Delayed secretory activation and low milk production in women with gestational diabetes: a case series
BMC Pregnancy and Childbirth volume 22, Article number: 350 (2022)
Gestational diabetes mellitus (GDM) is major pregnancy complication that is associated with short- and long-term consequences for both mother and infant, including increased risk of diabetes later in life. A longer breastfeeding duration has been associated with a reduced risk of diabetes, however, women with GDM are less likely to exclusively breastfeed and have shorter breastfeeding duration. While the timing of breastfeeding initiation and milk removal frequency affects subsequent breastfeeding outcomes, little is known about early infant feeding practices and milk production in women with GDM. This case series offers detailed prospective breastfeeding initiation data, as well as the first report of objective measures of milk production in women with GDM.
In this case series, we present the early infant feeding practices of eight women with GDM that gave birth at term gestation. Women recorded the timing of initiation of breastfeeding and secretory activation, as well as their breastfeeding, expression and formula feeding frequencies on postpartum days 1, 7 and 21. Measurement of 24 h milk production volume was performed at 3 weeks postpartum using the test weight method. We observed a delayed first breastfeed (> 1 h) in 6 (75%) cases, formula use in hospital in 5 (63%) cases and delayed secretory activation in 3 (38%) cases. At 3 weeks postpartum, 2 cases had measured milk productions that were insufficient to sustain adequate infant weight gain.
Our data suggest that despite early and frequent milk removal, women with GDM are at greater risk of delayed secretory activation and low milk supply. Cohort studies that consider co-morbidities such as obesity are needed to determine the lactation outcomes of women with GDM.
Gestational diabetes mellitus (GDM) is defined as impaired glucose tolerance with the first onset during pregnancy . Although GDM commonly resolves after pregnancy, exposure to GDM is associated with short- and long-term consequences for mothers and their infants, including maternal risk of developing type 2 diabetes (T2D) 10 times higher than women without GDM . Furthermore, GDM may impact the lifetime risk of offspring, fuelling a vicious circle of offspring obesity, impaired glucose metabolism, and metabolic syndrome that contribute to the subsequent development of T2D later in life [3, 4].
The postnatal period is an important window for metabolic programming in setting future chronic disease risk . There is evidence that continued breastfeeding after a pregnancy complicated by GDM reduces the risk of developing T2D for women and their infants [6, 7]. However, breastfeeding difficulties are common among women with GDM, with lower rates of predominant breastfeeding on hospital discharge [8, 9] and shorter breastfeeding duration [10, 11]. Indeed, results from a recent systematic review and meta-analysis indicate that GDM-exposed infants had 40% higher rates of formula supplementation in hospital, 1 month shorter duration of breastfeeding, and a 30% decrease in breastfeeding rates at 12 months .
Milk production is dependent on appropriate breast development in pregnancy. Insulin metabolism has been reported as an important regulator of milk secretion, playing a major role in the mammary gland switch from proliferation to differentiation. Insulin upregulates genes associated with mammary epithelial cell (MEC) proliferation and downregulates genes related to MEC differentiation [13, 14]. Therefore, lower insulin sensitivity in diabetes may be associated with impaired secretory differentiation, with subsequent delayed secretory activation and reduced milk production .
Early infant feeding practices impact subsequent milk production , and so may confound the breastfeeding outcomes of women with GDM. Evidence from healthy mothers with term infants suggests that on-demand breastfeeding ≥8 times per 24 h is positively associated with milk production; therefore, reduced milk removal frequency during the early postpartum days and weeks may compromise the 24 h milk production [16, 17]. The existing evidence regarding early infant feeding practices and milk production is limited in this population. Therefore, this case-series aimed to examine early infant feeding practices among women with GDM, measure 24 h milk production and report breastfeeding outcomes at 3 weeks postpartum.
Women with GDM were recruited from a maternity care clinic “One For Women” in Perth, Western Australia, and provided informed consent to participate in an observational study (UWA Human Research Ethics, RA/4/20/5657). Women were diagnosed with GDM based on the Australasian Diabetes in Pregnancy Society criteria using the oral glucose tolerance test (OGTT) between 24 and 28 weeks of gestation . Maternal demographic data were collected at enrolment, including age, ethnicity, education, medication use, parity, and smoking status. Bra cup sizes before and during pregnancy were recorded to detect breast growth. Height and pre-pregnancy weight were collected to determine pre-pregnancy body mass index (BMI).
