ELSEVIER

European Journal of Obstetrics & Gynecology and Reproductive Biology 68 (1996) 53-58

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Anaemia in pregnancy

is the current definition meaningful?

Terence T. Lao*, Ting-Chung Pun

Department of Obstetrics and Gynaecology, The University of Hong Kong, Tsan Yuk and Queen Mary Hospitals, 30 Hospital Road Hong Kong, Hong Kong
Received 27 November 1995; revised 15 April 1996; accepted 8 May 1996

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Objective: To determine if the current definition of antenatal anaemia (haemoglobin < 10 g/dl) has any clinical significance. Study design: A retrospective study on all singleton deliveries over a 3-year period in two teaching hospitals under one university department was conducted by the extraction of data from a computer database. The major pregnancy complications and perinatal outcome were compared between mothers with and without anaemia and adjusted for parity. Results: The incidence of multiparity was significantly higher in the 817 anaemia patients compared to the 10 125 non-anaemia patients, but there was no difference in the incidence of other major antenatal complications, type of labour or mode of delivery, incidence of preterm delivery, or perinatal mortality or morbidity, after adjusting for parity. Among the anaemia patients, those with thalassaemia trait (54.8%) had a significantly higher incidence of gestational glucose intolerance but the incidences of other complications and the perinatal outcome were similar to the iron deficiency patients. Conclusion: Antenatal anaemia, defined as a maternal haemoglobin of < 10 g/dl, does not adversely affect pregnancy outcome. This raises the question of whether the diagnosis of anaemia should be redefined. Keywords: Antenatal anaemia; Iron deficiency; Thalassaemia trait; Pregnancy outcome

1. Introduction

Anaemia is considered the commonest medical disorder in pregnancy, the incidence in developed countries being around 5% [1]. Historically, it has been associated with adverse pregnancy outcome such as preterm birth, low birthweight and increased perinatal mortality [2-5]. However, the review of Hemminki and Starfield [6] had shown that iron supplementation had no significant impact on pregnancy outcome, which was affected mainly by other risk factors. Furthermore, there is increasing evidence from developed countries to indicate that a high haemoglobin may be as bad as, or even worse than, a low haemoglobin, for the incidence of low birthweight and perinatal mortality are increased with increased haemoglobin even in normal pregnancies [7-18]. From these reports, the pregnancy outcome was optimal when the haemoglobin level was between 9 and 13 g/dl [7-15, 18]. Since the normal cutoff for maternal
* Corresponding author. Tel.: +852 2589 2221; fax: +852 2517 3278.

haemoglobin level recommended by the World Health Organisation (WHO) is 11 g/all [19], below which the mother is considered anaemic, it is apparent that a significant proportion of the 'anaemic' mothers would also have optimal pregnancy outcome. This therefore calls into question the validity of the current WHO definition of the diagnosis of anaemia in pregnancy. In Tsan Yuk and Queen Mary Hospitals, we have been using the haemoglobin level of < 10 g/dl to diagnose antenatal anaemia [20], a level that is even lower than the WHO recommendation. Despite an overall incidence that is higher (9% vs. 5%) than that quoted [1], it did not appear to us that mothers with anaemia fared worse than those without. We have therefore conducted a retrospective study comparing the pregnancy complications and perinatal outcome in singleton pregnancies with and without antenatal anaemia managed over a 3-year period to determine whether the current practice of diagnosing antenatal anaemia using an arbitrary cut-off value has any clinical significance. Multifetal pregnancies were excluded from our study even though

0301-2115/96/$15.00 1996 Elsevier Science Ireland Ltd. All rights reserved PII S0301-2115(96)02479-7

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T. T. Lao, T.-C Pun/European Journal of Obstetrics & Gynecology and Reproductive Biology 68 (1996) 53-58
Table I Maternal demographic data in the anaemia and non-anaemia patients

the incidence of anaemia is higher in this group, because the majority of the pregnancy complications in multifetal pregnancies could be related to, or accounted for, by the multifetal pregnancy itself, so that the results would be difficult to interpret.
2. Materials and methods

(%)

Anaemia group n = 817 Maternal age in years 28.4 5.2 (mean S.D.) Multiparas 464 (57.0)* Smokers 21 (3.0) *P < 0.01.

