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Doppler Parameters Predicting

Fetal Heart Rate Abnormalities

in Diabetic Pregnancies

Parametry badania dopplerowskiego pozwalające

przewidywać zaburzenia w akcji serca płodu

u ciężarnych chorych na cukrzycę

First Clinic of Gynecology and Obstetrics, Wroclaw Medical University, Poland Adv Clin Exp Med 2009, 18, 5, 481–486

ISSN 1230−025X

ORIGINAL PAPERS

© Copyright by Wroclaw Medical University

Abstract

Background.Uteroplacental insufficiency is reflected by an increased pulsatility index in the umbilical artery (Umb PI). This leads to a redistribution of blood in the fetus (brain sparing), which is reflected by an increased middle cerebral artery PI (MCA PI) to Umb PI ratio (AI – acidemic index) and may cause a reduction in blood flow. An abnormally low AI is connected with unfavorable pregnancy outcome.

Objectives. The primary purpose of this study was to determine diabetes mellitus and circulatory variables that could relate to low arterial pH in the umbilical cord measured immediately after birth.

Material and Methods. The study group comprised 64 diabetic women with class B, C, D, or F diabetes and at least 26 weeks pregnant. Umb PI and MCA PI were measured every two days from admission to delivery. Doppler MCA PI, Umb PI, and AI were compared with fetal heart traces (NST) and pH from the umbilical artery measured immediately after birth.

Results. During the study about 34% of the fetuses of the diabetic mothers showed flow redistribution and nearly 22% abnormal NSTs. Abnormal AI was associated with abnormal NST in nearly 19% of cases. Doppler velocime− try is in itself good in confirming acidosis, detecting 90% of all acidemias (pH < 7.1). Abnormal Doppler velocime− try predicted fetal heart rate abnormalities in patients with B, C, D, or F diabetes about 8 days before they occurred. Conclusions. No cardiotocographic parameter alone was found to be a good predictor of umbilical acidemia. An abnormal NST in diabetic pregnancies should be verified by the AI. Both methods are noninvasive and safe. Abnormal cardiotocographic changes were usually preceded by abnormal MCA PI, Umb PI, and AI which occurred on average about 8 days earlier. Using both methods together, a predictive and a predisposal value of umbilical acidemia of 91.7 and 95% were obtained (Adv Clin Exp Med 2009, 18, 5, 481–486).

Key words: NST (non−stress test), CTG (cardiotocography), PI (pulsatility index), BCDF diabetes mellitus, AI (acidemic index), FHR (fetal heart rate).

Streszczenie

Wprowadzenie. Około 40% noworodków rodzących się w naszej klinice z ciąż matek chorych na cukrzycę klasy B, C, D, F według klasyfikacji White, ma bezpośrednio po porodzie kwasicę (pH < 7,1).

Cel pracy. Celem pracy było zidentyfikowanie wskaźników świadczących o zagrożeniu kwasicą płodów matek chorych na cukrzycę B–D oraz F wg White.

Materiał i metody. Wykonując u ciężarnych chorych na cukrzycę B–F wg klasyfikacji White badania KTG oraz

* The preliminary results of this study were presented at the 41st_{European Association for the Study of Diabetes Annual}

In this hospital there are about 144 pregnan− cies treated annually in which the mothers, both hospitalized and day patients, have diabetes melli− tus (classes B, C, D, and F according to the White classification [1]). Of these pregnancies, an aver− age of 132 are delivered in this clinic. This consti− tutes about 8.3% of all deliveries (ca. 1600). About 40% of the 132 infants are acidemic (pH < 7.1). In 2000, a special obstetric care program for diabetic pregnancies was introduced in this province. Diabetic mothers are directed to a special clinic in this hospital. Since then the number of cesarean sections (c.s.) in the group of class B–F diabetic pregnancies has dropped from 91 to 85%. However, about 70% of the c.s. were carried out as a consequence of abnormal CTGs (abnormal non− stress tests, NSTs) in a group of class B and C dia− betes mellitus [2]. Since then, the average duration of a diabetic pregnancy has also become longer by an average of five days. This may be attributed to better diagnostic methods (daily CTG, USG eval− uation, biophysical profile, rigid control of glycemia) and better training of the personnel. Preterm delivery in diabetic pregnancies was done to reduce the stillbirth rate, but it often resulted in neonatal death or morbidity caused by prematurity

and its complications. In 2007, Doppler examina− tion was introduced for routine examination in this hospital. In introducing Doppler flow velocimetry, a further increase in the duration of diabetic preg− nancies was expected owing to reductions in the numbers of elective cesarean sections, premature newborns, and newborns with low Apgar score and/or acidemia.

Perinatal morbidity is generally related to the class of diabetes, as indicated in Table 1. Very rigid glycemic control decreases the incidence of macrosomia, jaundice, anomalies, and hypogly− cemia in newborns.

