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Oladapo A Ladipo
ABSTRACT Pregnancy is associated with physiologic notes that anemia in pregnancy and pregnancy-induced hyper-
changes that result in increased plasma volume and red blood tension are common and thought to contribute significantly to
cells and decreased concentrations of circulating nutrient-binding maternal mortality and morbidity in developing countries. Maine
proteins and micronutrients. In many developing countries, these (10), however, shows there is little evidence that nutrition plays
physiologic changes can be aggravated by undernutrition, lead- a role in pregnancy-induced hypertension.
ing to micronutrient deficiency states, such as anemia, that can This paper discusses minerals and trace elements as well as
have disastrous consequences for both mothers and newborn fat- and water-soluble vitamins in pregnancytheir concentra-
infants. Multiple micronutrients are often taken by pregnant tions, the requirements for them, the consequences of their defi-
280S Am J Clin Nutr 2000;72(suppl):280S90S. Printed in USA. 2000 American Society for Clinical Nutrition
MICRONUTRIENTS IN PREGNANCY 281S
Data on vitamin and mineral metabolism and requirements dietary intakes based on the bioavailability of dietary iron and,
during pregnancy are scanty, and determining the consequences as shown in Table 1, the range increases between 187% and
of apparently deficient or excessive intakes is not easy (1). In 407% for pregnant women eating a diet with low or very low
pregnancy, maternal metabolism is altered by hormones that bioavailable iron, which is the situation in many developing
mediate the redirecting of nutrients to the placenta and mam- countries. The RDA for zinc in pregnancy increases by 44%, that
mary gland as well as the transfer of nutrients to the developing for iodine by 33%, and that for selenium by 26% to cover fetal
infant. Kidney function changes to handle the clearance of both demands; copper requirements remain unchanged.
fetal and maternal metabolic waste, which is associated with
Deficiency
increased urinary excretion of water-soluble vitamins (eg, folate)
(2). Blood volume and composition also change; by the third Calcium deficiency is rare in pregnancy but appears in cases of
trimester, blood volume increases by 3540% over the nonpreg- hypoparathyroidism and severe dietary inadequacy and in individu-
nant state, largely because of a 4550% expansion of plasma vol- als who are unable to eat a diet rich in dairy products (41, 42). Low
ume and a 1520% expansion of red blood cell mass. calcium and magnesium concentrations have been associated with
Nutrient requirements during pregnancy are usually calculated hypertensive disorders of pregnancy, although a causal effect has
by adding an increment to the value for nonpregnant and nonlac- not been shown (10; MJ Keirse, unpublished observations, 2000).
tating women that covers the cost of fetal growth and develop- Most foods contain phosphorus, and dietary deficiency is rare (33).
ment and the associated changes in maternal tissue metabolism. Iron deficiency resulting mainly from poor dietary iron
This factorial approach, however, may not necessarily be correct bioavailability causes anemia (26) and has been associated with
because it does not take into account metabolic changes in maternal mortality (9). Iron deficiency is known to affect immune
absorption or excretion that may compensate for the additional status by reducing the delayed-type hypersensitivity reaction,
nutrient requirements without the need for an increase in intake. graft rejection, and cytotoxic activity of phagocytes (43). A low
TABLE 1
Recommended dietary allowances and intakes for adolescent girls; nonpregnant, nonlactating women; and pregnant women1
Percentage
Nonpregnant, increase over
Adolescent girls nonlactating women Pregnant women nonpregnant,
NRC, IOM, FAO/WHO, NRC, IOM, FAO/WHO, (3rd trimester) nonlactating women:
Nutrient 1518 y 1418 y 1519 y 2549 y 1950 y 1860 y NRC IOM FAO/WHO pregnant women2
%
Calcium (mg)3 1200 1300 500600 800 10004 400500 1200 10004 10001200 140150
Phosphorus (mg) 1200 1250 800 700 1200 700
Magnesium (mg) 300 360 280 310320 320 350360
Iron (mg) 15 15 30
Very low bioavailability5 60 59 179299 203407
Low bioavailability5 32 32 92152 187375
Medium bioavailability5 16 16 4676 187375
High bioavailability5 10 11 3161 182454
Zinc (mg)6,7 12 1.5 12 1.4 15 2.0 43
Iodine (mg)6 150 150 150 150 175 200 33
Selenium (mg)6 50 21.5 55 21.5 65 27 26
Copper (mg)6 1.15 1.53.08 1.15 1.53.08 1.15 0
Vitamin A (mg RE)5 800 600 800 500 800 600 20
Pregnancy-related magnesium deficiency has not been shown mental iron is taken to overcome the interaction effects. Zinc
(52, 53) and there is no evidence in the literature that magnesium supplementation may improve pregnancy outcomes for chron-
supplementation is worthwhile in either high- or low-risk preg- ically deficient pregnant women (JC King, unpublished observa-
nancies (MJ Keirse, unpublished observations, 2000). The UL tions, 2000). Prophylactic doses of 2025 mg elemental zinc/d
for magnesium in pregnancy is the same as that for other adults, have generally been used in pregnant women in developing
namely 350 mg/d (34). countries (58), and the WHO (49) set the UL at 35 mg/d.
