A Systematic Review: The use of desmopressin for treatment and prophylaxis of bleeding disorders in pregnancy

Authors


Rezan A Kadir, MD, MRCOG, FRCS(Ed), Consultant Obstetrician and Gynaecologist, The Royal Free Hospital, London NW3 2QG, UK.
Tel.: +44 2077940500; fax: +44 2074726759;
e-mail: rezan.abdul-kadir@.nhs.net

Abstract

Summary.  Desmopressin (DDAVP) is commonly used for treatment and prevention of bleeding complications in patients with bleeding disorders including haemophilia A, von Willebrand’s disease (VWD) and other less common disorders. This article reviews the current evidence for the use of DDAVP in pregnancy to clarify its efficacy and safety with regard to maternal and foetal outcome. A search of the literature found 30 studies that reported DDAVP use in pregnancy for prophylaxis or treatment of bleeding complications with 216 pregnancies reported in total. The most common indication was prophylaxis for prevention of bleeding during pregnancy and postpartum haemorrhage. DDAVP was used successfully in the first and early second trimester for bleeding prophylaxis in 50 pregnancies. No postpartum bleeding complications were reported in 167 out of 172 pregnancies when DDAVP was used for peripartum haemostatic cover. Twenty-nine studies reported no significant adverse events as a result of treatment with DDAVP. One case of water intoxication seizure and one case of premature labour following the use of DDAVP was reported in a single study. Other maternal side effects included facial flushing and headache and were reported by one study. These side effects were generally well tolerated by patients. There were no other significant adverse events reported in any of the studies as a result of DDAVP use. Foetal outcome was recorded in ten studies with no adverse foetal outcomes. In conclusion, this review shows that DDAVP in selected cases is effective in reducing bleeding complications associated with pregnancy and childbirth with a good safety record. Further research is needed to confirm these findings as they are based on the currently available evidence from small studies and case series only.

Introduction

Desmopressin, DDAVP (1-deamino-8-D-arginine vasopressin) is a synthetic analogue of the antidiuretic pituitary hormone, arginine vasopressin. It is established as one of the key therapies for prevention and treatment of bleeding in patients with bleeding disorders such as mild haemophilia A and VWD [1]. The main pharmacological action of DDAVP is a type 2 vasopressin receptor agonist. In vivo, it causes increased factor VIII (FVIII) levels and stimulates the release of von Willebrand factor (VWF) from endothelial cells. It has little activity at type 1 vasopressin receptors found in the uterus and blood vessels [2]. Its use in pregnancy has been and remains controversial. Many Haematologists and Obstetricians remain reluctant to use it in pregnant women due to potential risks of maternal and foetal hyponatraemia as well as the theoretical risk of uterine contraction and preterm labour via its effect on smooth muscle V1 receptors and the risk of intrauterine growth retardation because of its vasopressor effect. DDAVP has been used during pregnancy successfully to prevent and treat bleeding complications in women with bleeding disorders such as type 1 VWD, carriers of haemophilia A and platelet function defects in a growing number of small case series and case reports [3–5].

Desmopressin was first used during pregnancy for the treatment of diabetes insipidus for its antidiuretic effect. A review of literature by Ray (1998) reported 53 cases in 20 publications and showed safe treatment of diabetes insipidus in pregnancy with no maternal or neonatal adverse outcomes [6]. However, the average daily dose of DDAVP used in these cases was 29 μg intranasally (range 7.5–100 μg), which is significantly smaller than the doses of DDAVP needed for haemostatic purposes.

This systematic review aims to report the available clinical evidence associated with the use of DDAVP for prophylaxis and treatment of haemorrhage during pregnancy, delivery and postpartum to help provide a more informed view about the safety of DDAVP in this setting.

Methods

Identification of literature

A search was conducted using the electronic databases Medline (September 1975–2010), Scopus (September 1975–2010) and Cochrane library (2004–2010). The combination of medical subject headings (MeSH) used to search each databases were ‘Desmopressin’ or ‘DDAVP’ and ‘Pregnancy’ or ‘Gestation’ or ‘Delivery’. The references of the retrieved articles were also hand-searched for additional citations not identified by the initial electronic search. ISI web of Knowledge was used to extract additional citations.