The main aims of this study were to determine diabetes mellitus and circulatory variables (fetal heart rate, FHR; Doppler velocimetry) that could be related to low arterial pH in the umbilical cord measured immediately after birth and to learn if better monitoring of classes B–F diabetes accom− panied by Doppler velocimetry can help lengthen the duration of diabetic pregnancies and reduce the number of cesarean sections in this group.

Uteroplacental insufficiency is reflected by an increased pulsatility index (PI) in the umbilical artery. This leads to a redistribution of blood in the fetus (brain sparing). Brain sparing is reflected by

USG w ciągu ponad 2 lat, autorzy stwierdzili, że u ok. 34% płodów wystąpiły w badaniu dopplerowskim cechy re− dystrybucji, na podstawie pomiarów PI (pulsatility index) w tętnicy pępowinowej i tętnicy środkowej mózgu. Wyniki. U około 22% ciężarnych wystąpiły patologiczne zapisy kardiotograficzne. Nieprawidłowy wskaźnik kwa− sicy (acidemic index), będący stosunkiem MCA PI do Umb PI (z punktem odcięcia 1.1) towarzyszył patologicz− nym zapisom KTG w ok. 19%. Indeks kwasicy (acidemic index) pozwala dobrze zidentyfikować te noworodki, które nie będą miały kwasicy (pH < 7,1) bezpośrednio po porodzie (95,2%). Około 81% noworodków z nieprawi− dłowymi wynikami badań dopplerowskich, opisanych w pracy, będzie miało kwasicę (pH < 7,1), jeśli obydwa wskaźniki, tj. KTG i AI, będą nieprawidłowe, to dla kwasicy PPV wynosi 91,7%, a NPV 95%.

Wnioski. Badanie dopplerowskie jest samo w sobie dobrym wskaźnikiem kwasicy. Pozwala na wychwycenie 90% wszystkich kwasic wykrytych w krwi pępowinowej bezpośrednio po porodzie. Nieprawidłowe wartości wskaźników badania dopplerowskiego wyprzedzały średnio o 8 dni patologiczne zmiany w KTG. Oba sposoby przewidywania kwasicy po porodzie są metodami bezpiecznymi i nieinwazyjnymi i pozwalają zrezygnować z ko− nieczności stosowania kordocentezy oraz pozwalają zmniejszyć liczbę cięć cesarskich wykonywanych z powodu nieprawidłowych zapisów KTG u ciężarnych chorych na cukrzycę (Adv Clin Exp Med 2009, 18, 5, 481–486).

Słowa kluczowe:test niestresowy, kardiotokografia, cukrzyca ciężarnych klasy B, C, D, F, wskaźnik kwasicy, ak− cja serca płodu.

Table 1. Perinatal morbidity and class of diabetes [3–11]

Tabela 1. Częstość powikłań u płodów i noworodków w zależności od klasy cukrzycy Morbidity (Powikłania u płodu Diabetes Class (Klasy cukrzycy wg White)

i noworodka) _{B, C, D, R % F %}

Polyhydramnios 1.6–27 31

Fetal demise 0.3–2, 2.5–4.5 7.7

IUGR

(intrauterine growth retardation) 2.4 20 Neonatal RDS

(respiratory distress syndrome) 0.8, 8, 9, 21 24

Jaundice 22–37 44

Macrosomia 40–41.3 12

an increased ratio of the PI in the middle cerebral artery (MCA PI) to the PI in the umbilical artery (Umb PI), called the acidemic index (AI), and it may cause a reduction in blood flow to, for exam− ple, the gastrointestinal tract and other peripheral organs [12, 13]. A normal AI decreases with gesta− tional age, while abnormally low AIs are connect− ed with unfavorable pregnancy outcome [14, 15].

Material and Methods

The study group was divided into group 1, consisting of 32 women pregnant for 26–31 weeks plus 6 days, and group 2, consisting of 32 women pregnant for at least 32 weeks. Umb PI and MCA PI were measured every two days from admission until delivery. AI was calculated as (MCA PI)/(Umb PI). The normal cut−off limit was 1.1. Doppler MCA PI, Umb PI, and AI were compared with fetal heart traces (non−stress test, NST) and the pH from the umbilical artery measured imme− diately after birth. All the women were diabetic (classes B–F according to White) and were admit− ted to the university hospital from the whole region of Lower Silesia. The study was prospec− tive and observational and carried out in the obstetrics department for more than two years. All patients had at least one ultrasound exam to date the pregnancy during the first trimester (less than 12 weeks) and their last menstrual period was known. Doppler flow velocimetry was measured by three different examiners. The Umb PI and fetal MCA PI were measured as proposed by Nicolaides [16]. The inclusion criteria for the study were sin− gleton pregnancy of ≥26 weeks and intact mem− branes. The exclusion criteria were congenital and/or chromosomal abnormalities.