Non-anaemia group n = 10 125 28.2 5. I 5190 (51.0) 258 (3.0)

The Obstetric Units of Tsan Yuk and Queen Mary Hospitals are under the Department of Obstetrics and Gynaecology of the University of Hong Kong, and are regional tertiary centres. The population we serve and the antenatal management of our patients have been reported before [20]. The antenatal care, management of complications, labour and delivery, are according to established practice. Routine multivitamin and iron supplements (with 29 mg of elemental iron in a proprietary preparation) is given to all mothers. The information of each pregnancy that was delivered in our hospital was coded and entered into a computer database. All antenatal patients have blood drawn for the estimation of haemoglobin and measurement of the mean cell volume (MCV) at the time of booking. The measurement of the MCV is used in the screening of both ot and thalassaemia carriers to whom prenatal diagnosis could be offered should the diagnosis be confirmed by a follow-on haemoglobin electrophoresis test. The maternal haemoglobin is estimated again at least once at the beginning of the third trimester, or at any time when clinical features suggest the development of anaemia. Antenatal anaemia is diagnosed when the lowest haemoglobin level falls below 10 g/dl at any time before delivery. All patients with antenatal anaemia have their iron status examined and the cause of the anaemia classified, which is coded in the final summary for entry into our obstetric database.

In this retrospective study, the data on all mothers with singleton pregnancies who delivered between January 1990 and December 1992 were retrieved. The ones with the coding for antenatal anaemia were identified and the incidence of major maternal complications and the pregnancy outcome in this group was compared with the remaining mothers who did not have anaemia, as well as between mothers with iron deficiency and thalassaemia trait. Statistical analysis is performed with the chi-square test and Student's t-test where appropriate.
3. Results

Of the 10 942 singleton pregnancies delivered during the study period, 817 (7.5%) were diagnosed to have antenatal anaemia. Among these 817 patients, 448 (54.8%) had either or- or ~-thalassaemia trait, while another 21 (2.6%) had iron deficiency in addition to thalassaemia trait. The remaining 348 (42.6%) were classified as iron deficiency. In the whole group, the lowest haemoglobin was between 8 and 8.9 g/dl in 128 (15.7%) patients, and between 7and 7.9 g/dl in 20 (2.4%) patients. Another five (0.6%) patients had the lowest

Table 2 Antenatal complications in the anaemia and non-anaemia patients adjusted for parity Nulliparas Controls n = 4935 Diabetes mellitus Pre-existing IGT (WHO criteria) Gestational Venereal diseases Monilial infection Other vaginal infections Pregnancy-induced hypertension Chronic hypertension Placenta previa Accidental hemorrhage Anaemia n = 353 Multiparas Controls n = 5190 Anaemia n = 464

0.1 5.2 0.7 0.9 I0.3 3. I 6.3 0.8 0.6 2.0

0 4.0 0.6 0.3 I0.8 5. I 6.8 0.8 0.6 1.4

0.3 7.2 0.8 0.4 8.9 2.2 2.9 1.5 1.0 2.3

0.2 8.8 0.6 0.4 I 1.2 4. I* 3.0 0.6 0.9 1.3

Results expressed in percentages. IGT, impaired glucose tolerance. *P < 0.025 compared with multiparous controls.