Inclusion and exclusion criteria

Eligible studies provided data on the use of DDAVP during pregnancy, delivery or the puerperum as a treatment for active bleeding or bleeding prophylaxis in patients with known bleeding disorders. Studies were excluded if DDAVP was used for treatment of diabetes insipidus or in nonpregnant women.

Data extraction

From the studies that met the selection criteria, the following information was extracted and tabulated: the author and year of publication, underlying bleeding disorder, indication and stage of pregnancy at which treatment with DDAVP was initiated, dose of DDAVP and any other treatment given, clinical and relevant laboratory haemostatic values, mode of delivery, maternal side effects and neonatal outcome. Two reviewers (IS and PP) independently extracted data from the included articles. Evaluation of eligibility for inclusion of the extracted articles was performed by a third reviewer (RK).

Results

Using the search criteria above, 30 studies were found eligible for inclusion in this review. The main clinical characteristics of these are summarized in Tables 1–3. There were a total of 216 pregnancies included in these studies: eight prospective studies with a total of 111 pregnancies (Table 1) [7–14] and six retrospective studies with a total of 85 pregnancies (Table 2) [15–20]. The most common study design case report, which accounted for 16 of the studies and 20 of the total pregnancies (Table 3) [3,5,21–34].

Table 1.   Prospective studies reporting pregnancies using desmopressin for treatment of bleeding disorders.
ReferencesPregnancies using DDAVP/total pregnancies (n)Bleeding disorderIndication for DDAVPTreatment/doseMode of deliveryMaternal outcomeNeonatal outcome
  1. NVD, normal vaginal delivery; LSCS, lower segment Caesarean section; TOP, termination of pregnancy; NS, not specified CVS, chorionic villus sampling; PPH, post partum; i.v., intravenous; i.n., intranasal; Tx, transfusion; VWD, von Willebrand disease; BSS, Bernard–Soulier syndrome; EDS, Ehlers–Danlos syndrome; HPS –Hermansky–Pudlak syndrome; SROM, spontaneous rupture of membranes; FFP, fresh frozen plasma.

Bjoring et al. [7]7/19VWDSecond stage of labour – bleeding prophylaxisDesmopressin 0.3 mg kg−1 i.v. Oxytocin 20 U i.v.NSPPH in one patient after desmopressin prophylaxis. no side effects reportedNo adverse foetal effects
Gojnic et al. [11]32/32VWDBleeding prophylaxis – 36 weeks gestation until 4 weeks postpartumDesmopressin 300 μg i.n. Cryoprecipitate FFP Hemate P (VIII concentrate)NVD × 26 LSCS × 6No abnormal bleeding, no side effects reportedNo adverse foetal effects
Mannucci et al. [8]32/32VWD × 5 haemophilia A carrier × 27CVS × 20 amniocentesis × 12Desmopressin 0.3 μg kg−1 i.v.NSNo abnormal bleeding, Mild facial flushing and headache20 healthy live births 12 elective TOP
Castaman et al. [12]5/6VWDDelivery – bleeding prophylaxisDesmopressin 0.3 μg kg−1 i.v. immediately after delivery and 24 h postpartumNVD × 5 with desmopressin, LSCS × 1 without desmopressinNo abnormal bleeding, no side effects reportedNS
Chediak et al. [10]2/8VWDPatient 1 – postpartum bleeding prophylaxis
Patient 2 – test dose
Patient 1 – Cryoprecipitate i.v. desmopressin 0.3 μg kg−1 × 3 doses
Patient 2 – Desmopressin 0.4 μg kg−1 i.v.
Patient 1 – LSCS
Patient 2 – NS
Patient 1 – hyponatraemia and water intoxication seizure
Patient 2 – premature abour
NS
Schulman et al. [13]1/1Functional platelet disorderBleeding prophylaxis post deliveryDesmopressin 0.2 μg kg−1 i.v.NSImproved bleeding indicies, no side effects reported in pregnant patientNS
Castaman et al. [14]31/31VWDBleeding prophylaxis – Desmopressin given immediately after deliveryDesmopressin 0.3 μg kg−1 i.v.NVD × 31No abnormal bleeding, no side effects reportedNS
Conti et al. [9]1/5VWDSecondary PPH treatment for one patient following NVDFour unit red cell Tx, desmopressin 0.4 μg kg−1 i.v. MethylergonovineNVD × 2 LSCS × 3Bleeding stopped post desmopressin and Tx. No side effects reportedNS
Table 2.   Retrospective studies reporting pregnancies using desmopressin for treatment of bleeding disorders.
ReferencesPregnancies using DDAVP/total pregnancies (n)Bleeding disorderIndication for DDAVPTreatment/doseMode of deliveryMaternal outcomeNeonatal outcome
  1. NVD, normal vaginal delivery; LSCS, lower segment Caesarean section; TOP, termination of pregnancy; NS, not specified CVS, chorionic villus sampling; PPH, post partum; i.v., intravenous; i.n., intranasal; Tx, transfusion; VWD, von Willebrand’s disease ; BSS, Bernard–Soulier syndrome; EDS, Ehlers–Danlos syndrome; HPS, Hermansky–Pudlak syndrome; SROM, spontaneous rupture of membranes; FFP, fresh frozen plasma.

