diabetes is one of the most common chronic diseases among women of reproductive age , observed in about 10% of pregnancies in the us and approximately 0.20.5% of these are in women with type 1 diabetes ( t1d ) . t1d pregnancies are associated with an increased rate of complications , including late intrauterine death or major congenital malformations , which can lead to increased fetal morbidity and mortality compared to non - diabetic pregnancies . maternal complications are also more frequent , with increased rates of preeclampsia , cesarean section and maternal mortality . poor glycemic control at the time of conception and organogenesis during the first trimester is a major cause for an increased risk of birth defects and pregnancy complications . it has been recognized that a positive correlation exists between hemoglobin a1c ( hba1c ) levels during early pregnancy and the incidence of fetal malformations . therefore , good glycemic control could lead to a reduction of congenital abnormality rates to almost non - diabetic levels . preconception counseling and strict glycemic control have improved pregnancy outcomes in women with t1d , as evident from reduced rates of congenital malformations , preterm delivery and decreased neonatal morbidity , manifested by reduced macrosomia and admissions to neonatal care units . this is further exemplified by a case study from our clinic ( table 1 ) . patients receiving prenatal care have been shown to maintain better hba1c levels , resulting in a reduction of infant mortality from 20% in the 1950s to less than 3% in the 1980s . this would not have been possible without the significant evolution in glucose monitoring methods , the introduction of insulin pumps and the development of insulin analogs.table 1.prenatal care for a pregnant t1d patient  a case study.patienta 31-year - old female with t1d presented to the office for evaluation . she had just relocated and found out that she was pregnant and expressed a wish for  things [ to ] go better this time.historyshe developed diabetes at age 14 and always had poor glycemic control . her diabetes was complicated by retinopathy with laser surgery , peripheral neuropathy , autonomic neuropathy in the form of hypoglycemic unawareness and diabetic cystopathy with frequent urinary tract infections and incontinence . an analysis showed an unspecified developmental defect . with her second pregnancy she developed preeclampsia at 31 weeks of gestation , requiring antihypertensive medications . this patient had never seen an endocrinologist or maternal fetal medicine specialist , as these specialists were not available where she lived . her diabetes had always been treated with two injections per day of nph and regular insulin.treatmentafter meeting with a certified diabetes educator her insulin regimen was intensified to four injections per day , with a variable amount of aspart at meals , as determined by carbohydrate counting . . the insulin regimen was adjusted multiple times , and her hba1c declined to 6.9% . following a dilated retinal exam , an ophthalmologist treated her with panretinal photocoagulation laser therapy.outcomethe patient developed preeclampsia at 36 weeks of gestation , and was treated with antihypertensives . both the mother and her neonate were discharged to home . 
  prenatal care for a pregnant t1d patient  a case study . one of the main challenges in the care for pregnant women with diabetes is the proper control of blood glucose . metabolic changes occurring as a result of the pregnancy complicate this task . during the first trimester , increased insulin sensitivity combined with the constant attempts to achieve normoglycemia through insulin therapy , raise the risk of hypoglycemia . the second and third trimesters of pregnancy are characterized by an enhanced secretion of placental hormones , growth factors and cytokines , leading to an increased insulin resistance and hyperglycemia . hyperglycemia results in the transport of increased amounts of glucose across the placenta , causing fetal hyperinsulinemia and macrosomia . macrosomia can cause maternal and fetal complications and is observed in about 2762% of infants of mothers with diabetes . careful monitoring of glucose levels and constant adjustment of insulin therapy are needed to prevent hyperglycemia during pregnancy . t1d diabetic ketoacidosis ( dka ) , common in t1d patients , develops faster during pregnancy due to decreased insulin sensitivity in the second and third trimesters . dka remains a major cause of fetal loss , affecting 13% of patients with pregestational diabetes . gestational hypertension is a common complication and a major risk factor for cardiovascular events , retinopathy and nephropathy . furthermore , rates of preeclampsia are 2- to 4-times higher in pregnant women with t1d , leading to infant complications , including poor growth and premature birth . preeclampsia can also be associated with serious maternal problems such as eclampsia and  hemolysis , elevated liver enzymes , low platelet count  ( hellp ) hellp syndrome , a life - threatening complication , has been linked to severe hypoglycemia attacks during pregnancy . t1d women who develop preeclampsia tend to have significantly higher hba1c values before and during pregnancy . severe hypoglycemia , a major challenge in the