Prophylactic iron supplementation is recommended in Results of zinc supplementation trials are mixed. In US women
developing countries (54) and in the United States (49) for all with low plasma zinc concentrations who were at high risk of
pregnant women in the second and third trimesters of preg- having low-birth-weight infants and whose intake of zinc was
nancy; in other countries, iron supplementation is recom- inadequate, supplementation with 25 mg Zn/d, beginning at an
mended only for anemic women with proven iron deficiency average of 19 wk gestation, resulted in an upward shift in the
anemia, as in Great Britain (55), or for women with low gestational age distribution and greater fetal growth (including
prepregnancy iron stores, as in Canada (56). Safety issues head circumference) that was independent of gestational age
related to iron are discussed by Yip (57). (59). These findings occurred primarily in women with a body
For zinc, the IOM (49) concluded there was insufficient mass index (expressed as kg/m2) < 26. Although the authors con-
evidence on which to base a recommendation for routine clude that their findings support the inclusion of zinc in multiple-
supplementation during pregnancy. Nevertheless, the IOM rec- micronutrient supplements, they note that unless the improved
ommends zinc supplementation when 30 mg/d of supple- outcomes are also associated with decreased morbidity and
MICRONUTRIENTS IN PREGNANCY 283S
mortality, there is no reason to be enthusiastic about the allowance for pregnant women increases 300% to take into
improved birth weight alone. Hakimi et al (60) reported prelim- account calcium deposition and bone mineralization in the fetus
inary data from an ongoing randomized, placebo-controlled trial (32). The RDA for vitamin E intakes during pregnancy has not
in which pregnant women are being given a daily low dose of been established because of difficulties in determining require-
20 mg zinc sulfate. Of the 680 women for whom data were avail- ments (49). The NRC (33) assumed that vitamin E is needed for
able, zinc did not affect postpartum infection measured as ele- fetal growth and recommends that intakes be increased by 25%
vated body temperature (>38 8C) on at least day 1 postpartum in pregnancy. Sufficient data are not available for setting a spe-
[relative risk (RR) = 0.97; 95% CI: 0.43, 2.16]. Caulfield et al cific RDA for vitamin K in pregnancy and the recommendation
(61) showed that supplementing pregnant Peruvian women for nonpregnant, nonlactating women is used (33).