After meeting the inclusion criteria, 64 pa− tients were examined during the study period. The patients ranged in age from 17 to 42 years. For ca. 80% (n = 50) it was the first pregnancy, for ca. 14% (n = 9) the second, and for ca. 6% (n = 4) the

third. A Voluson 730 Expert ultrasound device was used. The statistical program used was SPSS (Statistical Package for Social Sciences). The first examiner collected 40% of the data, the second examiner 21%, and the third 39%. Analysis of variance (ANOVA) of the data obtained by the dif− ferent examiners showed no significant differ− ences. The pregnancies in the study group were also complicated by: anemia (n = 11), hypertension (n = 18), syphilis (n = 1), hypothyreosis (n = 2), stenosis aortae (n = 1), and leukopenia (n = 1). Fetal distress, defined by an umbilical artery pH < 7.1, clearly pathological CTG traces, or abnormal Doppler, was found in 31.3%, 21.9%, and 34.4% of the cases, respectively. Cardiotocograms were made once a day (the routine frequency of exami− nation in this clinic). A clearly pathological CTG was compared with the Doppler flow velocimetry of the same patient. CTG analyses were performed by at least two qualified obstetricians. The retro− spective part of this study was a case−controlled review including the newborns with arterial pH in the umbilical cord < 7.1 determined immediately after birth.

Results

The statistics of the events observed during the study period are described in Table 2.

The mean pregnancy duration of the patients with classes B, C, D, or F diabetes was 35 weeks ± 4 days. The time between abnormal Doppler flow velocimetry and abnormal CTG range was 6–10 days (mean: 8 days). Umbilical acidemia was found in 20 cases (20/64, 31.3%), with 8 (25%) in group 1 and 12 (37.5%) in group 2. In the patients with normal NST and normal Doppler (n = 40) there were 2 acidemic newborns, in those with abnormal NST and normal Doppler (n = 2) there were no acidemic newborns, in those with normal NST and abnormal Doppler (n = 10) there were 7 acidemic newborns, and in those with abnormal

Table 2. Events observed during the study period

Tabela 2. Statystyka powikłań występujących u płodów i noworodków w czasie prowadzonego badania

Event (Powikłania u płodu Diabetes class (Klasy cukrzycy wg White) i noworodka) _{B, C, D; n = 56 % F; n = 8 %}

Polyhydramnios 21.4 37.5

Fetal death 1.8 0

IUGR 5.4 37.5

RDS 1.8 25

Hypoglycemia 25 37.5

Jaundice 1.8 37.5

Macrosomia 32.1 0

NST and abnormal Doppler (n = 12) there were 11 acidemic newborns.

Abnormal Doppler findings and abnormal NST together were strongly associated with the pH value measured immediately after birth (PPV: 91.7%, NPV: 95%, sensitivity: 84.6%, specificity: 97.4%.) Of the 20 infants with low pH, 4 (20%) were transferred to the neonatal intensive care unit (NICU) and another 6 (30%) required special pediatric care in the presence of hypoglycemia, jaundice, and mild respiratory disorders (both parameters abnormal).

Discussion

In 1997, the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus of the American Association of Diabetes made significant changes in introducing a new classifi− cation and new recommendations for screening diabetes mellitus [17]. Some studies showed that in diabetic pregnancies, blood samples obtained by cordocentesis demonstrated significant acid− emia and hyperlacticemia in the absence of fetal hypoxemia [18, 19, 20]. In the present study, only 4 of the 20 acidemic babies (20%) were trans− ferred to the NICU, compared with 40% in [10]. The remaining 16 did not require intensive care in spite of low pH.

Fetuses react to hypoxemia with activation of the sympathetic system and a redistribution of car− diac output. If the hypoxic−asphyxic insult per− sists, the fetus is unable to maintain circulatory centralization and cardiac output and cerebral per− fusion fall. Hypoxia−ischemia initiates a series of neurochemical changes during reperfusion which result in neuronal damage [21]. Not all steps of this process have been studied in sufficient detail. The theories that seem most feasible indicate the relevance of the following factors: energy failure, intracellular calcium regulation [22], excitatory neurotransmitters [21], oxygen free radicals [23], and nitric oxide [24, 25]. This is supported by the evidence showing that excitatory neurotransmit− ters increase, while calcium channel blockers, free radical scavengers, and nitric oxide inhibitors reduce the severity of brain injury [25, 21]. A pro− minent feature of fetal brain damage during hypoxia−ischemia is apoptosis rather than necrosis [23]. Hypothermia [26] is considered the most effective method of neuroprotection following ischemia, as it almost completely blocks caspase activation after hypoxia [27].