Lactation related data were also collected including breast surgery, previous and intended breastfeeding durations. Birth mode, birth gestation, infant anthropometrics and sex were recorded. Detailed breastfeeding data were collected at 1, 7 and 21 days postpartum. Early initiation of breastfeeding was defined as putting the newborn to the breast within 1 h of birth, irrespective of infant suckling or milk transfer from the breast infant . The timing of the first breastfeed (infant attached and suckled at breast) and timing of first breast expression (by hand or pump), as well as frequency of milk removal in the first 24 h were recorded. We combined these data to report timing of first milk removal, and frequency of milk removal was reported as the sum of breastfeeding and expression sessions over a 24 h period. Secretory activation is the onset of copious milk secretion that typically occurs at 48 – 72 h after birth and is reported clinically as the time of milk ‘coming in.’ Different milk biomarkers indicate the onset of secretory activation between 7 and 24 h before the mother’s perception of her milk “coming in” or breasts being fuller [20, 21]. However we used maternal perception of milk coming in as published reviews have concluded this is valid and feasible indicator of the onset of secretory activation [21,22,23]. Onset of milk “coming in” after day 3 postpartum was considered to indicate delayed secretory activation.
Maternal milk production was measured at 3 weeks postpartum using the 24 h test weigh method. Mothers use an electronic scale (BabyWeigh; Medela, McHenry, IL; resolution, 2 g; accuracy, 0.034%) to measure their infants’ weight before and after each feed and the volume of any milk expressed over a 24 h period . Emerging evidence suggests that a full milk supply may be achieved at 2 weeks postpartum . The mean 24 h milk production of fully breastfeeding dyads at 1 – 6 months postpartum is 788 ± 169 mL/24 h, with low milk production classified as < 600 mL/24 h }.We did not use a stable isotope technique such as deuterium dilution, because it requires repeated sampling of maternal and infant saliva over 14 days, and (expensive) analysis of isotopes . Further, stable isotope technique measurements correlate with 24 h test weights when electronic scales are used . The 24 h test weight method offers the benefit of additional data including frequency of milk removal by breastfeeding and/or pumping, and volumes of any supplementary feeds given.
Maternal and infant characteristics
Eight women participated in a study designed to examine infant feeding practices and 24 h milk production after pregnancies complicated by GDM. Maternal and infant characteristics are reported in Table 1. All eight women had intended breastfeeding durations of at least 12 months and the multiparous case had previously breastfed for 12 months. Three cases were within the healthy BMI range, one was overweight, and four were obese. Histories of anxiety (n = 4) and depression (n = 2) were reported. None had previous breast surgeries or smoking history. Three had medical histories of polycystic ovary syndrome (cases D and E) and endometriosis (case E). Pregnancy complications other than GDM were shortened cervix (case F), and anemia (case G). All gave birth at term gestation, and one had a postpartum haemorrhage. No other birth complications were reported. The median infant birth weight was 3310 g (range 2590 - 4000 g), and four (50%) infants were male.
Early initiation of breastfeeding and timing of first breastfeed: All infants had contact with the breast within an hour of birth and so all achieved early initiation of breastfeeding according to the World Health Organization definition . However, for 6 cases the first breastfeed was delayed > 1 h after birth: cases A, G, and H first breastfed at 1.5, 1.16, and 1.5 h after birth, respectively. Cases D and F first breastfed > 24 h postpartum, and case E did not breastfeed during the hospital stay due to latching difficulties. Seven women commenced breast expression within 2 to 5 h of birth. The interval between birth and first removal of milk from the breast (by breastfeeding or expression) ranged from 0.16 to 3 h (Table 1).
Milk removal frequency: Frequencies of milk removal on days 1, 7, and 21 postpartum were median (range) 9.5 (3 - 17), 8.5 (7 - 11), and 8 (7 - 12), respectively (Table 2).
The reported timing of milk ‘coming in’ ranged from 3 to 8 days postpartum, with delayed secretory activation reported in 5 cases (Table 1). Of those, 3 were overweight or obese, and 6 achieved a 24 h milk production within the reference range by week 3 (Table 2).
At 3 weeks postpartum, 2 women had low 24 h milk production (< 600 mL/24 h); both were obese (Table 2). Another two exclusively breastfeeding women had milk productions close to 600 mL/24 h; their infants’ WHO weight-for-age centiles at birth and 3 weeks were 88th and 55th centile, and 94th and 75th centile respectively. The case with the longest delay in secretory activation (8 days postpartum) had a milk production of 834 mL/24 h and was using a galactagogue and formula supplementation. There were no obvious trends between OGTT results and milk production, however the small sample size precluded statistical analysis.