beginning at gestation week 1024 with a prenatal supplement
Deficiency
containing 60 mg Fe and 250 mg folate with or without 15 mg
Zn improved maternal zinc status but did not raise it to concen- Vitamin A deficiency is widespread and occurs when the intake
trations found in well-nourished populations. They concluded of dairy products and carotene-rich vegetables and fruit is limited
that higher amounts of zinc may be needed. and, occasionally, with malabsorption syndrome. Vitamin A defi-
In regions of moderate to severe iodine deficiency, pregnant ciency in pregnancy is known to result in night blindness (69, 70),
women need iodized salt before or iodized oil before or during has been shown to increase the risk of maternal mortality (71), and
pregnancy (14, 62). This regimen reduces reproductive loss is associated with premature birth, intrauterine growth retardation,
(47), morbidity, and adverse fetal outcomes (14). The WHO low birth weight (17), and antepartum hemorrhage (72) due to
(49) did not set an UL for pregnancy although it cites a report abruptio placentae. Vitamin A deficiency reduces leukocyte num-
saying that iodine intakes of < 100 mg/d are safe and that the UL bers, lymphoid tissue weights, complement, T cell functions, tumor
could be as high as 200 mg/d. resistance, natural killer cell numbers, antigen-specific immuno-
placebo-controlled trial showed for the 680 women for whom and a small increase in energy utilization (40). Niacin dietary
data were available that the number of episodes of elevated body allowances are 10% higher for the same reasons (40), despite a
temperature (> 38 8C) on at least day 1 postpartum was reduced possibility that bioconversion from tryptophan may increase as a
by 78% in women given 2400 mg vitamin A daily during preg- result of increased energy requirements (49). Vitamin B-6 defi-
nancy compared with the control group who received no vitamin ciency rarely occurs; thus, the FAO/WHO has not recommended
A supplement (RR = 0.22; 95% CI: 0.08, 0.65). additional requirements for pregnant women but the IOM (35)
Hypervitaminosis A increases the risk of fetal malformation, has. Because vitamin B-6 is not stored in the body to any great
and supplementation should not exceed 3000 mg/d (84). Excess extent and the increased need is concentrated in the second half
vitamin A also has adjuvant effects that increase lymphocyte of pregnancy, the IOM (35) has recommended that the RDA be
proliferation, tumor resistance, graft rejection, and cytotoxic increased by 46% to ensure sufficiency throughout pregnancy.
T cell activity, possibly by inhibiting T cell apoptosis (43). Besides the need for folate at periconception to prevent neural
Vitamin D supplementation is not likely needed during preg- tube defects, folate dietary allowances during pregnancy increase
nancy except perhaps in high-risk population groups, for exam- substantially by 147% (37) to build or maintain maternal stores
ple, in women whose clothing limits exposure to direct sunlight and to meet the needs of rapidly growing maternal and fetal tissues
and in women who live in northern latitudes with few hours of (35). The FAO/WHO (40) recommends a 40% increase in the vita-
daylight. Vitamin D can be toxic to both the mother and fetus if min B-12 dietary allowance to meet fetal demands and increased
given in large doses in pregnancy, although the intake at which metabolic needs. No recommended daily allowances are available
this occurs is uncertain because interindividual sensitivity to for biotin and pantothenic acid because of the absence of evidence
excessive intakes varies (49). When used, however, daily low of increased requirements during pregnancy (35).
doses are preferable to a few large doses because the risk of tox-
Deficiency
icity is reduced. The IOM (34) concluded there are insufficient
In West Africa, the frequency of megaloblastic anemia was lic health authorities. Nevertheless, few data show that coverage
reduced by 50% after antimalarial prophylaxis and it was com- is good or that anemia prevalence rates are declining (115).
pletely abolished with folate supplementation (103). A specific
thermolabile variant of the folate-metabolizing enzyme, 5,10- Multiple-micronutrient supplementation
methylene tetrahydrofolate reductase, which causes decreased Although much more needs to be done to ensure that women
enzymatic activity, has been described in 515% of populations in need of iron and folate supplements have good access to them,
with low folate status (104106). This variant increases the risk of multiple-micronutrient supplements are being advocated over
homocysteinemia and neural tube defects, necessitating additional conventional iron and folate supplements (116). Manipulating
requirements for folate before pregnancy (104). the formulation, however, simply adds to the cost of the treat-
Vitamin B-12 deficiency is rare in pregnancy, especially ment with no added benefit in efficacy except when other
where nonvegetarianism is the norm. Vitamin B-12 deficiency micronutrient deficiencies coexist (117). Moreover, an abrupt
in association with megaloblastic anemia was reported in preg- change in direction is questionable because it does not address
nant women in Zimbabwe and India (103, 107) and low blood the underlying problem of inadequate prenatal iron and folate
concentrations were observed in Mexico (108). Strict vegetari- coverage and, indeed, could divert attention and resources away
ans or individuals who lack intrinsic factor and suffer from mal- from correcting existing program problems. Better data are
absorption resulting from diseases affecting the terminal ileum needed to show that iron and folate supplementation is effective
can be vitamin B-12 deficient. Deficiency in pregnancy can lead in reducing the prevalence of anemia, but this does not mean that
to intrauterine death and possibly to adverse infant neurobehav- existing programs should be changed. Instead, the evidence to
ioral development (109). Vitamin B-12 deficiency depresses justify changing current iron and folate supplementation prac-
phagocyte functions, delayed-type hypersensitivity responses, tice, which includes identifying and defining the measurable out-
and T cell proliferation (43). comes, needs to be generated. This is important because the
other concerns are related to interactions between and among supplements should be taken shortly after meals to limit gastric
nutrients. Lonnerdal and Keen (120) classified these into interaction to reduce side effects (117). Clearly, there are trade-
2 groups. In the first group, deficiency of one element affects the offs in terms of interactions and the number of tablets women
metabolism of another. Copper deficiency, for example, causes can be expected to take regularly. For these reasons, these issues
low ferroxidase activity, which induces an iron-deficiency-like need to be discussed and agreement reached on the priority out-
anemia (121). In the second group, 2 or more trace elements comes for both the mother and the fetus.
