Diabetes and Lactation

Alaa Wafa . MDAssociate Professor of Internal Medicine

Diabetes & Endocrine Unit.Mansoura University

Question My patient was taking glipizide for type 2 DM. Now, she is pregnant and taking insulin instead.She is very anxious to return to her previoustreatment immediately after delivery because of the pain and hurdles associated with the administration of insulin. Can sulfonylurea cross into human milk

and, if so, is it safe for her to breastfeed her infant?

Since 1986, the American Diabetes Association has recommended that diabetic women should be encouraged to breastfeed . Recommendations from the Fourth International Workshop-Conference on Gestational Diabetes Mellitus encouraged women to breastfeed, although data demonstrating efficacy were lackingAmerican Diabetes Association: Position statement on gestational diabetes mellitus. Diabetes Care 9:430–431, 1986American Diabetes Association: Gestational diabetes mellitus (Position Statement). Diabetes Care 27 (Suppl. 1):S88–S90, 2004

Breastfeeding is recommended as the preferred method of infant feeding for the first year of life or longer, and exclusive breastfeeding is recommended for the first 6 months of life .

The Institute of Medicine defines exclusive breastfeeding as an infant's consumption of human milk with no supplementation of any type (no water, juice, nonhuman milk, or foods) except for vitamins, minerals, and medications

• Institute of Medicine: Nutrition During Lactation. Washington, DC, National Academy Press, 1991

Benefits of lactation Breastfeeding provides important health benefits to both women

and their offspring.

Lactation improves glucose tolerance in the early postpartum period

Health benefits of lactation for women include a lower risk of breast and ovarian cancer and possibly protection against type 2 diabetes

• Collaborative Group on Hormonal Factors in Breast Cancer: Breast cancer and breastfeeding: collaborative reanalysis of individual data from 47 epidemiological studies in 30 countries, including 50302 women with breast cancer and 96973 women without the disease. Lancet 360:187–195, 2002

• ↵ Stuebe AM, Rich-Edwards JW, Willett WC, Manson JE, Michels KB: Duration of lactation and incidence of type 2 diabetes. JAMA 294:2601–2610, 2005

Benefits of lactation

For the offspring, breastfeeding confers protection against both undernutrition and overnutrition during early childhood and may lower risk of developing obesity, hypertension, cardiovascular disease, and diabetes later in life .

Postnatal feeding is one of several critical or sensitive developmental periods hypothesized to result in “metabolic programming” of future chronic disease risk

Arenz S, von Kries R: Protective effect of breastfeeding against obesity in childhood: can a meta-analysis of observational studies help to validate the hypothesis? Adv Exp Med Biol 569:40–48, 2005

Ravelli AC, van der Meulen JH, Osmond C, Barker DJ, Bleker OP: Infant feeding and adult glucose tolerance, lipid profile, blood pressure, and obesity. Arch Dis Child 82:248–252, 2000

LACTATION AND SUBSEQUENT OBESITY AND DIABETES IN

WOMEN

LACTATION AND SUBSEQUENT OBESITY AND DIABETES IN WOMEN

• Lactation may have lasting effects on risk factors that influence future chronic disease risk for women . .

• Longer duration of breastfeeding has also been associated with lower maternal weight gain 10–15 years later .

• Lactation may also influence long-term regulation of body weight as well as regional fat distribution in women

Lactogenesis in Diabetic women

• Lactation may be more difficult for women with DM because both maternal diabetes and obesity can delay the onset of lactogenesis .

• Furthermore, medical management of their newborns that involves provision of supplemental milk feedings may interfere with maternal milk production.

• In obese women, lactogenesis may be impaired because of lower physiological levels of prolactin in response to suckling .

• Delayed milk production may lead to lower rates of breastfeeding and shorter duration among obese women .

Biological plausibility for breastfeeding and lower risk of overweight and diabetes

• The average daily milk volume consumed by an infant increases from 50 ml on day 1 to 500 ml by day 5 of life .

• Macronutrient composition (i.e., protein, fat, lactose content) of breast milk may influence hormonal responses that influence metabolic programming of body fat and rates of growth.

• Levels of insulin, leptin, and ghrelin that regulate energy homeostasis in early neonatal life may be affected by the mode of infant feeding

Postulated mechanisms: constituents of breast milk and metabolic programming

• Breastfeeding may exert protective biologic effects through behavioral and hormonal mechanisms that influence metabolic programming.

• Breast milk contains bioactive substances that may influence regulation of energy balance and fat deposition and has less protein relative to formula milk..

• Leptin levels have been reported to be higher for breastfed than formula-fed infants .

• The circulating leptin levels were not only related to adipose tissue production, but may be contributed from human milk

Lactation: immediate and post-weaning effects on maternal metabolic parameters• Lactation markedly alters maternal fuel metabolism and increases energy

expenditure by 15–25% • .• The 400–500 kcal/day required for milk production during the first 6

months by exclusively breastfeeding women is derived from maternal dietary intake, with an additional 170 kcal/day mobilized from fat stores .