Exclusivity of breastfeeding
Exclusive breastfeeding was reported for 3 cases and mixed feeding from birth was reported for 3 cases. Five of the 8 cases reported infant formula supplementation in hospital (Table 2). Of the 2 cases that were feeding infant formula on days 7 and 21 postpartum, one had commenced formula use in hospital, and both had low milk production confirmed by measurement.
This case series reported the early breastfeeding patterns and 24 h milk production of eight women following pregnancies complicated by GDM. Our observations showed a delay in timing of the first breastfeed, delayed secretory activation, and low milk production within a sample of women who had GDM, despite strong breastfeeding intentions and frequent milk removal at postpartum days 1, 7 and 21.
In this case series, commencement of breastfeeding > 1 h after birth was observed in 6 of 8 cases. Breastfeeding within an hour of birth is considered very important to the establishment of breastfeeding in healthy dyads with uncomplicated pregnancies . Limited and conflicting evidence is available on the timing of the first breastfeed in women with GDM; one Vietnamese study reported no difference between women with and without GDM , while a North American study found significantly fewer mothers with GDM initiated breastfeeding within an hour of birth . Women with GDM are likely at higher risk of delayed commencement of breastfeeding due to several inter-related factors, and so may need additional support to breastfeed within an hour of birth or to express colostrum when breastfeeding is not possible.
We observed 5 cases with delayed secretory activation despite 4 of these cases achieving early and frequent milk removal in the first 24 h after birth. Milk coming in after 72 h postpartum, or delayed secretory activation, is associated with GDM as well as other risk factors that may co-exist in women with GDM including pre-pregnancy overweight and obesity, caesarean birth, and medical management of neonatal hypoglycaemia such as early formula supplementation [30, 31]. These factors may contribute to reduced frequency of milk removal from the breast that is assumed to delay secretory activation, however the timing of secretory activation is not different in healthy women that choose not to initiate breastfeeding [32, 33]. It is possible that insulin resistance might be a potential mechanism that links GDM and delayed secretory activation. An animal model with modified MEC insulin receptors showed diminished mammary ductal growth and alveolar development . Similarly, a recently published study used human-derived MECs for mammosphere culture to show the regulatory role of insulin in human MEC differentiation. The human mammosphere model suggests that insulin is essential for mammosphere formation by upregulation of differentiation, cell-cell junctions, and cytoskeleton organisation functions through integrin-linked kinase signalling . The impact of biochemical aberrations on early mammary gland secretion is likely the causative mechanism of delayed secretory activation , with altered concentrations of biochemical markers of milk “coming in” such as lactose and citrate observed in women with diabetes . However, the exact pathways that explain these outcomes are complicated and required further investigation.
Milk removal (breastfeeding) was delayed in most cases, however the case with the lowest milk production started breastfeeding within an hour of birth and had subsequent frequent milk removal. While lower milk production at 1 and 6 weeks postpartum has been linked to delayed and infrequent milk removal [16, 34], milk production also depends on intrinsic factors such as adequate functional glandular tissue and endocrine factors that impact proliferation and differentiation [16, 35]. Therefore, pathways contributing to the unintended breastfeeding outcomes of women with GDM are complex and challenging to interpret.
Despite regular milk removal, low milk production was measured in two women whose infants were supplemented with formula to maintain optimal weight gain (Table 2). Maintenance of milk removal ≥8 times per 24 h, whether by breastfeeding and/or pumping, typically enables the achievement of adequate milk production [33, 36]. Several factors may impact milk production, such as inadequate breast development, and possible biochemical aberrations associated with GDM and obesity. While it has been thought that social factors impact lactation in women with obesity, recent evidence supports endocrine factors, with the influences of progesterone and oestrogen within the mammary fat pad yet to be examined . Large cohort studies are required to determine possible biochemical pathways for reduced milk production in women with obesity and GDM, while accounting for other lactation risk factors.
Our case series is limited by the small sample size that prevented controlling for co-existing lactation risk factors and measurement of an effect size. There is growing evidence for endocrine effects of both GDM and obesity on lactation. While it is not possible to differentiate the effects in a case series, observations from our study highlight the complexity of lactation in women with co-existing risk factors.
Our observations of delayed secretory activation in 5 of 8 cases, and low milk supply in 2 of 8 cases emphasise the need for cohort studies to better understand the lactation challenges faced by women with GDM, including the examination of endocrine and molecular pathways that lead to delayed secretory activation and low milk production.