Sanchez-Luceros [15]75/75VWDRetroplacental haematoma × 1, prior to cervical cerclage × 4, prior to delivery × 75Desmopressin 0.3 μg kg−1 i.v.NVD × 30 LSCS × 45Haematoma resolution. No abnormal bleeding during delivery or postpartum, no side effects reported. No hyponatraemia or thrombotic eventsNo neonatal bleeding events, no prematurity. Mean birth weight 3.3 kg (range 2.2–4.5 kg)
Ramsahoye et al. [19]1/24VWDBleeding prophylaxis, Desmopressin given immediately after deliveryDesmopressin 0.4 μg kg−1 i.v. at delivery, and at 24 and 82 h post deliveryLSCSNo abnormal bleeding for patient given desmopressin prophylaxis no side effects reportedNS
Kadir et al. [17]4/82Haemophilia A carrierBleeding prophylaxis postpartum × 3, Treatment of primary PPH × 1Desmopressin 0.3 μg kg−1 i.v.NS × 3 NVD × 1No abnormal bleeding in three patients given prophylactic treatment, No side effects reported.NS
Ito et al. [18]1/14VWDTermination of pregnancy, bleeding prophylaxisDesmopressin dose not specifiedN/ANo abnormal bleeding, no side effects reportedN/A
Kadir et al. [16]1/112VWD FXI deficiencyTreatment of primary PPH in VWD patientDesmopressin dose not specifiedNVDNo side effects reportedNS
Castaman et al. [20]3/6VWDBleeding prophylaxis post deliveryDesmopressin (i.v.) dose not specifiedNVD × 3No abnormal bleeding, no side effects reportedNS
Table 3.   Case reports of pregnancies using Desmopressin for treatment of bleeding disorders.
Author (year)Pregnancies using DDAVP/total pregnancies (n)Bleeding disorderIndication for DDAVPTreatment/doseMode of deliveryMaternal outcomeNeonatal outcome
  1. NVD, normal vaginal delivery; LSCS, lower segment Caesarean section; TOP, termination of pregnancy; NS, not specified CVS, chorionic villus sampling; PPH, post partum; i.v., intravenous; i.n., intranasal; Tx, transfusion; VWD, von Willebrand’s disease; BSS, Bernard–Soulier syndrome; EDS, Ehlers–Danlos syndrome; HPS, Hermansky–Pudlak syndrome; SROM, spontaneous rupture of membranes; FFP, fresh frozen plasma.