• About 50 g/day glucose is diverted for lactogenesis (the process of milk synthesis and secretion) via non–insulin-mediated pathways of uptake by the mammary gland .

Thus, lactating women exhibit lower blood glucose and insulin concentrations along

with higher rates of glucose production and lipolysis compared with nonlactating women

Antidiabetic drugs &

Lactation

Sulphonlyurea &

Lactation

Sulfonylureas and lactation

• To date, the use of sulfonylureas during breast-feeding has been discouraged. Earlier studies with two first-generation sulfonylureas, showed that there was significant transfer of these drugs into breast milk

• Mothers who had recently delivered were given a single dose of glyburide, 5 mg (n = 6) or 10 mg (n = 2), and maternal blood and milk were tested at 8 hours after the dose.

• Another group of mothers (N = 5) received daily doses of glyburide (nonmicronized 5 mg) or glipizide (immediate-release 5 mg).

• Neither glyburide nor glipizide could be detected in breast milk.

• Blood glucose levels were normal in all infants who were exclusively breastfed (glyburide [n = 1], glipizide [n = 2]).

• Based on these data, maternal exposure to these drugs seems unlikely to exert any clinically significant pharmacologic action on breastfed infants

CONCLUSIONS—Neither glyburide nor glipizide were detected in breast milk, and hypoglycemia was not observed in the three nursing infants. Both agents, at the doses tested, appear to be compatible with breast-feeding.

Glyburide Breastfeeding Warnings There is limited data which suggests negligible levels of this

drug are present in breast milk.

A study in 8 women receiving a single-dose shortly after delivery estimates the maximum dose a fully breastfed infant would receive with 5 and 10 mg doses at

less than 1.5% and less than 0.7% of the maternal weight-adjusted dose, respectively.

Due to the limited data available and the potential for hypoglycemia in the nursing infant, the manufacturer

suggests women who are not able to manage their blood sugar on diet alone consider insulin therapy while

breastfeeding

Metformin& breastfeeding

5 women taking a median dose of 1500 mg/d of metformin had average breast milk levels of 0.27 mg/L, amounting to an estimated 0.28% of the maternal weight-adjusted dose ingested by the infant. Very low or undetectable concentrations of metformin were observed in the plasma of the 4 babies studied.

CONCLUSIONS/INTERPRETATION: The concentrations of metformin in breast milk were generally low and the mean infant exposure to the drug was only 0.28% of the weight-normalized maternal dose. As this is well below the 10% level of concern for breastfeeding, and because the infants were healthy, we conclude that metformin use by breastfeeding mothers is safe. Nevertheless, each decision to breastfeed should be made after conducting a risk:benefit analysis for each mother and her infant

A second study looking at breast milk transfer of metformin enrolled 7 women who took 1000 mg/d of the drug. The milk concentrations observed were similar to those of the previous study, with estimated doses ingested by the infants below 1% of the maternal weight-adjusted dose

CONCLUSION: Metformin is excreted into breast milk, but the amounts seem to be clinically insignificant. No adverse effects on the blood glucose of the 3 nursing infants were measured

CONCLUSION:Metformin appears to be "safe" during lactation because of low infant exposure. The unusual concentration-time profile for metformin in milk suggests that the transfer of metformin into milk is not solely dependent on passive diffusion

A prospective study followed 61 breastfed and 50 formula-fed infants born to 92 mothers with polycystic ovary syndrome taking 1.5 to 2.55 g of metformin daily throughout pregnancy and lactation. ConclusionMetformin use during lactation had no adverse effects on breastfed infants’ growth, motor-social development, or intercurrent illnesses, compared with formula-fed infants.

• Metformin is considered a first-line agent for the treatment of type 2 diabetes, and has also been proposed as a useful drug for the management of gestational diabetes.

• The very limited amounts of metformin observed in breast milk are highly unlikely to lead to substantial exposure in the breastfed baby.

• Metformin can be considered a safe medication for the treatment of type 2 diabetes in a breastfeeding mother.

Conclusions

Conclusions :Use of oral hypoglycemic and lactation

• The available data suggest that the levels of glyburide and glipizide in milk are negligible and would not be expected to cause adverse effects in breastfed infants;

• Treatment with metformin during lactation is unlikely to lead to toxicity in the breastfed infant. Given the safety profile of metformin, as compared with sulfonylureas, it is advisable to consider metformin as first-line treatment during lactation if this drug is appropriate for the particular patient. Nevertheless, second-generation sulfonylureas are also likely to be safe during lactation.

• However, as data are based on a single study with a limited sample size, monitoring of the breastfed infant for signs of hypoglycemia is advisable during maternal therapy with any of these agents.

• Other oral medications currently used for the treatment of type 2 diabetes, such as the thiazolidinediones and acarbose,DPP-4 inhibitors have not been studied in the lactation period

Insulin and lactation

Insulin and lactation

• Mothers with diabetes using insulin may nurse their infants.

• Insulin is a normal component of breastmilk and may decrease the risk of type 1 diabetes in breastfed infants.

Insulin requirements are reduced postpartum in women with type 1 diabetes.