T.T. Lao, T.-C Pun/European Journal of Obstetrics & Gynecology and Reproductive Biology 68 (1996) 53-58
Table 3 Labour and delivery in the anaemia and non-anaemia patients adjusted for parity Nulliparas Controls n = 4935 Induction of labour Augmentation of labour Delivery Instrumental Breech Elective C section Emergency C section Complications Prolapsed cord Postpartum hemorrhage Primary Secondary Retained products Uterine atony Postpartum pymxia Results expressed in percentages. 14.5 39.3 24.6 1.6 2.4 13.0 0.2 3.0 0.3 0.4 1.7 4.0 Anaemia n = 353 13.0 40.2 22.9 0.8 2.3 11.6 0.6 2.5 0.6 0.6 0.8 4.5 Multiparas Controls n = 5190 7.6 3 I.I 7.6 1.8 7. I 6.6 0.3 3.2 0.2 0.6 2.1 2.2 Anaemia n = 464 7. I 32.9 9.7 0.6 6.7 8.0 0.9 4.7 0.4 1.3 1.7 2.2

55

haemoglobin, between 6.5 and 6.9 g/dl. No patient had a haemoglobin <6.5 g/dl. There was no difference in the maternal age or in the incidence of smokers between patients with and without anaemia (Table 1), but there were more multiparous patients in the anaemia group (57.0% vs. 51.0%, P <

o.o]).

Since there were more multiparas in the anaemia group, comparison between the patients with and without anaemia was analysed according to parity (Table 2). The only difference in the antenatal complications was in the incidence of non-eandidal vaginal infection, which was higher (4.1% vs. 2.2%, P < 0.025) in the multiparous anaemia patients. After adjusting for par-

Table 4 Perinatal outcome in the anaemia and non-anaemia patients adjusted for parity Nulliparas Controls n = 4935 Preterm delivery < 37 weeks < 33 weeks < 28 weeks Birthweight (g) (mean 4- S.D.) <251)0 g 1001-1500 g ~; I000 g Male infants Stillbirth Neonatal death Apgar score (livebirths) ~;4 at 1 min ~; 4 at 5 min Congenital anomalies Chromosomal CNS Gastrointestinal Cardiovascular Urogenital Multiple/others Results expressed in percentages. Anaemia n = 353 Multiparas Controls n = 5190 Anaemia n=464

8.1 2.4 0.8 3086 4- 519 8.7 1.8 0.7 50.7 0.6 0.6 1.7 0.9 4.5 0.2 0.4 0.1 0.5 0.6 2.6

6.5 2.0 0.6 31 1 3 4 6 6 6.8 1.4 0.6 43.6 0.6 0.8 I.I 0.3 4.0 0.3 0.3 0 0.3 l.I 2.0

6.6 1.8 0.5 32025~ 5.6 1.3 0.6 52.1 0.5 0.6 1.5 0.8 4.4 O.2 0.3 0.2 0.3 0.7 2.5

5.6 1.9 0.9 3246 495 5.4 0.9 0.2 52.4 0.4 0.2 2.2 I.I 4.5 0 0 0 0 l.l 3.2

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T.T. Lao, T.-C. Pun/European Journal of Obstetrics & Gynecology and Reproductive Biology 68 (1996) 53-58

Table 5 Comparison of pregnancy complications between iron deficiency and thal~_~mfia trait patients Iron deficiency
n = 348

Thalassaemia trait
n =469

Diabetes mellitus
Pre-existing Gestational DM/IGT 0.3 4.6 0.3 12.1 5.5 4.0 0.9 1.1 1. I 0.6 4.6 0.6 1.4 i.4 2.9 0 9.4* 0.4 10.2 3.8 5.1 0.9 0.4 1.5 0.9 3.2 0.4 0.6 1.3 3.4

Venereal diseases
Monilial infection

Other vaginal infections Pregnancy-induced hypertension Chronic hypertension Placenta previa Accidental haemorrhage Prolapsed cord Postpartum haemorrhage
Primary