management of t1d , has been reported in 1944% of pregnant diabetes patients treated with intensive insulin therapy , especially in the first trimester . severe hypoglycemia is dangerous for the mother and can lead to loss of consciousness , seizures and death . repeated hypoglycemic episodes can lead to hypoglycemia unawareness , causing further loss of symptoms associated with the autonomic response to hypoglycemia . additionally , symptoms of hypoglycemia ( nausea , anxiety , etc . ) might be mistaken for normal pregnancy symptoms , increasing the danger of severe hypoglycemia . a major goal in the management of t1d during pregnancy is the prevention of hypoglycemic episodes . table 2 summarizes recommendations from the american diabetes association ( ada ) and the american congress of obstetricians and gynecologists ( acog ) for glycemic goals , glucose monitoring and prevention of severe hypoglycemia . the patient might , in fact , need to reduce the insulin dose during the first trimester in order to prevent hypoglycemic episodes . several studies suggest that the use of insulin analogs instead of human insulin may lower the risk of severe hypoglycemia in women with diabetes [ 911 ] . in addition , real - time continuous glucose monitoring ( cgm ) with set alarms for low glucose values , might be useful for pregnant women with hypoglycemia unawareness.table 2.selected ada and acog recommendations .adaacogglycemic goals  pre - meal values of 3.35.5  mmol / l ( 6099  mg / dl ) . peak postprandial glucose of 5.57.2  mmol / l ( 100129  mg / dl ) .   bedtime and overnight glucose of 3.35.5  mmol / l ( 6099  mg / dl ) . mean daily glucose of < 6.1  mmol / l ( < 110  mg / dl ) and hba1c < 6.0%.  fasting glucose level of < 5.3  mmol / l ( < 95  mg / dl ) .   pre - meal values of < 5.5  mmol / l ( < 100  mg / dl ) .   1-h postprandial levels < 7.8  mmol / l ( < 140  mg / dl ) , and 2-h postprandial values of < 6.7  mmol / l ( < 120  mg / dl ) .   during the night , glucose levels should not decrease to < 3.3  mmol / l ( < 60  mg / dl ) . mean capillary glucose levels should be maintained at an average of 5.5  mmol / l ( 100  mg / dl ) ; hba1c 6.0%.glucose monitoring  daily self - monitoring both before and after meals , at bedtime and occasionally at 2:00 am4:00 am . hba1c test at the initial visit during pregnancy , monthly tests until target levels < 6.0% are achieved , followed by testing every 23 months thereafter.  daily self - monitoring in the fasting state , before and 1 or 2  h after each meal and before bed . in selected patients , especially those on insulin pumps , glucose determinations at 2:00 am3:00 hba1c measurement provides an indication of glycemic control over the past 23 months and should be performed during each trimester.prevention of severe hypoglycemia  assess the presence of clinically diminished counter - regulatory responses to hypoglycemia and educate patients to minimize its occurrences . cgm may be a supplemental tool to self - monitoring for selected patients with t1d , especially those with hypoglycemia unawareness.  patients should be questioned to determine if they can recognize when their glucose levels decrease to < 3.3  mmol / l ( < 60  mg / dl ) . patients and their families should be taught how to respond quickly and appropriately to hypoglycemia . 
  selected ada and acog recommendations . for patients with t1d , the therapeutic insulin dose is adjusted to the patient s glucose profile . daily monitoring is essential for proper insulin dosing , as insulin requirements vary during pregnancy . ada and acog recommend self - monitoring several times throughout the day and occasionally at night in order to detect nocturnal hypoglycemia ( table 2 ) . ada and acog also recommend maintaining mean daily glucose levels between 5.2 and 6.1  mmol / l ( 95110  mg / dl ) and hba1c < 6.0% , with specific goals for preprandial , postprandial and bedtime glucose . the goal during labor is to avoid maternal hyperglycemia in order to prevent subsequent neonatal hypoglycemia ( by maintaining blood glucose levels < 6.1  mmol / l [ < 110  mg / dl ] , as assessed by hourly blood glucose readings ) . currently , the treatment of pregnant women with t1d is influenced by the fact that patients are better informed about the disease . a higher percentage of pregnancies are planned , providing an opportunity for adequate preparation of the patient in anticipation of potential complications from t1d . glucose levels are controlled through the administration of long - acting ( basal ) insulin analogs and rapid - acting ( bolus ) insulin analogs . patients follow a multiple daily injection regimen ( mdi ) that involves four , and even up to seven , insulin injections administered before meals and pre - bedtime . compared with regular human insulin , bolus insulin analogs have a more rapid onset and a shorter duration of action ( table 3 ) , resulting in a more effective reduction of postprandial hyperglycemia and avoidance of hypoglycemic events between meals .table 3.characteristics of insulin and insulin analogs .insulin or insulin analogonset of action ( minutes)time to peak concentration ( minutes)maximum duration of action ( hours)insulin  regular insulin306090120512  nph insulin601202404801020bolus insulin analogs  insulin lispro1015306034  insulin aspart1015405035  