Heslop et al. [25]1/1BSSSuperficial wound haematoma. Secondary PPH one month postpartumDesmopressin 0.4 μg kg−1 × 3 platelet Tx oxytocin tranexamic acidLSCSCord prolapse at 35 wks, Emergency LSCS, satisfactory wound healing, PPH resolved, no side effects reportedTwin pregnancy, Twin 1 intubated after delivery for short period. Both twins recover uneventfully
Weinbaum et al. [21]1/1EDSBleeding prophylaxis prior to LSCSDesmopressin 12 μg i.v.LSCSBlood loss 500–750 mL, Subcutaneous haematoma, no side effects reportedNo adverse foetal effects
Naorose et al. [26]2/2Acquired FVIII inhibitorSoft tissue haemorrhage postpartumDesmopressin dose not specifiedNSClinical improvement, no side effects reportedNS
Peaceman et al. [27]1/1BSSSecondary PPHDesmopressin 0.3 μg kg−1 i.v. Platelet Tx ImmunoglobulinLSCSBleeding decreased, no side effects reportedNS
Miki et al. [33]1/1VWDBleeding prophylaxis at induction of labourDesmopressin dose not specifiedNVDNo abnormal bleeding, no side effects reportedNS
Kleiman et al. [3]1/1Platelet disorderBleeding prophylaxis – Desmopressin initiated at full dilatationDesmopressin (i.v.) dose not specifiedNVDNo abnormal bleeding, no side effects reportedApgar 9 and 9. No adverse foetal outcome
Rochelson et al. [32]1/1EDSBleeding prophylaxis at delivery and five days post partumDesmopressin 20 μg (i.v.)NVDNo abnormal bleeding, Bleeding time reduced. Increased frequency of contractionsNS
Greinacher et al. [29]1/1BSSBleeding prophylaxis prior to emergency LSCS for retroplacental haemorrhage. Desmopressin used at delivery and 24 h postpartumDesmopressin 0.4 μg kg−1 i.v.Emergency LSCSNo abnormal bleeding, Bleeding time reduced. No side effects reportedNo adverse foetal effects
Fragneto et al. [30]1/1Pre-eclampsia induced platelet dysfunctionBleeding prophylaxis to cover application of epidural anaesthesiaDesmopressin 0.3 μg kg−1 i.v.NVDNo abnormal bleeding, Bleeding time reduced. Uncomplicated epidural. No side effects reportedNo adverse foetal effects
Charles et al. [24]2/2Inherited storage pool diseaseBleeding prophylaxis – prior to delivery × 1 Prior to TOP and ERCP × 1Desmopressin 0.3 μg kg−1 i.v.NVD TOPNo abnormal bleeding, no side effects reportedNS
Kailash et al. [31]2/2VWDBleeding prophylaxis and use of spinal anaesthesiaDesmopressin 300 μg nasally in first pregnancy, 0.3 μg kg−1 i.v. in second pregnancyElective LSCS700 mL blood loss. No side effects reportedNo adverse foetal effects
Zatik et al. [22]2/2HPSBleeding prophylaxis – Desmopressin given at induction of labour in first pregnancy, at SROM in second pregnancyDesmopressin 0.3 μg kg−1 i.v. Platelet Tx and red cell TXEmergency LSCS in first pregnancy, elective LSCS in second pregnancy1600 mL primary postpartum haemorrhage at first delivery, no abnormal bleeding at delivery of second pregnancyNo adverse foetal effects
Poddar et al. [34]1/1HPSPostpartum bleeding prophylaxis and removal of epidural catheterDesmopressin 0.3 μg kg−1 i.v., red cell Tx, Gelofusine and vaginal packingNVDNo significant bleeding, uneventful removal of vaginal pack and epidural catheterNS
Porteous et al. [28]1/1Acquired FVIII inhibitorTreatment of primary postpartum haemorrhageDesmopressin 0.3 μg kg−1 × 2 i.v., red cell Tx, Vaginal packing, internal pudendal artery embolisationNVDNo improvement after desmopressin. No side effects reportedNS
Rahman et al. [5]1/1Platelet storage pool diseaseBleeding prophylaxis prior to induction of labourDesmopressin 0.3 μg kg−1 i.v., tranexamic acid, oxytocin, ergometrine, haemabate, misoprostol, Cryoprecipitate, red cell and platelet Tx, hysterectomyNVDMassive primary postpartum haemorrhage. Laparotomy and hysterectomy to stop bleeding. No side effects reported with DesmopressinNS
Beesley et al. [23]1/1HPSSecond stage of labour – bleeding prophylaxisDesmopressin 0.3 μg kg−1 i.v., red cell and platelet Tx, oxytocin, bimanual massageNVDPrimary postpartum haemorrhage. No side effects reportedNS

The most common bleeding disorder reported by these studies was VWD with 168 pregnancies followed by carriers of haemophilia A with 31 pregnancies reported. DDAVP was used in 12 pregnancies with disorders of platelet function including Bernard–Soulier syndrome (three pregnancies), Hermansky–Pudlak Syndrome (four pregnancies), storage pool disorder (three pregnancies) and unspecified functional platelet disorders (two pregnancies). Other disorders with reported DDAVP use were acquired factor VIII inhibitors (three pregnancies) and Ehlers–Danlos syndrome (two pregnancies).