share the same absorptive pathway and a high concentration of
one may interfere with the absorption of the other; thus, trace Other concerns
element ratios are important. Another important concern is the use of coloring in micronu-
trient supplements. Although coloring may make the tablets
Multinutrient interactions more attractive, it raises safety concerns, particularly regarding
Lonnerdal (121), in his review and summary of iron-zinc- children, who may consume the tablets on the premise that they
copper interactions, notes that a high concentration of iron can are sweets and thus poison themselves (114). This issue is very
interfere with zinc uptake when no dietary ligands are present important in developing countries, where commercial interests
(ie, in a fasting state). High iron intakes may interfere with cop- often conflict with public health needs despite regulations to
per absorption if both are taken simultaneously, even when the control the inappropriate use of dangerous drugs (personal
differences in iron-copper ratios are relatively small. Modest observations). There is also a need for proper quality assurance
increases in zinc intakes can also affect copper absorption, even systems to ensure bioavailability of the nutrients in supplement
with small changes in the ratio. Lonnerdal (121) concluded that preparations.
these interactions are more likely to occur when the elements are
given as a supplement, and that the outcomes can vary greatly Cost of supplements
It is often argued that the marginal cost of adding other vita- education. Clearly, pregnant women need to be provided with
mins and minerals to iron and folate supplements is small, but this information that will reduce or close their knowledge gap about
is not the issue. The issue is the total costs to the program that the nutritional value of locally available foodstuffs, what they
includes the wholesale price and the costs of packaging, transport actually eat, and the need for prophylactic micronutrient supple-
or logistics, storage, and distribution. For a country such as India ments. The challenge is how to do all this effectively.
that has 26 million pregnant women, the budget implications are
enormous: $7.02 million for the WHO/MSM iron-folate tablets,
$11.96 million for the UNICEF/UNIPAK iron-folate supple- CONCLUSION
ments, $66.3 million for the unnamed companys product, and To decide which micronutrients are of greatest concern in
$113.1 million calculated by using the average wholesale price of developing countries, a more systematic and comprehensive
the existing multiple-micronutrient supplements in the market. approach is needed that will result in agreement on the objectives
Health ministries have to make tough decisions about the way of prophylactic multiple-micronutrient supplementation, the cri-
they allocate resources; thus, the scientific basis and rationale for teria for identifying and setting concentrations, and the outcomes
making decisions must be unequivocal. Costs, however, do not to be measured. This will require carefully reviewing the dietary
have to be perceived to be prohibitive if the government has a intakes of both nonpregnant, nonlactating women and pregnant
basis forand becomes committed tocontrolling micronutrient women; the micronutrient status of nonpregnant, nonlactating
deficiencies and the commercial pharmaceutical sector works in women; and the cost-effectiveness of ongoing interventions in
collaboration to support the governments effort. developing countries. At the same time, discussion and agree-
ment is needed about issues related to what motivates women to
Programmatic challenges change behavior that can result in improved nutrition statusbe
In addition to the economic constraints, a major programmatic it through improved dietary practices or the use of supplements
5. Barker DJ. Maternal nutrition, fetal nutrition and disease in later 33. National Research Council. Recommended dietary allowances. 10th
life. Nutrition 1997;13:80713. ed. Washington, DC: National Academy Press, 1989.
