Obstetric Outcome with Low Molecular Weight Heparin Therapy during
J Donnelly, J Byrne, K Murphy, F McAuliffe
Department of Obstetrics and Gynaecology, National Maternity Hospital, Holles St, Dublin 2
This was a prospective study of women attending a combined haematology/obstetric antenatal clinic in the National
Maternity Hospital (2002-2008). Obstetric outcome in mothers treated with low molecular weight heparin (LMWH) was
compared to the general obstetric population of 2006. There were 133 pregnancies in 105 women. 85 (63.9%) received
prophylactic LMWH and 38 (28.6%) received therapeutic LMWH in pregnancy. 10 (7.5%) received postpartum prophylaxis
only. The perinatal mortality rate was 7.6/1000 births. 14 (11.3%) women delivered preterm which is significantly
higher than the hospital population rate (5.7%, p<0.05). Despite significantly higher labour induction rates (50% vs
29.2% p<0.01), there was no difference in CS rates compared to the general hospital population (15.4% vs 18.9%, NS).
If carefully managed, these high-risk women can achieve similar vaginal delivery rates as the general obstetric
Venous thromboembolism remains the leading cause of morbidity and mortality amongst pregnant women in developed world.
Effective primary prevention and acute management is therefore vital to reduce morbidity and mortality. Over the last
15 years management of VTE in pregnancy has been revolutionized with the introduction of low molecular weight heparin
(LMWH) as a treatment option in pregnancy. LMWH has replaced unfractionated heparin (UFH) as agent of choice for
prevention and treatment of VTE in pregnancy. The efficacy and safety of LMWHs have been demonstrated by a number of
Obstetricians and Gynaecologists and the American Academy of Chest Physicians.
unlicensed for use in pregnancy.
1,2 Their conclusions have been endorsed by international guidelines, including the Royal College of
3-5 Despite this, LMWH still remains
Compared to unfractionated heparin, LMWH has many advantages; the pharmacokinetics of LMWHs are stable and predictable
with increased bioavailability and significantly longer half lives compared to unfractionated heparin. As a result,
LMWHs produce more predictable anticoagulant responses allowing less frequent, fixed or weight based dosing without
the need for regular laboratory monitoring. Subcutaneous administration allows for ease of use. LMWHs demonstrate less
binding to platelet factor
bleeding, as severe obstetric haemorrhage remains a leading cause of severe obstetric morbidity.
4, substantially reducing the risk of heparin induced thrombocytopenia (HIT) and osteoporotic
1,6 In the obstetric setting, one of the main advantages of LMWHs over UFH is the potential reduced risk of
Much of the literature to date has been focused on the essential objective of establishing the safety to fetus and
mother of LMWH. There is less information available on the effect of LMWH on labour outcomes and complications. High
risk pregnancy status is automatically conferred to women who are prescribed LMWH. It is reassuring to note that there
does not appear to be an increased risk of massive obstetric haemorrhage (>1,500mls), compared to women managed
with most studies showng prematurity to be iatrogenic rather than spontaneous preterm delivery.
suggested an association between LMWH and shortened labour length at term without increased operative intervention in
women prescribed prophylactic LMWH.
controversial, with a wealth of literature both supporting and refuting its use.
outcome in mothers treated with low molecular weight heparin (LMWH) during pregnancy and to compare their obstetric
outcome with the general obstetric population.
7 Prematurity has been postulated as a possible complication of LMWH, but the evidence for this is weak,
8 Recent work has
9,10 The use of LMWH in pregnancy for reasons other than prevention of VTE is
11 Our aim was to observe the obstetric
The National Maternity Hospital is one of three tertiary level units serving the city of Dublin and its surrounding
areas. It has an annual delivery rate of approximately 9200. All women who require ongoing therapeutic or prophylactic
treatment with low molecular weight heparin during pregnancy attend a dedicated multidisciplinary clinic staffed by an
obstetrician, haematologist and midwives trained in teaching administration of LMWH. Delivery of antenatal care for
these high-risk women in a multidisciplinary clinic is a cornerstone of their management.
Women attending the combined haematology ??? obstetric antenatal clinic are entered prospectively into a database.
Cases receiving LMWH were identified by reviewing the database into which the name, diagnosis and date of delivery of
all women attending the high-risk clinic are entered. To ensure completeness of data, additional information on
patients was obtained from chart review and extraction of information from the electronic Patient Administration
System (PAS). Indications for treatment with LMWH included a history of venous thromboembolism (VTE) in a current or
previous pregnancy; cardiac valve replacement; the presence of thrombophilia (including factor V Leiden homozygote and
heterozygote, antithrombin deficiency, anti-phospholipid syndrome); recurrent miscarriage or previous intrauterine
death. The prophylactic and therapeutic dosages were calculated by maternal weight. Tinzaparin was administered at a
dose of 75IU / Kg for prophylaxis and at 175 IU/Kg for treatment. Enoxparin was administered depending on maternal
weight as per RCOG guidelines 2009.
anti Xa levels. The decision to use one LMWH over the other was a clinical decision on the part of the treating
4 For women receiving therapeutic LMWH, dosage adjustments were made on the basis of
Data was entered into a database for analysis and included age, parity, gestation at delivery, indication for
induction/delivery, mode of delivery. For comparison of obstetric outcomes, data from the general hospital population
was obtained from the National Maternity Hospital Annual Clinical Report, 2006.
Chi-square and Student t test were used for univariable two-group comparisons. Spearman correlations were used to
evaluate the association between continuous measures. Statistical computations were performed using SPSS (version 12)
software. Two-tailed p values less than 0.05 were judged statistically significant.