Dosing regimes for DDAVP were mostly based on patient weight with an intravenous infusion of 0.3 μg kg−1 DDAVP being the most commonly used (166 cases). Other intravenous dosing regimes were 0.4 μg kg−1 (five cases), 0.2 μg kg−1 (one case), 12 μg (one case) and 20 μg (one case). Intranasal DDAVP was used in two studies (33 cases) at a dose of 300 μg and in nine cases the dose of DDAVP was not recorded.

Antenatal use of DDAVP

Desmopressin was used during the first and early second trimester in 51 pregnancies. DDAVP was reported for prevention of bleeding prior to invasive procedures including chorionic villus sampling (20 cases), amniocentesis (12 cases), cervical cerclage (four cases) and termination of pregnancy (14 cases) [8,15,24]. All these procedures had successful outcomes without significant complication or bleeding. DDAVP was also used as treatment for bleeding complications in one case of first trimester retroplacental haematoma [15]. There were no reported neonatal complications reported in those pregnancies that were carried to term. Maternal side effects associated with DDAVP were recorded in one study and were generally mild and included facial flushing and headache [8].

Peripartum use of DDAVP

The most common indication for use of DDAVP was prevention of postpartum haemorrhage (PPH) in women with bleeding disorders. This accounted for 172 of the pregnancies in 21 of the studies. Of these 172 pregnancies that received DDAVP prophylaxis there were no significant bleeding complications in 167 deliveries. Adverse bleeding events were reported in five pregnancies – postpartum haemorrhage (four cases) and sub-cutaneous haematoma (one case). The underlying bleeding disorder for patients who developed bleeding complications despite prophylactic treatment with DDAVP were two cases of Hermansky–Pudlak Syndrome (HPS) and a single case each of storage pool disorder, Ehlers–Danlos syndrome (EDS) and VWD [5,7,21–23]. DDAVP was used as a treatment for established bleeding complications in six cases of postpartum haemorrhage and two cases of postpartum soft tissue haemorrhage [9,16,17,25–28]. Clinical improvement was seen in five of six cases of postpartum haemorrhage and in both cases of soft tissue haemorrhage that received DDAVP as part of their treatment. Other therapies were used in conjunction with DDAVP in 11 studies for both prophylaxis and treatment of bleeding complications associated with delivery. These additional therapies included oxytocin, cryoprecipitate, fresh frozen plasma, tranexamic acid, platelet transfusion and red cell transfusion. Two pregnancies that developed the most severe postpartum haemorrhage required internal pudendal artery embolization in one case and hysterectomy in the second case were in patients with acquired factor VIII inhibitor and storage pool disorder respectively [5,28].

Serious adverse maternal events were reported in one case study after use of DDAVP in the perinatal period. One patient with severe type 1 von Willebrand‘s disease was reported to have a seizure after receiving DDAVP infusions at a dose of 0.3 μg kg−1 every 18 h during the postpartum period. The indication was to prevent bleeding complications following an emergency Caesarean section. The patient developed a grand mal seizure secondary to severe hyponatraemia. A second patient with von Willebrand’s disease developed premature labour after a trial infusion of DDAVP at a dose of 0.4 μg kg−1 intended to establish response to DDAVP during the last month of pregnancy. Both complications were thought by the author of this article to be due to water intoxication as a result of treatment with DDAVP [10]. One further study recorded a mild increase in uterine contractility with relatively high dose of 20 μg DDAVP intravenously and was observed 30 min after discontinuation of an oxytocin infusion. There was no adverse effect on the pregnancy or delivery in this case [32].