6. Barker DJP. Fetal nutrition and cardiovascular disease in later life. 34. Institute of Medicine. Dietary reference intakes. Calcium, phospho-
Br Med Bull 1997;53:96108. rus, magnesium, vitamin D, and fluoride. Washington, DC: National
7. Susser M, Levin B. Ordeals for the fetal programming hypothesis. Academy Press, 1999.
BMJ 1999;318:8556. 35. Institute of Medicine. Dietary reference intakes. Thiamin, riboflavin,
8. Gittelsohn J, Thapa M, Landman LT. Cultural factors, caloric intake niacin, vitamin B-6, folate, vitamin B-12, pantothenic acid, biotin,
and micronutrient sufficiency in rural Nepali household. Soc Sci and choline. Washington, DC: National Academy Press, 1998 (pre-
Med 1997;44:173949. publication edition).
9. Rush D. Nutrition and maternal mortality in the developing world. Am 36. Food and Agriculture Organization of the United Nations. Calcium
J Clin Nutr 2000;72(suppl):212S40S. requirements. Report of a joint FAO/WHO Expert Consultation.
10. Maine D. Role of nutrition in the prevention of toxemia. Am J Clin Rome: FAO, 1962. (FAO Nutrition Meeting Report no. 30.)
Nutr 2000;72(suppl):298S300S. 37. Food and Agriculture Organization of the United Nations, World
11. Rooney C. Antenatal care and maternal health: how effective is it. A Health Organization. Requirements for vitamin A, iron, folate, and
review of the evidence. Geneva: WHO, 1992. (WHO/MSM/92.4.) vitamin B-12. Report of a joint FAO/WHO Expert Consultation.
12. Kirke PN, Daly LE, Molloy A, Weir DG, Scott JM. Maternal folate Rome: FAO, 1988.
status and risk of neural tube defects. Lancet 1996;348:678 38. World Health Organization. Trace elements in human nutrition and
13. Medical Research Council Vitamin Study Groups. Prevention of neural heath. Geneva: WHO, 1996.
tube defects: result of the MRC vitamin study. Lancet 1991;238:1317. 39. World Health Organization. Handbook of nutritional requirements.
14. Delange F. Administration of iodized oil during pregnancy: a sum- Geneva: WHO, 1974.
mary of the published evidence. Bull World Health Organ 1996; 40. Food and Agriculture Organization of the United Nations, World
74:1018. Health Organization. Requirements of vitamin A, thiamin, ribo-
15. Gulmezoglu M, de Onis M, Villar J. Effectiveness of interventions flavin, and niacin. Report of a joint FAO/WHO Expert Group.
57. Yip R. Significance of an abnormally low or high hemoglobin con- mothers, and infants. Report of the XVIII International Vitamin A
centration during pregnancy: special consideration of iron nutrition. Consultative Group Meeting. Cairo, Egypt, 2226 September, 1997.
Am J Clin Nutr 2000;72(suppl):272S9S. Washington, DC: ILSI Press, 1998:86.
58. Gibson RS, Ferguson EL. Nutrition intervention strategies to com- 80. Fawzi WW, Msamanga GI, Spiegelman D, et al. Randomised trial of
bat zinc deficiency in developing countries. Nutr Res Rev 1998;11: effects of vitamin A supplements on pregnancy outcomes and T cell
11531. counts in HIV-1-infected women in Tanzania. Lancet 1998;351:
59. Goldenberg RL, Tamura T, Neggers Y, et al. The effect of zinc sup- 147782.
plementation on pregnancy outcome. JAMA 1995;274:4638. 81. Mellanby E, Green HN. Vitamin A as an anti-infective agent: its use
60. Hakimi M, Dibbley MJ, Suryono A, et al. Impact of vitamin A and in the treatment of puerperal septicemia. Br Med J 1929;1:9846.
zinc supplements on maternal post partum infections in rural central 82. Green HN, Pindar D, Davis G, Mellanby E. Diet as a prophylactic
Java, Indonesia. Report of the XIX International Vitamin A Consul- agent against puerperal sepsis. Br Med J 1931;2:5958.
tative Group Meeting. Durban, South Africa, 811 March, 1999. 83. Cameron SJ. An aid to the prevention of puerperal sepsis. Trans
Washington, DC: ILSI Press, 1999:34. Edinburgh Obstet Soc 1931;52:93103.