In one study, insulin requirements were lower than prepregnancy dosage only during the first week postpartum: 54% of prepregnancy dosage on day 2 and 73% on day 3 postpartum. On day 7 postpartum, insulin dosage returned to prepregnancy requirements.

Another study found that dosage requirements did not return to normal for up to 6 weeks in some mothers.

A third study found that at 4 months postpartum, patients with type 1 diabetes who exclusively breastfed had an average of 13% lower (range -52% to +40%) insulin requirement than their prepregnancy requirement Breastfeeding appears to improve postpartum glucose tolerance in mothers with gestational diabetes mellitus and in normal women.

Insulin requirements are reduced postpartum in women with type 1 diabetes.

A small, well-controlled study of women with type 1 diabetes mellitus using continuous subcutaneous insulin found that the average basal insulin requirement in women with type 1 diabetes who breastfed was 0.21 units/kg daily and the total insulin requirement was 0.56 units/kg daily.

In similar women who did not breastfeed, the basal insulin requirement was 0.33 units/kg daily and the total insulin requirement was 0.75 units/kg daily.

The 36% lower basal insulin requirement was thought to be caused by glucose use for milk production.

Effects on Lactation and Breastmilk

Proper insulin levels are necessary for lactation.Good glycemic control enhances maternal serum

and milk prolactin concentrations and decreases the delay in the establishment of lactation that can occur in mothers with type 1 diabetes.

• Eight hundred eighty-three patients with gestational diabetes were interviewed at 6 to 9 weeks postpartum.

• Those who had been treated with insulin more frequently reported having a delayed onset of lactogenesis II (>72 hours) postpartum than those not treated with insulin.

• The odds ratio of having delayed lactogenesis II was 3.17 among insulin-treated mothers.

Stanadarad of Medical care in Diabetes 2015

Lactation• All women should be supported in attempts to nurse their babies, given immediate

nutritional and immunological benefits of breastfeeding for the baby; there may also be a longer-term metabolic benefit to both mother and offspring , though data are mixed.

Type 1 Diabetes• Insulin sensitivity increases in the immediate postpartum period and then returns to

normal over the following 1–2 weeks, and many women will require significantly less insulin at this time than during the prepartum period. Breast-feeding may cause hypoglycemia, which may be ameliorated by consuming a snack (such as milk) prior to nursing. Diabetes self-management often suffers in the postpartum period.

Type 2 Diabetes• If the pregnancy has motivated the adoption of a healthier diet, building on these gains

to support weight loss is recommended in the postpartum period.

Stanadarad of Medical care in Diabetes 2015

Gestational Diabetes Mellitus Because GDM may represent preexisting undiagnosed type 2 diabetes, women with GDM

should be screened for persistent diabetes or prediabetes at 6–12 weeks postpartum using nonpregnancy criteria and every 1–3 years thereafter depending on other risk factors.

Women with a history of GDM have a greatly increased risk of conversion to type 2 diabetes over time and not solely within the 6–12 weeks’ postpartum time frame .

Interpregnancy or postpartum weight gain is associated with increased risk of adverse pregnancy outcomes in subsequent pregnancies and earlier progression to type 2 diabetes.

Both metformin and intensive lifestyle intervention prevent or delay progression to diabetes in women with a history of GDM. Of women with a history of GDM and impaired glucose tolerance, only 5–6 individuals need to be treated with either intervention to prevent one case of diabetes over 3 years .

Blood glucose control, medicines and breastfeeding

• Women with insulin-treated pre-existing diabetes should reduce their insulin immediately after birth and monitor their blood glucose levels carefully to establish the appropriate dose.

• Explain to women with insulin-treated pre-existing diabetes that they are at increased risk of hypoglycaemia in the postnatal period, especially when breastfeeding, and advise them to have a meal or snack available before or during feeds.

• Women who have been diagnosed with gestational diabetes should discontinue blood glucose-lowering therapy immediately after birth.

Blood glucose control, medicines and breastfeeding

• Women with pre-existing type2 diabetes who are breastfeeding can resume or continue to take metformin and glibenclamide immediately after birth, but should avoid other oral blood glucose-lowering agents while breastfeeding.

• Women with diabetes who are breastfeeding should continue to avoid any medicines for the treatment of diabetes complications that were discontinued for safety reasons in the preconception period.

ConclusionThe role of breastfeeding in diabetes• In the mother, breastfeeding has been suggested to reduce

the incidence of type 2 diabetes and reduce the risk of premenopausal breast cancer and ovarian cancer.

• In the neonate and infant, among other benefits, lactation confers protection from future both type 1 and type 2 diabetes.

Breastfeeding could be considered a modifiable risk factor for thedevelopment of diabetes and even a potential protective lifestyle measurefrom future cardio-metabolic . Therefore, health care professionals should encourage both women with

and without diabetes to breastfeed their children

Conclusion• Importantly, for diabetic mothers, antidiabetic

treatment itself may affect breastfeeding. • There is not enough data to allow the use of oral

hypoglycaemic agents.• Therefore, insulin currently remains the optimal

antidiabetic treatment during lactation.

Thank you

dralaawafa@hotmail.com