Low molecular weight heparin use was identified in 133 pregnancies in 105 women during the period 2004 to 2008. Fifty
eight women were nulliparous (43.6%) and 75 were multiparous (56.4%). Eighty five (63.9%) women received prophylactic
LMWH and 38 (28.6%) received therapeutic LMWH in pregnancy. Ten (7.5%) received postpartum prophylaxis only so these
women were not included in the obstetric analysis. Tinzaparin was administered in 98 cases and enoxaparin was
administered in 38 cases. The indications for treatment with LMWH included venous thromboembolism in current or
previous pregnancy, and the other indications and reasons for thromborprophylaxis are shown in Table 1.
Obstetric Outcome with Low Molecular Weight Heparin Therapy during Pregnancy1
LMWH= low molecular weight heparin, DVT= deep vein thrombosis, PE= pulmonary embolus,
FVL= factor V Leiden, VTE=venous thromboembolism, IUD= intrauterine death, CVA= cerebrovascular accident, AT=
Two women had early second trimester losses. One of these women was on prophylactic LMWH as she had a history of DVT
in the past. The other woman was on therapeutic LMWH. She had a history of antitphospholipid syndrome with three
previous midtrimester losses and renal impairment. One woman had a stillbirth at 25 weeks, therefore the perinatal
mortality rate was 7.6/1000 births. She had a diagnosis of antiphospholipid syndrome and was receiving prophylactic
LMWH. One woman on prophylactic LMWH had an abruption at 36 weeks resulting in a live birth. No congenital defects
There was no significant difference in age (30.4, 31.7 years; p=0.64) , spontaneous vaginal delivery rates (65.9%,
63.2%; p=0.67), emergency Caesarean section (CS) rates (8.2%, 7.9%; p=0.73), admission to neonatal intensive care unit
(8.2%, 5.3%; p=0.43), epidural usage (28.2%, 18.4%; p=0.17) or mean estimated blood loss (359ml, 361mls; p=0.86)
between women taking prophylactic or therapeutic LMWH. Details of this are shown in Table 2. There was no massive
obstetric haemorrhage of greater than 1500mls recorded immediately post partum.
Fourteen (11.3%) women who were receiving LMWH delivered preterm (< 37 weeks) which is significantly higher than the
hospital population rate of 5.7% (p<0.05). Nine of the premature deliveries were as a result of spontaneous preterm
labour. Seven of these were cephalic spontaneous vaginal deliveries (range 25-36 weeks gestation), one was a
spontaneous vaginal breech delivery at 33 weeks, one was a forceps delivery at 36 weeks gestation. One woman was
induced at 36 weeks gestation, 3 were elective caesarean sections between 34 to 36 weeks gestation and 1 was a planned
emergency caesarean section at 36 weeks gestation.
SVD= spontaneous vaginal delivery, CS= caesarean section, EBL= estimated blood loss, NICU= neonatal intensive care
Overall the CS rate in all women receiving LMWH was 15.4% (19/123) which was similar to that of the entire general
obstetric population which had a rate of 18.9% (1508/7985)(p=0.3). The overall CS rate in nulliparous women at any
gestation who received LMWH was 16% (8/50). This was not significantly different to the general nulliparous obstetric
population who had a 21.4% CS rate (765/3577)(p=0.48). There was a significantly higher rate (p<0.01) of induction in
single cephalic nulliparas e37 weeks gestation who received LMWH (50.0%22/44) compared to the single cephalic
nulliparas e37 weeks gestation in the general obstetric population (924/3159, 29.2%), (p< 0.05). Interestingly,
despite the significantly higher induction rate in women on LMWH, there was no difference in the CS rate in induced
single cephalic nulliparas e37 weeks on LMWH (22.7% 5/22%) and induced nulliparas in the general obstetric population
(272/924, 29.4%) (p=0.17).
Obstetric Outcome with Low Molecular Weight Heparin Therapy during Pregnancy2
LMWH=low molecular weight heparin
Women receiving low molecular weight heparin experienced a higher preterm delivery rate than that of the general
obstetric population. The majority of these deliveries were as a result of spontaneous preterm labour rather than
iatrogenic deliveries. This was a surprising finding. Due to the high-risk nature of the population, prematurity
relating to iatrogenic intervention would perhaps be expected. While thrombophilia has been associated with recurrent
miscarriage and late pregnancy loss, it has not been associated with prematurity, thus ruling this out as a potential
However, this elevation was non-significant.
11 Previous work has reported an increased risk of preterm birth in women receiving LMWH during pregnancy.
The overall CS rate in nulliparas was similar to the general obstetric population. Heparin has been shown to have
immunomodulatory properties which may have an effect on modifying inflammatory pathways involved in the onset or
progress of labour.
cervical remodelling in vitro
spontaneous preterm labour and a relatively low CS rate in induced nulliparas. Further work in this area is warranted.
In conclusion LMWH appears to be safe in pregnancy. If carefully managed during pregnancy and labour, our cohort shows
that high risk women receiving LMWH can achieve similar high vaginal delivery rate as the general obstetric
13 Eckman-Ordeberg et al have demonstrated that LMWH stimulates myometrial contractility and
14. This may be a potential explanation for our findings of increased rates of
Correspondence: J Donnelly
Department of Obstetrics and Gynaecology, Rotunda Hospital, Parnell Square, Dublin 1
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Obstetric Outcome with Low Molecular Weight Heparin Therapy during Pregnancy3