Availability of data and materials
The datasets generated and/or analysed during the current study are not publicly available to further preserve the confidentiality of the participants.
Gestational diabetes mellitus
Type two diabetes
Mammary epithelial cell
Oral glucose tolerance test
Body mass index
Polycystic ovary syndrome
American Diabetes Association. 2. Classification and diagnosis of diabetes: standards of medical care in diabetes-2019. Diabetes Care. 2019;42(Suppl 1):S13–28.
Vounzoulaki E, Khunti K, Abner SC, Tan BK, Davies MJ, Gillies CL. Progression to type 2 diabetes in women with a known history of gestational diabetes: systematic review and meta-analysis. BMJ. 2020;369:m1361.
Mitanchez D, Yzydorczyk C, Simeoni U. What neonatal complications should the pediatrician be aware of in case of maternal gestational diabetes? World J Diabetes. 2015;6(5):734–43.
Plows JF, Stanley JL, Baker PN, Reynolds CM, Vickers MH. The pathophysiology of gestational diabetes mellitus. Int J Mol Sci. 2018;19(11):3342.
Hanson M, Gluckman P. Developmental origins of noncommunicable disease: population and public health implications. Am J Clin Nutr. 2011;94(6 Suppl):1754S–8S.
Aune D, Norat T, Romundstad P, Vatten LJ. Breastfeeding and the maternal risk of type 2 diabetes: a systematic review and dose-response meta-analysis of cohort studies. Nutr Metab Cardiovasc Dis. 2014;24(2):107–15.
Horta BL, de Lima NP. Breastfeeding and type 2 diabetes: systematic review and meta-analysis. Curr Diab Rep. 2019;19(1):1.
Finkelstein SA, Keely E, Feig DS, Tu X, Yasseen AS 3rd, Walker M. Breastfeeding in women with diabetes: lower rates despite greater rewards. A population-based study. Diabet Med. 2013;30(9):1094–101.
Haile ZT, Oza-Frank R, Azulay Chertok IR, Passen N. Association between history of gestational diabetes and exclusive breastfeeding at hospital discharge. J Hum Lact. 2016;32(3):NP36–43.
Nguyen PTH, Binns CW, Nguyen CL, Ha AVV, Chu TK, Duong DV, et al. Gestational diabetes mellitus reduces breastfeeding duration: a prospective cohort study. Breastfeed Med. 2019;14(1):39–45.
Pang WW, Geddes DT, Lai CT, Chan SY, Chan YH, Cheong CY, et al. The association of maternal gestational hyperglycemia with breastfeeding duration and markers of milk production. Am J Clin Nutr. 2021;114(3):1219–28.
Manerkar K, Harding J, Conlon C, McKinlay C. Maternal gestational diabetes and infant feeding, nutrition and growth: a systematic review and meta-analysis. Br J Nutr. 2020;123(11):1201–15.
Neville MC, Webb P, Ramanathan P, Mannino MP, Pecorini C, Monks J, et al. The insulin receptor plays an important role in secretory differentiation in the mammary gland. Am J Physiol Endocrinol Metab. 2013;305(9):E1103–14.
Watt AP, Lefevre C, Wong CS, Nicholas KR, Sharp JA. Insulin regulates human mammosphere development and function. Cell Tissue Res. 2021;384(2):333–52.
Nommsen-Rivers LA. Does insulin explain the relation between maternal obesity and poor lactation outcomes? An overview of the literature. Adv Nutr. 2016;7(2):407–14.
De Carvalho M, Robertson S, Friedman A, Klaus M. Effect of frequent breast-feeding on early milk production and infant weight gain. Pediatrics. 1983;72(3):307–11.
Yamauchi Y, Yamanouchi I. Breast-feeding frequency during the first 24 hours after birth in full-term neonates. Pediatrics. 1990;86(2):171–5.
Nankervis A, McIntyre HD, Moses R, Ross GP, Callaway L, Porter C, et al. ADIPS consensus guidelines for the testing and diagnosis of hyperglycaemia in pregnancy in Australia and New Zealand 2014. 2014.
World Health Organization. Indicators for assessing infant and young child feeding practices: definitions and measurement methods. Geneva: World Health Organization and the United Nations Children’s Fund (UNICEF); 2021.
Pang WW, Hartmann PE. Initiation of human lactation: secretory differentiation and secretory activation. J Mammary Gland Biol Neoplasia. 2007;12(4):211–21.