ity, there was no difference in the type of labour, modes of delivery or postpartum complications (Table 3), or in the pregnancy outcome (Table 4), between the anaemia and non-anaemia patients. Within the anaemia group, the patients were further analysed according to the cause of anaemia. Patients with thalassaemia trait had a significantly higher incidence of gestational diabetes mellitus/impaired glucose tolerance (9.4% vs. 4.6%, P < 0.025, Table 5). There was no difference however in the pregnancy outcome, and even though the perinatal mortality appeared higher in the thalassaemia trait patients (1% vs. 0.3%, Table 6), the difference was not statistically significant. 4. Discussion Maternal anaemia was usually attributed to malnutrition, and tends to be more common in developing and less affluent countries. In these countries, the association between anaemia and adverse pregnancy outcome could also be related to co-existing complications such as chronic infection, or protein malnutrition, and the anaemia being a marker or index of the prevalence or extent of these underlying problems. With the general improvement in socioeconomic condition in most countries in the recent decade, the health status would have been improved in the general population. With the improvement in health and nutritional status in the pregnant population, the relative contribution of nutritional deficiency, especially iron, to antenatal anaemia is probably diminishing, and the role of haemodilution due to plasma volume expansion is probably a more important factor. Although the mothers in this study were all general and not private patients, even mothers from the lower social class in Hong Kong were not necessarily nutritionally deprived because of the economic growth in the past decade. The educational level on the whole is also improved, and family planning is commonly practised. This is illustrated by the incidence of anaemia in our hospital which has decreased from 19.1% in 1963 to 9% in 1992, the contribution of iron deficiency having decreased from 97.9% in 1963 to 40.9% in 1992, while c~and B-thalassaemia trait have become progressively a more common cause for anaemia in our patients (data from the Annual Reports of our Department). With this background, we compared the pregnancy outcome between our mothers with and without anaemia in the 1990s. We have excluded multifetal pregnancies because anaemia may be more a coincidental finding than a cause of complications such as pre-eclampsia, antepartum haemorrhage, preterm labour, and adverse perinatal outcome. The results of our study indicated that antenatal anaemia, as currently diagnosed, did not have any significant impact on maternal and perinatal outcome for both the nulliparous and multiparous patients in our

Secondary
Retained products

Uterine atony Postpartum pyrexia

Results expressed in percentages. DM/IGT, diabetes'impaired glucose tolerance.

*P < 0.025.

Table 6 Perinatai outcome in the iron deficiency and thalassaemia trait patients Iron deficiency
n = 348

Thalassaemia trait
n =469

preterm delivery
<37 weeks < 33 weeks < 28 weeks 6.0 1.7 0.9 3 2 2 7 482 4.0 I.l 0.3 5.0 48.5 0 0.3 1.4 0.3 3.0 0 0 0 0.3 0.9 1.7 6.0 2.1 0.6 3159 482 7.5 l.I 0.4 8.0 48.6 0.4 0.6 1.9 1.1 5.0 0.2 0.2 0 0.2 1.3 3.4

Birthweight (g) (mean 4- S.D.)

<2500 g 1001-1500 g

< 1000 g Small for age Male infants Stillbirth Neonatal death Apgar score (livebirths)
,:4 at ! min :4 at 5 min

Congenital anomalies Chromosomal

CNS

Gastrointestinal Cardiovascular Urogenital Multiple/others Results expressed in percentages.

T.T. Lao, T.-C Pun~European Journal of Obstetrics & Gynecology and Reproductive Biology 68 (1996) 53-58