insulin glulisine10155535basal insulin analogs  insulin glargine60120none24  insulin detemir60120none2024adapted from trujillo ai two rapid - acting insulin analogs , lispro and aspart , are currently classified as pregnancy risk category b , based on reports demonstrating fetal , perinatal and maternal outcomes similar to regular human insulin [ 1315 ] . lispro and aspart are at least as effective as regular human insulin in achieving glucose control , as evident from hba1c levels . the main benefit of insulin analogs is the reduction of severe hypoglycemic events in pregnant t1d patients . glulisine is another rapid - acting insulin analog available for use in the general diabetic population . however , there are no controlled studies addressing its safety in pregnancy , and glulisine is not recommended for pregnant women with t1d . basal insulin is required for the maintenance of glycemic control between meals . until recently , neutral protamine hagedorn ( nph ) , an intermediate - acting insulin , was the only insulin approved for use as basal therapy in pregnant t1d patients and was considered as the standard of care for diabetes in pregnancy . however , nph use can be associated with a peak in concentration 48  h post - injection ( table 3 ) and high intrasubject variability that may lead to an increased risk of hypoglycemic events between meals and at night . in recent years , glargine and detemir have become the basal insulin analogs of choice in the general t1d population . glargine shows a relatively flat action profile with a near 24-h duration ( table 3 ) . glargine also shows lower intrasubject variability compared to nph , as measured by the coefficient of variation for the 24-h glucose infusion rate glargine used in the general population leads to glycemic control that is at least comparable to that of nph , but with significantly lower risk for hypoglycemia . while there are numerous reports on the off - label use of glargine in pregnant women , there are no randomized clinical trials assessing its safety during pregnancy . therefore , insulin glargine is currently classified as pregnancy risk category c and is not approved for use in pregnant women . detemir also shows a flatter action profile with a longer duration of action than nph , approaching 24  h at clinically relevant doses . these characteristics suggest that detemir has the potential to be an improvement over nph for the control of t1d . a significant advance in the care for pregnant women with t1d was marked in 2012 with the reclassification of detemir as pregnancy risk category b , based on results from a randomized , active - controlled study by mathiesen et al . . this study evaluated the efficacy and safety of detemir in 310 pregnant t1d patients , randomized 1:1 to receive either detemir or nph in a basal - bolus regimen with aspart . treatment was initiated up to 1 year before pregnancy ( 48% ) or at 8 to 12 weeks during pregnancy ( 52% ) . additional endpoints included maternal safety . in terms of efficacy , detemir demonstrated non - inferiority to nph with respect to the primary endpoint of the study . a significant number of women in both groups ( 41% in the detemir group ; 32% in the nph group ) reached the target of hba1c 6.0% at 24 and 36 weeks of gestation . interestingly , fasting plasma glucose was significantly lower in the detemir group at 24 and 36 weeks of gestation , especially in patients initiating treatment with detemir before pregnancy . the incidence of preeclampsia was slightly higher in the detemir group , but within expected rates for pregnancies complicated by diabetes . no significant differences in early fetal death or the health of the fetus and newborn were seen with detemir . insulin premixes have proven somewhat useful for the treatment of the general population with diabetes , especially patients who need simplified dosing regimens . however , premixes are not useful for the treatment of pregnant t1d patients , as premixed formulations can not provide the required dosing flexibility during the different periods of pregnancy . currently , the treatment of pregnant women with t1d is influenced by the fact that patients are better informed about the disease . a higher percentage of pregnancies are planned , providing an opportunity for adequate preparation of the patient in anticipation of potential complications from t1d . glucose levels are controlled through the administration of long - acting ( basal ) insulin analogs and rapid - acting ( bolus ) insulin analogs . patients follow a multiple daily injection regimen ( mdi ) that involves four , and even up to seven , insulin injections administered before meals and pre - bedtime . compared with regular human insulin , bolus insulin analogs have a more rapid onset and a shorter duration of action ( table 3 ) , resulting in a more effective reduction of postprandial hyperglycemia and avoidance of hypoglycemic events between meals .table 3.characteristics of insulin and insulin analogs .insulin or insulin analogonset of action ( minutes)time to peak concentration ( minutes)maximum duration of action ( hours)insulin  regular insulin306090120512  nph insulin601202404801020bolus insulin analogs  insulin lispro1015306034  insulin aspart1015405035  insulin glulisine10155535basal insulin analogs  insulin