Perez-Escamilla R, Chapman DJ. Validity and public health implications of maternal perception of the onset of lactation: an international analytical overview. J Nutr. 2001;131(11):3021S–4S.
Lai CT, Rea A, Mitoulas LR, Kent JC, Simmer K, Hartmann PE, et al. Short-term rate of milk synthesis and expression interval of preterm mothers. Arch Dis Child Fetal Neonatal Ed. 2020;105(3):266–9.
Medina Poeliniz C, Engstrom JL, Hoban R, Patel AL, Meier P. Measures of secretory activation for research and practice: an integrative review. Breastfeed Med. 2020;15(4):191–212.
Kent JC, Mitoulas LR, Cregan MD, Ramsay DT, Doherty DA, Hartmann PE. Volume and frequency of breastfeedings and fat content of breast milk throughout the day. Pediatrics. 2006;117(3):e387–95.
Kent JC, Gardner H, Geddes DT. Breastmilk production in the first 4 weeks after birth of term infants. Nutrients. 2016;8(12):756.
Kent JC, Perrella SL, Geddes DT. Measurement of human milk production and infant milk intake—challenges and opportunities. In: McGuire M, O'Connor DL, editors. Human Milk. San Diego: Academic Press; 2021. p. 35–66.
Scanlon KS, Alexander MP, Serdula MK, Davis MK, Bowman BA. Assessment of infant feeding: the validity of measuring milk intake. Nutr Rev. 2002;60(8):235–51.
Inano H, Kameya M, Sasano K, Matsumura K, Tsuchida A, Hamazaki K, et al. Factors influencing exclusive breastfeeding rates until 6 months postpartum: the Japan environment and Children's study. Sci Rep. 2021;11(1):6841.
Oza-Frank R, Gunderson EP. In-hospital breastfeeding experiences among women with gestational diabetes. Breastfeed Med. 2017;12:261–8.
De Bortoli J, Amir LH. Is onset of lactation delayed in women with diabetes in pregnancy? A systematic review. Diabet Med. 2016;33(1):17–24.
Stevens DR, Taylor SN, Roberts JR, Neelon B, Newman RB, Vena JE, et al. Breastfeeding initiation as related to the interaction of race/ethnicity and maternal diabetes. Breastfeed Med. 2019;14(9):630–9.
Kulski JK, Hartmann PE, Martin JD, Smith M. Effects of bromocriptine mesylate on the composition of the mammary secretion in non-breast-feeding women. Obstet Gynecol. 1978;52(1):38–42.
Kulski JK, Hartmann PE. Changes in human milk composition during the initiation of lactation. Aust J Exp Biol Med Sci. 1981;59(1):101–14.
Parker LA, Sullivan S, Krueger C, Mueller M. Association of timing of initiation of breastmilk expression on milk volume and timing of lactogenesis stage II among mothers of very low-birth-weight infants. Breastfeed Med. 2015;10:84–91.
Golan Y, Assaraf YG. Genetic and physiological factors affecting human milk production and composition. Nutrients. 2020;12(5):1500.
Hill PD, Aldag JC, Chatterton RT. Initiation and frequency of pumping and milk production in mothers of non-nursing preterm infants. J Hum Lact. 2001;17(1):9–13.
Knight CH. An endocrine hypothesis to explain obesity-related lactation insufficiency in breastfeeding mothers. J Dairy Res. 2020;87(1):78–81.
We thank all women for participating in the study.
Suwaydi received a scholarship from Jazan University, Saudi Arabia. Prof Geddes, Drs Lai and Perrella receive salaries from an unrestricted research grant that is paid by Medela AG, Switzerland to The University of Western Australia. The funding bodies had no involvement in the study design, data collection, analysis and interpretation, writing of the manuscript and decision to submit the paper for publication.
Ethics approval and consent to participate
The study was approved by the Human Research of The University of Western Australia (UWA Human Research Ethics, RA/4/20/5657). The participants gave informed written consent to participate in this research.
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Written informed consent for publication was obtained from all participants.
Medela AG provides an unrestricted research grant to The University of Western Australia, from which CTL, DTG and SLP and receive salaries. Medela AG was not involved in the study design, collection, analysis and interpretation of the data, writing of the manuscript and the decision to submit the manuscript for publication.
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Suwaydi, M.A., Wlodek, M.E., Lai, C.T. et al. Delayed secretory activation and low milk production in women with gestational diabetes: a case series. BMC Pregnancy Childbirth 22, 350 (2022). https://doi.org/10.1186/s12884-022-04685-0
- Gestational diabetes mellitus
- Human milk
- Case series