithelial cell, it is postulated that calcium is shuttled across the cell from the maternal to the fetal side by calcium binding proteins and then released into the fetal circulation [45,46]. Fetal 1,25-dihydroxyvitamin D Although maternal 1,25-dihydroxyvitamin D levels rise during pregnancy, the fetal level remains low. It appears that 1,25-dihydroxyvitamin D is prevented from crossing the placenta into the fetal circulation by the action of a placental 24hydroxylase, which converts 1,25-dihydroxyvitamin D to 24,25-dihydroxyvitamin D3, a less active metabolite of vitamin D than its precursor [8]. SUMMARY AND RECOMMENDATIONS

The high fetal demand for calcium during gestation is facilitated by a remarkable physiologic interaction between mother and fetus. (See 'Introduction' above.)

The maternal ionized calcium level does not change significantly during pregnancy; total serum calcium declines across gestation. (See 'Calcium concentration' above.) Maternal calcium absorption from the gut increases significantly in the second and third trimesters. Increased intestinal calcium absorption satisfies the fetal demand to mineralize the skeleton, while sparing the calcium contained in the maternal skeleton. (See 'Calcium absorption and excretion' above and 'Bone metabolism' above.) The placenta produces an increased amount of 1,25-dihydroxyvitamin D, which enters the maternal bloodstream. The 1,25-dihydroxyvitamin D acts on the maternal intestine to increase calcium absorption from the gut. (See 'Role of 1,25-dihydroxyvitamin D and PTH' above.) An increased level of 1,25-dihydroxyvitamin D and a high level of intestinal calcium absorption serve to down-regulate maternal PTH production. (See 'Role of 1,25dihydroxyvitamin D and PTH' above.) The fetus is relatively hypercalcemic compared to the mother. Hypercalcemia inhibits fetal PTH activity and stimulates fetal calcitonin release. This environment (high calcium, low PTH, high calcitonin) is ideal for skeletal mineralization. (See 'Fetal calcium physiology' above.) Calcium from the maternal serum is transported into the fetal bloodstream against its concentration gradient. This process is stimulated by PTHrP derived from the fetal membranes, and by the activity of an ATP-dependent calcium pump on the surface of the cytotrophoblast cells, at the interface of maternal and fetal circulations. The end result of this process is that fetal bones are mineralized using calcium derived from maternal diet, rather than from maternal bone. (See 'Placental transport' above.) The Institute of Medicine of the National Academy of Sciences recommends intake of 1300 mg of calcium daily for girls ages 14 to 18 and 1000 mg per day for women ages 19 to 50. This recommendation is the same during pregnancy and lactation. The minimum intake of vitamin D should be 600 international units daily. The intake at which the dose of vitamin D becomes toxic is not clear, but is somewhere above 4000 international units per day. (See 'Calcium and vitamin D requirements' above.)

Use of UpToDate is subject to the Subscription and License Agreement.

REFERENCES
1. Gertner JM, Coustan DR, Kliger AS, et al. Pregnancy as state of physiologic absorptive

hypercalciuria. Am J Med 1986; 81:451.

2. Seki K, Makimura N, Mitsui C, et al. Calcium-regulating hormones and osteocalcin

levels during pregnancy: a longitudinal study. Am J Obstet Gynecol 1991; 164:1248.

3. Seely EW, Brown EM, DeMaggio DM, et al. A prospective study of calciotropic

hormones in pregnancy and post partum: reciprocal changes in serum intact parathyroid hormone and 1,25-dihydroxyvitamin D. Am J Obstet Gynecol 1997; 176:214.
4. Cross NA, Hillman LS, Allen SH, et al. Calcium homeostasis and bone metabolism

during pregnancy, lactation, and postweaning: a longitudinal study. Am J Clin Nutr 1995; 61:514.