61. Caulfield LE, Zavaleta N, Figueroa A. Adding zinc to prenatal iron 84. World Health Organization. Safe vitamin A dosage during preg-
and folate supplements improves maternal and neonatal zinc status
nancy and lactation. Geneva: WHO, 1998. [WHO/NUT/98.4.]
in a Peruvian population. Am J Clin Nutr 1999;69:125763.
85. Hytten FE. Nutrition. In: Hytten F, Chamberlain G, eds. Clinical
62. Dunn JT. Iodized oil in the treatment and prophylaxis of IDD. In:
physiology in obstetrics. Oxford, United Kingdom: Blackwell Sci-
Hetzel BS, Dunn JT, Stanbury JB, eds. The prevention and control
entific Publications, 1980:16392.
of iodine deficiency disorders. Amsterdam: Elsevier, 1987:12734.
86. Czeizel AB. Folic acid in the prevention of neural tube defects.
63. Xu GL, Wang SC, Gu BQ, et al. Further investigation on the role of
J Pediatr Gastroenterol Nutr 1995;20:416.
selenium deficiency in the aetiology and pathogenesis of Keshan
disease. Biomed Environ Sci 1997;10:31626. 87. Metz J, McGrath K, Bennett M, Hyland K, Bottinglieri T. Biochem-
64. Kohrle J. The trace element selenium and the thyroid gland. ical indices of vitamin B12 nutrition in pregnant patients with sub-
104. Kang SS, Wong PWK, Susmano A, Sorg J, Norusis M, Ruggie N. 120. Lonnerdal B, Keen CL. Trace element absorption in infants: poten-
Thermolabile methylenetetrahydrofolate reductase: an inherited risk tials and limitations. In: Clarkson TW, Nordberg GF, Sager PR, eds.
factor for coronary artery disease. Am J Hum Genet 1991;48: Reproductive and developmental toxicity of metals. New York:
53645. Plenum Press, 1983:75976.
105. de Franchis R, Sebastio G, Mandato C, Andria G, Mastroiacovo P. 121. Lonnerdal B. Iron-zinc-copper interactions. In: Micronutrient inter-
Spina bifida 677T- (mutation) and role of folate. Lancet 1995;345: actions: impact on child health and nutrition. Washington, DC: ILSI
1703 (letter). Press, 1996:310.
106. Molloy AM, Daly S, Mills JL, et al. Thermolabile variant of 5,10 122. Simmer K, Iles CA, James C, Thompson RPH. Are iron-folate sup-
methylenetetrahydrofolate reductase associated with low red-cell plements harmful? Am J Clin Nutr 1987;45:1225.
folate: implication for folate intake recommendations. Lancet 1997; 123. Ghishan FK, Said HM, Wilson PC, Murrell JE, Greene HC. Intesti-
349:15913. nal transport of zinc and folic acid: a mutual inhibitory effect. Am J
107. Baker SJ, Jacob E, Rajan KT, Swaminathan SP. Vitamin B12 Clin Nutr 1986;43:25862.
deficiency in pregnancy and puerperium. Br Med J 1962;1: 124. Milne DB, Canfield WK, Mahalko JR, Sandstead HH. Effect of oral
165861. folic acid supplements on zinc, copper, and iron absorption and
108. Allen L. The nutrition CRSP: what is marginal malnutrition and excretion. Am J Clin Nutr 1984;39:5359.
does it affect human function? Nutr Rev 1993;1:25567. 125. Tamura T, Goldenburg RL, Freeberg LE, Cliver SP, Cutter GR,
109. Shojania AM. Folic acid and vitamin B12 deficiency in preg- Hoffman HJ. Maternal serum folate and zinc concentrations and
nancy and in the neonatal period. Clin Perinatol 1984;11: their relationships to pregnancy outcome. Am J Clin Nutr 1992;56:
43359. 36570.
110. Bates CJ, Prentice AM, Watkinson M, et al. Efficacy of a food sup- 126. Mervyn L, ed. Dictionary of minerals. Wellingborough, NY: Thor-
plement in correcting riboflavin deficiency in pregnant Gambian sons Publishing, 1985:1737.
women. Hum Nutr Clin Nutr 1984;38C:36374. 127. Babior BM, Peters WA, Briden PM, Cetrulo CL. Pregnant womens
111. Department of Health, Scottish Office, Home and Health Depart- absorption of iron from prenatal supplements. J Reprod Med