It is well known that basal antepartum car− diotocographic variables show differences (fetal heart rate, amplitude) that correlate with differ−

ences in gestational age, as in groups 1 and 2 in the present study [28, 6]. These two groups also show differences in the resistance indices of the middle cerebral artery and umbilical artery and in the pul− satility index of the middle cerebral artery and umbilical artery [16]. Cardiac function may be studied by measuring fetal heart rate (NST) and Doppler velocimetry [16]. When the cardiograph− ic variables were compared with the variables of Doppler velocimetry of healthy pregnant women and fetuses, no significant difference was found [29–31]. On the other hand, it is known that NST has high specificity and low sensitivity. The absence of fetal heart rate reactivity and the pres− ence of decelerations were predictive of fetal dis− tress in labor, usually requiring termination of pregnancy by cesarean section [32]. In the present study group, NST alone predicted pH < 7.1 with a PPV of 78.6%, NPV of 82%, sensitivity of 55%, and specificity of 93.2%. Doppler velocimetry alone had a PPV of 81.8%, NPV of 95.2%, sensi− tivity of 90%, and specificity of 90.9%.

The incidence of cesarean section increases with abnormal NST results, but neonatal results do not vary with the way of delivery [33]. In the pre− sent study group the c.s. rate was 37.5% (because of abnormal CTG or Doppler velocimetry), com− pared with 68% in a group with class B or C dia− betes (abnormal CTG) examined previously in the same hospital [2]. In an attempt to reduce the num− ber of c.s. following abnormal NST, the present authors decided to complement the NST studies by Doppler velocimetry. In the present study the c.s. rate (37.5%) was comparable to that of the whole population of non−diabetic pregnancies in this clinic. The aim of this study was to observe changes in CTG and Doppler velocimetry and to find a bet− ter way of predicting fetal outcomes. Was this achieved? One thing is clear: abnormal Doppler was accompanied by low pH of newborns in 81.8% (18/22), while abnormal NST accompanied low−pH in 78.6% (11/14). Abnormal Doppler com− bined with abnormal NST were strongly correlated with low pH. The objective was to design a Doppler parameter (AI – acidemic index) which would take into account both the duration and the intensity of hypoxia in predicting the occurrence of abnormal fetal heart rate and fetal acidosis [34–36]. The present authors strove to improve the early detection of hypoxemia and acidemia in fetuses of diabetic mothers by noninvasive techniques.

ing diabetes have allowed a reduction in the con− sequences for the fetuses of diabetic pregnancies. The results have been constantly improving over the years, mainly due to the introduction of in− creasingly better diagnostic techniques and per− sonnel training. Additionally, Doppler waveform analysis of the feto−maternal circulation is being performed more and more often during the last two decades [15, 35, 37–39]. Umbilical artery velocity waveforms have been shown to be a re− flection of placental vascular resistance. Abnormal waveforms with absent or reversed end−diastolic flow of the umbilical artery have been reported to represent signs of hypoxia−acidemia and to be associated with high perinatal morbidity and mor− tality [14, 15]. Apart from this, the AI, which seems to be a good indicator of an unfavorable feto−maternal circulation leading to fetal acidosis before and during labor, was used here [40].

The Doppler study of umbilical artery and middle cerebral artery gives an opportunity to demonstrate the circulatory redistribution of hypoxic fetuses. Doppler indices in cerebral arter− ies decrease (decrease of “brain−sparing effect”) and in descending aorta increase [16]. Doppler

evaluation is actually an indirect way of evaluating the intrauterine environment. Cordocentesis is not performed in this hospital, but even if it were, it would only offer a temporary pH evaluation [34, 40], which is why in the case of class B, C, D, or F diabetes, noninvasive methods can be expected to be more useful in the future, not only in diabet− ic pregnancies complicated by IUGR or pre− eclampsia [15, 29, 30, 38].

The authors concluded that these data suggest that the AI may be a useful Doppler parameter which may help predict fetal outcome in pregnan− cies complicated by class B, C, D, or F diabetes mellitus. No cardiotocographic parameter alone was found to be a good predictive factor of umbil− ical acidemia. An abnormal NST in diabetic preg− nancies should be verified by the AI. Both meth− ods are noninvasive and safe. Abnormal car− diotocographic changes were usually preceded by abnormal MCA PI, Umb PI, and AI which occurred on average about 8 days earlier. Using both methods, predictive and predisposal values of umbilical acidemia of 91.7 and 95% were obtained. The sensitivity of both methods was 84.6 and specificity 97.4%.

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Address for correspondence:

First Clinic of Gynecology and Obstetrics Wroclaw Medical University

Chałubińskiego 3 50−368 Wrocław Poland

E−mail: [email protected] Tel.: +48 602 253 158

Conflict of interest: None declared