In total there were 109 vaginal deliveries recorded and 62 Caesarean sections. The mode of delivery was not recorded in 31 of the pregnancies. Foetal outcomes were recorded in 10 studies and all recorded no adverse effects for the foetus after delivery [3,7,8,11,15,21,22,29–31]. One study of 75 pregnancies with maternal VWD specifically records no premature births, no neonatal bleeding complications and mean birth weight of 3.3 kg (range 2.2–4.5 kg) with the use of DDAVP. Indications for DDAVP in this study were prior to labour to prevent postpartum haemorrhage, to treat retroplacental haemorrhage and prior to cervical cerclage. There were no recorded maternal hyponatraemia or thromboembolic events in this study [15].

Discussion

This article reviews the currently available evidence for the use of DDAVP in pregnancy in women with bleeding disorders. Pregnancy and childbirth present significant management challenges to Obstetricians and Haematologists who need to ensure that the risk of bleeding complications are minimized and that effective treatments are initiated rapidly when they do occur. DDAVP is effective in selected cases and has the benefit of avoiding the risk of blood-borne viruses associated with blood products. A test dose is advised to establish a therapeutic effect in the patient and has been shown to be an effective prophylaxis or treatment option in VWD, haemophilia A and functional platelet disorders [35]. The main therapeutic action of DDAVP is to increase FVIII levels and to stimulate VWF release from endothelial cells. Optimal increase in FVIII and VWF can be achieved using a dose of 0.3 μg kg−1 DDAVP as an intravenous infusion [35]. The subcutaneous route has been shown to also been shown to be effective but peak levels are reached more slowly. A recent study comparing response to 15 μg subcutaneous DDAVP to the standard 0.3 μg kg−1 i.v. found comparable responses to the different doses at one hour for patients with mild VWD and haemophilia A [36]. Three hundred microgram intranasally may also be used and this has been shown to provide the equivalent improvement in haemostasis as 0.2 μg kg−1 i.v. DDAVP infusion with similar reproducibility as the intravenous dose [37,38]. Most studies included in this article reported use of an intravenous infusion of DDAVP with intranasal use only recorded in two studies [11,31].

Desmopressin has been used successfully in the first and early second trimesters for bleeding prophylaxis before invasive procedures in cases of VWD and haemophilia A carriers. Factor VIII and VWF levels increase throughout pregnancy in women with normal coagulation as well as in haemophilia A carriers and VWD patients. In the latter group, with low baseline VWF and FVIII levels, the increase becomes significant to improve haemostasis only after the second trimester. Thus, any invasive procedure such as prenatal diagnosis technique can be associated with a significant risk of bleeding [16]. There is evidence of safe use of DDAVP for first trimester bleeding prophylaxis for chorionic villus sampling, amniocentesis and termination of pregnancy in several studies [8,18,24]. Of the pregnancies in which DDAVP was used to cover these procedures, there were no adverse bleeding events in relation to the procedure and the pregnancies that were carried to term had no significant complication. In the pregnancies that had elective termination of pregnancy after prenatal genetic testing, DDAVP was also used during the procedure as prophylaxis with no reported complications and no excessive blood loss. It is difficult to draw conclusions regarding the efficacy of DDAVP from the articles reviewed herein as they include a heterogeneous group of bleeding disorders at different stages of pregnancy. Most patients in these studies were patients with type I VWD that are more likely to respond well to DDAVP than other types of VWD, which may overestimate the efficacy of DDAVP.