57

population. In the literature, adverse outcome was found to be associated mainly with severe anaemia [5], and as only 3% of the anaemia group had haemoglobin level of < 8 g/dl, this would not have much impact on the overall outcome. Furthermore, as 54.8% of the anaemia patients had thalassaemia trait and they were used to having low haemoglobin levels even before pregnancy, the impact of their anaemia on the pregnancy outcome could well be different from the patients who developed iron deficiency anaemia only during pregnancy. Nevertheless, no difference could be demonstrated in the pregnancy complications or outcome between patients with iron deficiency and thalassaemia trait, with the exception of the higher incidence of gestational diabetes mellitus/impaired glucose tolerance in the thalassaemia trait patients, and the cause of which is unknown. From the literature, it is clear that a haemoglobin level that is either too high or low could be associated with adverse pregnancy outcome. For mothers with low haemoglobin level, the mean birthweight of their infants was found to be similar to those whose haemoglobin was in the middle range [11], and the birthweight was found to be inversely related to maternal haemoglobin and directly to the rate of apparent iron deficiency or red cell indices [11,12]. There is no increase in preterm birth, low birthweight infants, or perinatal death in mothers with haemoglobin between 9 and 10 g/dl [10-12]. On the other hand, maternal haemoglobin level > 13 g/dl is associated with adverse outcome such as prematurity, low birthweight, perinatal death, as well as pre-eclampsia [7-10,14-17]. The underlying factor appears to be the adequacy of maternal plasma volume expansion [12-15], and a good outcome is related not to the absolute value of haemoglobin but rather a 7-12% decrease in haemoglobin at 30 weeks gestation compared with the initial haemoglobin [12]. This decrease in haemoglobin is proportional to the protein intake, the largest fall in haemoglobin is found with the highest protein intake as well as the birthweight [11]. These reports [11,12] indicate that a drop in haemoglobin in pregnancy should not be regarded as the sign of maternal undernutrition. It is also clear from the literature that if the haemoglobin level is between 9 and 13 g/dl [7,10-12,14,15], the pregnancy outcome will be optimal. All these observations have been recently confirmed by the study of Steer et al. [18] which have demonstrated, using the lowest antenatal haemoglobin, that a level of 9.5 g/dl is optimal for fetal growth, with the maximum mean birthweight found in mothers whose haemoglobin was between 8.5 and 9.5 g/dl, and that the lowest incidence of low birthweight and preterm labour was found in mothers whose haemoglobin was between 9.5 and 10.5 g/dl. These findings applied to all the ethnic groups in the study. There are two other considerations in the interpreta-

tion of the hemoglobin level in relation to the pregnancy outcome, namely the ethnic background of the mother, and the altitude where the mothers reside. It has been shown that the haemoglobin in black mothers on the whole is 1 g/dl lower than that in the white mothers [10], and it is possible that in our Chinese mothers, the mean haemoglobin could be different as well. It has also been reported that at an altitude of 160 metres, the optimal haemoglobin ranged between 9.7 and 11.3 g/dl, while at 1600 metres, the range is between 12 and 13.6 g/all [12]. For our population residing at sea level, the optimal haemoglobin range would therefore be lower. The results of our study raise the important question of whether we should continue to make a diagnosis of maternal anaemia on the basis of the current definition, when the diagnosis itself has little clinical significance. This issue is further complicated by the controversy on the adverse effect of mate~al iron supplementation on the birthweight [21-23]. If iron supplementation, which increases packed cell volume [14,23,24], could be detrimental to fetal growth, then mild degrees of maternal anaemia may not need to be treated, and this would indirectly support the previous findings of Steer et al. [18] that optimal pregnancy outcome was associated with a haemoglobin level of 9.5 g/dl which would conventionally be considered as anaemic. With the accumulating data in the literature, it is time that the issue of antenatal anaemia be re-examined. If the diagnosis of anaemia were to have any clinical significance, then the 'normal' haemoglobin level needs to be redefined according to clear-cut parameters such as pregnancy outcome, the ethnic composition of the obstetric population, and the altitude at which the mothers reside. But is it the anaemia itself, or the underlying cause of the anaemia, that is of real clinical significance? It would have been more appropriate to diagnose underlying iron deficiency, thalassaemia trait, or haemodilution, and then manage accordingly. An alternative is to measure other haematologlcal indices such as the mean cell volume [18], which serves to identify the thalassaemia trait carriers as well. This issue should be addressed before one could interpret and utilise the data from studies on the prevention of anaemia by iron therapy.
References
[1] Whitfield CR. Blood disorders in pregnancy. In: Whitfield CR, editor. Dewhurst's Textbook of Obstetrics and Gynaecology for Postgraduates. 5th ed. Oxford: Blackwell, 1995; 228. [2] Meyer MB, Tonascia JA, Buck C. The interrelationship of maternal smoking and increased perinatal mortality with other risk factors. Further analysis of the Ontario Perinatal Mortality Study, 1960-1961. Am J Epiderm 1974; 100: 443-449. [3] Kaltreider DF, Johnson JCW. Patients at high risk for lowbirth-weight deliveries. Am J Obstet Gynecol 1976; 124: 251-256.

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