5. Bikle DD, Gee E, Halloran B, Haddad JG. Free 1,25-dihydroxyvitamin D levels in serum

from normal subjects, pregnant subjects, and subjects with liver disease. J Clin Invest 1984; 74:1966.
6. Ardawi MS, Nasrat HA, BA'Aqueel HS. Calcium-regulating hormones and parathyroid

hormone-related peptide in normal human pregnancy and postpartum: a longitudinal study. Eur J Endocrinol 1997; 137:402.
7. Delvin EE, Arabian A, Glorieux FH, Mamer OA. In vitro metabolism of 25-

hydroxycholecalciferol by isolated cells from human decidua. J Clin Endocrinol Metab 1985; 60:880.
8. Weisman Y, Harell A, Edelstein S, et al. 1 alpha, 25-Dihydroxyvitamin D3 and 24,25-

dihydroxyvitamin D3 in vitro synthesis by human decidua and placenta. Nature 1979; 281:317.
9. Kolthoff N, Eiken P, Kristensen B, Nielsen SP. Bone mineral changes during pregnancy

and lactation: a longitudinal cohort study. Clin Sci (Lond) 1998; 94:405. 10. http://ods.od.nih.gov/factsheets/Calcium-Consumer/ (Accessed on January 26, 2011).
11. Lips P. Vitamin D status and nutrition in Europe and Asia. J Steroid Biochem Mol Biol

2007; 103:620.
12. Bodnar LM, Catov JM, Roberts JM, Simhan HN. Prepregnancy obesity predicts poor

vitamin D status in mothers and their neonates. J Nutr 2007; 137:2437. 13. http://ods.od.nih.gov/factsheets/vitamind/ (Accessed on January 26, 2011).
14. Nesby-O'Dell S, Scanlon KS, Cogswell ME, et al. Hypovitaminosis D prevalence and

determinants among African American and white women of reproductive age: third National Health and Nutrition Examination Survey, 1988-1994. Am J Clin Nutr 2002; 76:187.
15. Ginde AA, Sullivan AF, Mansbach JM, Camargo CA Jr. Vitamin D insufficiency in

pregnant and nonpregnant women of childbearing age in the United States. Am J Obstet Gynecol 2010; 202:436.e1.
16. Heaney RP. The Vitamin D requirement in health and disease. J Steroid Biochem Mol

Biol 2005; 97:13.

17. Trumbo PR, Ellwood KC. Supplemental calcium and risk reduction of hypertension,

pregnancy-induced hypertension, and preeclampsia: an evidence-based review by the US Food and Drug Administration. Nutr Rev 2007; 65:78.
18. Hofmeyr GJ, Lawrie TA, Atallah AN, Duley L. Calcium supplementation during

pregnancy for preventing hypertensive disorders and related problems. Cochrane Database Syst Rev 2010; :CD001059.
19. Halhali A, Daz L, Avila E, et al. Decreased fractional urinary calcium excretion and

serum 1,25-dihydroxyvitamin D and IGF-I levels in preeclampsia. J Steroid Biochem Mol Biol 2007; 103:803.
20. Baker AM, Haeri S, Camargo CA Jr, et al. A nested case-control study of midgestation

vitamin D deficiency and risk of severe preeclampsia. J Clin Endocrinol Metab 2010; 95:5105.

21. Bodnar LM, Catov JM, Simhan HN, et al. Maternal vitamin D deficiency increases the

risk of preeclampsia. J Clin Endocrinol Metab 2007; 92:3517.

22. Powe CE, Seely EW, Rana S, et al. First trimester vitamin D, vitamin D binding protein,

and subsequent preeclampsia. Hypertension 2010; 56:758.

23. Bodnar LM, Catov JM, Zmuda JM, et al. Maternal serum 25-hydroxyvitamin D

concentrations are associated with small-for-gestational age births in white women. J Nutr 2010; 140:999.
24. Leffelaar ER, Vrijkotte TG, van Eijsden M. Maternal early pregnancy vitamin D status in

relation to fetal and neonatal growth: results of the multi-ethnic Amsterdam Born Children and their Development cohort. Br J Nutr 2010; 104:108.
25. Morley R, Carlin JB, Pasco JA, Wark JD. Maternal 25-hydroxyvitamin D and

parathyroid hormone concentrations and offspring birth size. J Clin Endocrinol Metab 2006; 91:906.
26. Zhang C, Qiu C, Hu FB, et al. Maternal plasma 25-hydroxyvitamin D concentrations and

the risk for gestational diabetes mellitus. PLoS One 2008; 3:e3753.
27. Zeghoud F, Vervel C, Guillozo H, et al. Subclinical vitamin D deficiency in neonates:

definition and response to vitamin D supplements. Am J Clin Nutr 1997; 65:771.