glargine60120none24  insulin detemir60120none2024adapted from trujillo ai two rapid - acting insulin analogs , lispro and aspart , are currently classified as pregnancy risk category b , based on reports demonstrating fetal , perinatal and maternal outcomes similar to regular human insulin [ 1315 ] . lispro and aspart are at least as effective as regular human insulin in achieving glucose control , as evident from hba1c levels . the main benefit of insulin analogs is the reduction of severe hypoglycemic events in pregnant t1d patients . glulisine is another rapid - acting insulin analog available for use in the general diabetic population . however , there are no controlled studies addressing its safety in pregnancy , and glulisine is not recommended for pregnant women with t1d . basal insulin is required for the maintenance of glycemic control between meals . until recently , neutral protamine hagedorn ( nph ) , an intermediate - acting insulin , was the only insulin approved for use as basal therapy in pregnant t1d patients and was considered as the standard of care for diabetes in pregnancy . however , nph use can be associated with a peak in concentration 48  h post - injection ( table 3 ) and high intrasubject variability that may lead to an increased risk of hypoglycemic events between meals and at night . in recent years , glargine and detemir have become the basal insulin analogs of choice in the general t1d population . glargine shows a relatively flat action profile with a near 24-h duration ( table 3 ) . glargine also shows lower intrasubject variability compared to nph , as measured by the coefficient of variation for the 24-h glucose infusion rate glargine used in the general population leads to glycemic control that is at least comparable to that of nph , but with significantly lower risk for hypoglycemia . while there are numerous reports on the off - label use of glargine in pregnant women , there are no randomized clinical trials assessing its safety during pregnancy . therefore , insulin glargine is currently classified as pregnancy risk category c and is not approved for use in pregnant women . detemir also shows a flatter action profile with a longer duration of action than nph , approaching 24  h at clinically relevant doses . these characteristics suggest that detemir has the potential to be an improvement over nph for the control of t1d . a significant advance in the care for pregnant women with t1d was marked in 2012 with the reclassification of detemir as pregnancy risk category b , based on results from a randomized , active - controlled study by mathiesen et al . . this study evaluated the efficacy and safety of detemir in 310 pregnant t1d patients , randomized 1:1 to receive either detemir or nph in a basal - bolus regimen with aspart . treatment was initiated up to 1 year before pregnancy ( 48% ) or at 8 to 12 weeks during pregnancy ( 52% ) . additional endpoints included maternal safety . in terms of efficacy , detemir demonstrated non - inferiority to nph with respect to the primary endpoint of the study . a significant number of women in both groups ( 41% in the detemir group ; 32% in the nph group ) reached the target of hba1c 6.0% at 24 and 36 weeks of gestation . interestingly , fasting plasma glucose was significantly lower in the detemir group at 24 and 36 weeks of gestation , especially in patients initiating treatment with detemir before pregnancy . the incidence of preeclampsia was slightly higher in the detemir group , but within expected rates for pregnancies complicated by diabetes . no significant differences in early fetal death or the health of the fetus and newborn were seen with detemir . insulin premixes have proven somewhat useful for the treatment of the general population with diabetes , especially patients who need simplified dosing regimens . however , premixes are not useful for the treatment of pregnant t1d patients , as premixed formulations can not provide the required dosing flexibility during the different periods of pregnancy . accurate determination of blood glucose levels is important for the proper control of diabetes . until recently , this was achieved solely by the self - monitoring of capillary blood glucose using glucose meters . the development of continuous glucose monitoring ( cgm ) devices represents an advance that can provide real - time measurements and warnings when patients face hypoglycemia . several studies have examined the benefits of cgm for the general population , but only a few studies have been performed in pregnant women with t1d . a study by yogev et al . showed that cgm use during pregnancy can detect hyperglycemic and nocturnal hypoglycemic events that might have gone unnoticed with intermittent blood glucose monitoring . a small , randomized trial performed by murphy et al . showed that cgm improved glycemic control in women with t1d and t2d , led to lower birth weight and reduced risk of macrosomia . based on these results , the american association of clinical endocrinologists ( aace ) recommended the use of cgm for all pregnant patients with t1d . a recent randomized trial investigated the intermittent use of real - time cgm during pregnancy ( study arm ) in addition to self - monitored plasma glucose levels seven times daily ( control arm ) . hba1c , self - monitored plasma glucose , severe hypoglycemia events and prevalence of large - for - gestational - age infants for women using cgm were comparable to controls . these results suggest that the intermittent use of cgm in pregnant patients with well - controlled diabetes does not further improve disease management and pregnancy outcomes . additional large controlled studies examining maternal and neonatal outcomes with cgm use are still needed to confirm its benefit . patients can choose between mdi using a syringe or insulin pen and continuous subcutaneous insulin infusion ( csii ) via an insulin pump . several observational studies have attempted to evaluate the effectiveness of insulin pumps versus mdi in pregnant women with t1d . in 2012 , the agency for healthcare research and quality ( ahrq ) published a systematic review summarizing the results of these studies . the ahrq found that hba1c values improved with either mdi or csii and there was no statistically significant difference in outcomes between the two delivery methods . because no randomized controlled trials had been performed , the strength of evidence was insufficient to show statistically significant differences in any other maternal or fetal outcomes ; therefore , the risk of bias was high . a newer , retrospective , observational study by wender - ozegowska et al . , confirmed a reduction in hba1c to similar levels with both csii and mdi use during pregnancy , although there were fewer hypoglycemic and hyperglycemic episodes in the csii group . insulin pump utilization is high ( about 40% ) in the general t1d us population due to improvement in the quality of life and observed decrease in hba1c . further studies focused on pregnant women with t1d are necessary to confirm any superiority of csii use . csii insulin delivery has drawbacks , such as higher cost of the pump and pump supplies , difficulty of use requiring the patient to be motivated and compliant and willingness to test glucose multiple times daily , that might limit its usefulness in pregnant t1d patients . in addition , there is a risk of hypoglycemia or even dka in case of a pump malfunction or infection at the infusion site . sensor - augmented pump ( sap ) therapy ( combinations of cgm and csii ) might improve the treatment of t1d patients even further . use of open - loop sap ( patient reads the cgm values and manually adjusts the pump ) in non - pregnant patients with inadequately controlled t1d results in a significant improvement of hba1c levels . the use of sap in pregnant women has been tested only on a small scale and did not show a significant benefit , except during the first trimester . however , the study was too small to be adequately powered . closed - loop sap therapy uses a control algorithm to guide insulin delivery based on real - time cgm measurements . closed - loop systems could be of great benefit to pregnant women with t1d as the algorithm should , in theory , be capable of maintaining optimal glucose levels . t1d in pregnancy is a high - risk clinical situation associated with significant chances of complications for the mother and the fetus . however , clinical practice and research have shown that pregnancy planning , preconception counseling and maintaining optimal glucose levels have a positive effect on pregnancy outcomes . the main goal in caring for the pregnant patient with t1d should be achieving near - normal blood glucose levels while minimizing the risk of hypoglycemia . the development of insulin analogs with improved safety and efficacy profiles has facilitated the achievement of normoglycemia . evidence supports the use of the bolus insulins , lispro and aspart , as the mealtime component of mdi or as used in csii . the recent reclassification of detemir to pregnancy risk category b provides pregnant t1d women with a basal insulin analog , further expanding treatment options for this patient population . evidence supports the use of insulin detemir , or nph , as the basal component of an mdi regimen . women with t1d should attend pre - pregnancy services and antenatal clinics led by professionals with endocrine and obstetrical expertise , in order to maximize the likelihood of positive pregnancy outcomes . the objective is to optimize glycemic control prior to pregnancy ( hba1c < 6.5% ) , to start folic acid supplementation ( recommended 4  mg daily ) , to alter medications unsuitable for pregnancy and to ensure that medical issues are addressed before conception and during pregnancy .
pregnancies affected by type 1 diabetes ( t1d ) carry a major risk for poor fetal , neonatal and maternal outcomes . 
 achieving normoglycemia while minimizing the risk of hypoglycemia is a major goal in the management of t1d as this can greatly reduce the risk of complications . 
 however , maintaining optimal glucose levels is challenging because insulin requirements are not uniform throughout the course of the pregnancy . over the past decade 
 , there has been significant improvement in the methods for glucose monitoring and insulin administration , accompanied by an increase in the number of treatment options available to pregnant patients with t1d . through study of the scientific literature and accumulated evidence , we review advances in the management of t1d in pregnancy and offer advice on how to achieve optimal care for the patient .