Concerns surrounding DDAVP use in pregnancy arise due to several reasons, but serious adverse maternal events after administration of DDAVP in this review were uncommon. One pregnancy was complicated by water intoxication seizure with DDAVP use in the postpartum period [10]. DDAVP acts via activating V2 receptors with very little activation of V1 receptors, which accounts for an antidiuretic effect with little pressor activity. This antidiuretic effect of DDAVP is not usually of clinical concern provided that the patient has normal renal function and appropriate fluid restriction [39]. In the nonpregnant patient to prevent water intoxication after treatment with DDAVP, a fluid restriction to 1 L for the next 24 h is recommended due to the prolonged antidiuretic effect of DDAVP [35]. It is possible that higher doses of DDAVP in addition to the oxytocin and intravenous fluid that are commonly used during labour, could increase the risk of hyponatraemia further. Therefore, care should be taken with fluid management when using DDAVP in pregnancy, particularly during labour or delivery and that DDAVP dosage is based on prepregnancy weight. If these factors are addressed then the risk of significant hyponatraemia can be minimized. There was no other evidence found for seizure activity resulting from DDAVP use in pregnancy in spite of many years of experience with the medication in pregnancy for treatment of bleeding disorders and diabetes insipidus. In the studies reviewed in this article, there were few reports of serum sodium measurements or blood pressure readings being recorded in the postpartum period. It is possible that these parameters may reveal a subclinical degree of fluid retention and resultant hyponatraemia in some patients given DDAVP during pregnancy. These parameters may help to assess those most at risk of hyponatraemia and help avoid complications as a result.

One patient in the last month of pregnancy had premature labour and delivery after a test dose was given to assess her response to DDAVP [10]. One other article was found reporting a mild increase of uterine contractility after administration of DDAVP and oxytocin. This increase in uterine activity was reported as mild and had no adverse effect on the pregnancy [32]. The British National Formulary also cautions that DDAVP can cause mild uterine contractions in the third trimester [40]. In this review, there were no other reported cases of increased uterine activity or premature labour. The effect of DDAVP on V1 receptors found in blood vessels and uterine smooth muscle is very small when compared to the naturally occurring vasopressin [41]. There were no reports of uterine hyperstimulation in the studies included in this review. Intrauterine growth retardation (IUGR) has also been a concern with use of DDAVP in pregnancy due to potential vasopressor effect and resultant reduced placenta blood flow. However, DDAVP has very weak vasopressor activity and is generally used for a very short duration during pregnancy to cover transient bleeding risks. Thus, it is unlikely to have a significant enough effect on medium or long-term placental blood flow to cause IUGR. There were no cases of IUGR in the population studied in this article. Observations of uterine blood flow and vascular tone show no change with intranasal DDAVP in women with intra-uterine-device-associated menorrhagia on Doppler ultrasound assessment [42]. The vasomotor side effects of DDAVP are usually mild and transient, but include mild tachycardia, headache and flushing [35]. The dose or route of DDAVP administration did not show any strong correlation with increased risk of complications or side effects. There was no evidence found to support an increased risk of pre-eclampsia or thromboembolic events as a result of treatment with DDAVP [6,15].

There are no robust data on the use of DDAVP with a breast-feeding infant but it is known that DDAVP is released in breast milk in very small quantities [43]. Coupled with negligible oral absorption, there is unlikely to be significant transfer of DDAVP to an infant from breast-feeding [44]. However, the manufacturer still recommends against the use of DDAVP during breast feeding [45].

The use of DDAVP in pregnancy with good safety profile echoes a previously published systematic review of intranasal DDAVP use in pregnant women with diabetes insipidus [6]. No structural abnormalities were observed in foetuses exposed to DDAVP during the first trimester. In vitro models of placentae do not show DDAVP crossing the placental barrier in detectable amounts, which also provides support for the safe use of DDAVP with regard to foetal outcome. No other adverse neonatal outcome has been attributable to DDAVP use [6,15].

In conclusion, there is a growing volume of data regarding the safe use of DDAVP in pregnancy. It appears to be a safe and effective measure for the prevention or treatment of bleeding episodes in pregnant women with various bleeding disorders. Safe use can be achieved by avoiding water overload and appropriate dosing of DDAVP. It is important that pregnant women with bleeding disorders are cared for by a multidisciplinary team of Obstetricians, Haematologists and Anaesthetists to optimize maternal and neonatal outcomes. An antenatal diagnosis of an underlying bleeding disorder allows for multidisciplinary planning and risk management of the pregnancy. Currently, the data available for DDAVP use in pregnancy are from a number of small trials and cases studies, so any conclusions drawn are from limited evidence which illustrates the need for further research in the role of DDAVP in the management of pregnancies complicated by bleeding disorders.

Disclosures

The authors stated that they had no interests which might be perceived as posting a conflict or bias.

Ancillary