28. Hollis BW, Pittard WB 3rd. Evaluation of the total fetomaternal vitamin D relationships

at term: evidence for racial differences. J Clin Endocrinol Metab 1984; 59:652.
29. Bodnar LM, Simhan HN, Powers RW, et al. High prevalence of vitamin D insufficiency

in black and white pregnant women residing in the northern United States and their neonates. J Nutr 2007; 137:447.
30. Javaid MK, Crozier SR, Harvey NC, et al. Maternal vitamin D status during pregnancy

and childhood bone mass at age 9 years: a longitudinal study. Lancet 2006; 367:36.
31. Hollis BW. Vitamin D requirement during pregnancy and lactation. J Bone Miner Res

2007; 22 Suppl 2:V39.

32. Schauberger CW, Pitkin RM. Maternal-perinatal calcium relationships. Obstet Gynecol

1979; 53:74.
33. Forbes GB. Letter: Calcium accumulation by the human fetus. Pediatrics 1976; 57:976. 34. Husain SM, Mughal MZ. Mineral transport across the placenta. Arch Dis Child 1992;

67:874.
35. Belkacemi L, Bdard I, Simoneau L, Lafond J. Calcium channels, transporters and

exchangers in placenta: a review. Cell Calcium 2005; 37:1.

36. Seki K, Wada S, Nagata N, Nagata I. Parathyroid hormone-related protein during

pregnancy and the perinatal period. Gynecol Obstet Invest 1994; 37:83.
37. Farrugia W, Ho PW, Rice GE, et al. Parathyroid hormone-related protein(1-34) in

gestational fluids and release from human gestational tissues. J Endocrinol 2000; 165:657.
38. Strid H, Care A, Jansson T, Powell T. Parathyroid hormone-related peptide (38-94)

amide stimulates ATP-dependent calcium transport in the Basal plasma membrane of the human syncytiotrophoblast. J Endocrinol 2002; 175:517.

39. Philbrick WM, Wysolmerski JJ, Galbraith S, et al. Defining the roles of parathyroid

hormone-related protein in normal physiology. Physiol Rev 1996; 76:127.

40. Hirota Y, Anai T, Miyakawa I. Parathyroid hormone-related protein levels in maternal

and cord blood. Am J Obstet Gynecol 1997; 177:702.

41. Slattery MM, O'leary MJ, Morrison JJ. Effect of parathyroid hormone-related peptide on

human and rat myometrial contractility in vitro. Am J Obstet Gynecol 2001; 184:625.
42. Moseley JM, Hayman JA, Danks JA, et al. Immunohistochemical detection of

parathyroid hormone-related protein in human fetal epithelia. J Clin Endocrinol Metab 1991; 73:478.
43. Hellman P, Ridefelt P, Juhlin C, et al. Parathyroid-like regulation of parathyroid-

hormone-related protein release and cytoplasmic calcium in cytotrophoblast cells of human placenta. Arch Biochem Biophys 1992; 293:174.
44. Bradbury RA, Sunn KL, Crossley M, et al. Expression of the parathyroid Ca(2+)-sensing

receptor in cytotrophoblasts from human term placenta. J Endocrinol 1998; 156:425.

45. Tuan RS. Ca2+-binding protein of the human placenta. Characterization,

immunohistochemical localization and functional involvement in Ca2+ transport. Biochem J 1985; 227:317.
46. Belkacemi L, Garipy G, Mounier C, et al. Calbindin-D9k (CaBP9k) localization and

levels of expression in trophoblast cells from human term placenta. Cell Tissue Res 2004; 315:107. 2012 UpToDate, Inc. All rights reserved. | Subscription and License Agreement |Support Tag: [ecapp0605p.utd.com-87.236.232.71-0BBA46923D-3689.14] Licensed to: Univ of Jordan

Help improve UpToDate. Did UpToDate answer your question? Yes No